Antimetabolite Chemotherapy Agents

Antimetabolite chemotherapy agents belong to the cell-cycle–specific drugs, which act on a specific phase of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle. Cancer cells more rapidly divide (or cycle) than normal cells, making them an easy target for chemotherapy. The different cell-cycle phases include G1, S, G2, and M. Antimetabolites target the S phase, when DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication occurs, thus inhibiting DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis of tumor cells. In this group, the drugs include antifolates (which block folic acid activity, an essential component of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure precursors), pyrimidine and purine analogs (which interfere with the process of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis), and ribonucleotide reductase inhibitors (which reduce production of deoxyribonucleotides). Cell-cycle–specific chemotherapy drugs cannot differentiate healthy from cancerous cells, thus adverse effects are seen. Myelosuppression is a common finding during treatment.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Cell-cycle kinetics

  • The cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle is a process of cell growth and maturation with several phases. 
  • Different phases and associated events:
    • G1 phase: cell growth in preparation for DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication
    • S phase: DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication
    • G2 phase: further cell growth (e.g., replication of organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles) in preparation for mitosis 
    • M phase: duplicated DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure separated and distributed to 2 identical daughter cells

Chemotherapy

  • The goal of chemotherapy is to stop cell growth or destroy cancerous cells.
  • Log-kill hypothesis: Chemotherapy dose kills the same fraction of tumor cells, regardless of the size of the tumor.
  • Antimetabolite chemotherapy agents are cell-cycle–specific drugs (act on a specific phase of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle):
    • Effective against cells cycling at a rapid rate (moving through the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle)
    • Analogs for the units of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure, which when incorporated, stop DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure synthesis.
    • Target the S phase of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle → inhibit normal DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure synthesis

Antimetabolite classification

The subtypes of antimetabolite chemotherapy agents are:

  • Antifolates (folic acid antagonists):
    • Methotrexate
    • Pemetrexed
    • Pralatrexate
  • Pyrimidine analogs:
    • Fluoropyrimidines:
      • 5-Fluorouracil
      • Capecitabine
    • Deoxynucleoside (deoxycytidine) analogs:
      • Cytarabine
      • Gemcitabine
  • Purine analogs:
    • Thiopurines:
      • 6-Mercaptopurine
      • 6-Thioguanine
    • Fludarabine
    • Cladribine
    • Pentostatin
  • Ribonucleotide reductase inhibitors: hydroxyurea

Drug resistance

  • Primary resistance is the absence of response on 1st exposure by some cancers due to genomic instability.
  • Acquired resistance:
    • ↑ Expression of MDR1 (multidrug resistance gene), encoding a P glycoprotein in the cell surface, which causes efflux of the drug
    • ↑ Ability to repair DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure 
    • ↑ Activity of tumor cell enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, which inactivate anticancer drugs
    • Change in the sensitivity of the target enzyme to the drug
    • ↓ Conversion of prodrugs by tumor cell enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
    • Expression of glutathione or glutathione-associated proteins, which conjugate some drugs 

Antifolates

Antifolate agents

  • Antimetabolite chemotherapy agents that block folic acid activity to inhibit cell division. 
  • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 or folic acid is essential in providing methyl groups for precursors of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure.
  • Medications in this drug class inhibit dihydrofolate reductase, in general:
    • Methotrexate 
    • Pemetrexed
    • Pralatrexate 
    • Proguanil (antimalarial)
    • Trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim (antibiotic/antibacterial)

Methotrexate (MTX)

  • Folic acid analog 
  • Mechanism of action:
    • Binds to dihydrofolate reductase (DHFR) → inhibits the formation of tetrahydrofolate (FH₄) → ↓ DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis
    • Folylpolyglutamate synthetase (FPGS) adds glutamyl residues to the molecule, making the molecule unable to cross cell membranes.
    • This mechanism of ion trapping permits prolonged retention of MTX in the cell.
  • Mechanism of resistance:
    • Altered DHFR (poor binding to MTX)
    • Impaired MTX transport into cells
    • ↓ Polyglutamation
  • Pharmacokinetics:
    • Absorption: oral, intrathecal, IV, IM routes of administration
    • Distribution: 50% plasma protein-bound
    • Metabolism and excretion: 90% unchanged and excreted in the urine (renal)
  • Indications:
    • Oncology uses:
      • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
      • ALL
      • Head and neck cancer
      • Cutaneous T-cell lymphoma
      • Gestational trophoblastic neoplasia
      • Non- Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma
      • Osteosarcoma Osteosarcoma Osteosarcoma is a primary malignant tumor of the bone characterized by the production of osteoid or immature bone by the tumor cells. The disease is most common in children and young adults and most frequently affects growth plates of the long bones, although it can involve any bone. Osteosarcoma
    • Nonneoplastic:
      • Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis
      • Psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis
      • Juvenile idiopathic arthritis Juvenile Idiopathic Arthritis Juvenile idiopathic arthritis (JIA), formerly known as juvenile rheumatoid arthritis, is a heterogeneous group of inflammatory diseases characterized by inflammation of 1 or more joints and is the most common pediatric rheumatic disease. Juvenile Idiopathic Arthritis
  • Adverse effects:
    • Myelosuppression: anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia, and thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
    • Hepatotoxicity: ↑ liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
    • Immunosuppression
    • GI: stomatitis Stomatitis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, nausea, vomiting 
    • Nephrotoxicity: crystal nephropathy and direct tubular toxicity
    • Neurotoxicity
    • Pulmonary toxicity: interstitial pneumonitis
    • Dermatologic: Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome ( SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome), erythema multiforme Erythema multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). Erythema Multiforme, toxic epidermal necrolysis (TEN)
  • Precautions:
    • Use chemotherapy-modulating agent L-leucovorin, a folate analog.
    • Counteract antifolate effects (rescue cells from toxicity).
    • Initiate within 24–36 hours of starting MTX.
  • Contraindications: 
    • Hypersensitivity to any antifolate drugs
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care (as drug causes neural tube and other birth defects due to ↓ folate)
  • Drug interactions:
    • Salicylates and NSAIDs: ↑ drug levels
    • Inactivated vaccines: Antifolates generally reduce the therapeutic effects of inactivated vaccines.
    • Live vaccines (avoid): Antifolates enhance the toxic effects of live vaccines.

Pemetrexed

  • Mechanism of action:
    • Inhibits DHFR and thymidylate synthase to ↓ thymidine 
    • Also inhibits the following enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
      • Glycinamide ribonucleotide formyl transferase (GARFT), aminoimidazole carboxamide ribonucleotide formyl transferase (AICARFT)
      • Results in ↓ nucleotide synthesis → ↓ protein synthesis
  • Pharmacokinetics:
    • Absorption: IV route of administration
    • Distribution: 80% protein-bound
    • Metabolism and excretion: minimal metabolism and up to 90% excreted unchanged in urine (renal)
  • Indications (labeled):
    • Mesothelioma Mesothelioma Malignant mesothelioma (usually referred to as simply "mesothelioma") is the malignant growth of mesothelial cells, most commonly affecting the pleura. The majority of cases are associated with occupational exposure to asbestos that occurred > 20 years before clinical onset, which includes dyspnea, chest pain, coughing, fatigue, and weight loss. Malignant Mesothelioma 
    • Non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer 
  • Adverse effects:
    • Myelosuppression
    • Skin rash
    • Nephrotoxicity
    • Pulmonary toxicity
    • GI: nausea, vomiting, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, stomatitis Stomatitis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis
  • Precautions: prophylactic folic acid and vitamin B12 to ↓ hematologic and GI toxicity
  • Contraindications: hypersensitivity to any antifolate drugs
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Salicylates and NSAIDs: ↑ drug levels
    • Inactivated vaccines: Antifolates generally reduce the therapeutic effects of inactivated vaccines.
    • Live vaccines (avoid): Antifolates enhance the toxic effects of live vaccines.

Pralatrexate

  • Mechanism of action:
    • Inhibits DHFR
    • Selectively enters cells expressing ↓ reduced folate carrier (RFC-1)
    • Also polyglutamated by FPGS
  • Pharmacokinetics:
    • Absorption: IV route of administration
    • Distribution: 67% protein-bound
    • Metabolism and excretion: minimally metabolized, with approximately 34% excreted unchanged in the urine
  • Indication: peripheral T-cell lymphoma (relapsed or refractory) 
  • Adverse effects:
    • Myelosuppression: anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, leukopenia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia 
    • GI: nausea, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, stomatitis Stomatitis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis
    • Fatigue
    • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Contraindications: hypersensitivity to any antifolate drugs
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Salicylates and NSAIDs: ↑ drug levels
    • Inactivated vaccines: Antifolates generally reduce the therapeutic effects of inactivated vaccines.
    • Live vaccines (avoid): Antifolates enhance the toxic effects of live vaccines.

Comparison of antifolate agents

Table: Comparison of antifolate agents
Agent Mechanism of action Labeled indications Adverse effects Additional considerations
Methotrexate Inhibit DHFR
  • ALL
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Gestational trophoblastic neoplasia
  • Head and neck cancer
  • Non- Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma
  • Cutaneous T-cell lymphoma
  • Osteosarcoma Osteosarcoma Osteosarcoma is a primary malignant tumor of the bone characterized by the production of osteoid or immature bone by the tumor cells. The disease is most common in children and young adults and most frequently affects growth plates of the long bones, although it can involve any bone. Osteosarcoma
  • Myelosuppression
  • Immunosuppression
  • Nephrotoxicity
  • Hepatotoxicity
  • Neurotoxicity
  • Pulmonary toxicity
  • GI side effects
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care: neural tube defects Neural tube defects Neural tube defects (NTDs) are the 2nd-most common type of congenital birth defects. Neural tube defects can range from asymptomatic (closed NTD) to very severe malformations of the spine or brain (open NTD). Neural tube defects are caused by the failure of the neural tube to close properly during the 3rd and 4th week of embryological development. Neural Tube Defects
Add leucovorin to rescue cells from toxicity.
Pemetrexed Inhibit:
  • Thymidylate synthetase
  • DHFR
  • GARFT
  • AICARFT
  • NSCLC
  • Mesothelioma Mesothelioma Malignant mesothelioma (usually referred to as simply "mesothelioma") is the malignant growth of mesothelial cells, most commonly affecting the pleura. The majority of cases are associated with occupational exposure to asbestos that occurred > 20 years before clinical onset, which includes dyspnea, chest pain, coughing, fatigue, and weight loss. Malignant Mesothelioma
  • Myelosuppression
  • Nephrotoxicity
  • Pulmonary toxicity
  • Rash
  • GI side effects
Add vitamin B12 and folate to ↓ toxicity.
Pralatrexate
  • Inhibit DHFR
  • ↑ Affinity to RFC-1 (better transport)
  • ↑ FPGS (↑ cytotoxic metabolites)
Peripheral T-cell lymphoma
  • Myelosuppression
  • GI side effects
Add vitamin B12 and folate to ↓ toxicity
NSCLC: non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer

Pyrimidine Analogs

Pyrimidine antimetabolites

  • Cytotoxic chemotherapy agents that inhibit DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis through the effects of precursor analogs entering tumor cells.
  • Background:
    • 4 bases that are precursors: 
      • 2 pyrimidines: cytosine and thymine (in RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure: uracil instead of thymine)
      • 2 purines: guanine and adenine
    • Purines and pyrimidines can be synthesized de novo, but some precursors are taken up by cells from the bloodstream:
      • Some bases (uracil) enter the cells, so analogs (5-fluorouracil, capecitabine) can be substitutes for these bases.
      • Other bases (cytosine, thymine) are transported into cells as deoxynucleosides (such as deoxycytidine).
      • As such, deoxycytidine analogs (cytarabine, gemcitabine) can compete with deoxycytidine and gain cell entry.
  • These pyrimidine antimetabolites are transported into the tumor cells and become activated intracellularly.

5-Fluorouracil (5-FU)

  • Fluorinated pyrimidine/fluoropyrimidine
  • Mechanism of action:
    • 5-FU activated to fluoro-uridine monophosphate (F-UMP), which inhibits cell growth by replacing uracil in RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure.
    • Also converted to 5-fluorodeoxyuridine monophosphate (5-FdUMP) → 5-FdUMP binds to thymidylate synthase (TS)
    • Inhibition of TS → deoxyuridine monophosphate (dUMP) cannot be converted to deoxythymidine monophosphate (dTMP) → ↓ DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and protein synthesis
  • Mechanism of resistance:
    • ↓ Activity of activating enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes of 5-FU
    • Amplification or mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of TS
  • Pharmacokinetics: 
    • Absorption: administered IV (poor oral absorption)
    • Distribution: well distributed throughout, including in CSF
    • Metabolism: hepatic
    • Excretion: renal 
  • Indications (labeled):
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
    • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer
    • Gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer
    • Pancreatic cancer
  • Adverse effects:
    • Myelosuppression
    • Cardiovascular toxicity: angina, arrhythmia, cardiac failure
    • Neurotoxicity: headache, confusion, disorientation
    • Rash, SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome, TEN
    • Hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand-and-foot syndrome (painful, erythematous swelling of the hands and feet)
    • Hyperammonemic encephalopathy
    • Stomatitis, anorexia, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Precautions: dihydropyrimidine dehydrogenase deficiency
    • Enzyme is important in detoxification.
    • Deficiency will lead to an increased risk of toxicity. 
  • Contraindications: hypersensitivity to 5-FU
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Inactivated vaccines: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
    • Warfarin: ↑ risk of bleeding

Capecitabine

  • Prodrug of 5-FU
  • Mechanism of action: 5-FU prodrug that is hydrolyzed to 5-FU
  • Pharmacokinetics:
    • Absorption: reduced by food
    • Distribution: approximately 35% bound to albumin
    • Metabolism: hepatic and tissue metabolism
    • Excretion: renal 
  • Indications (labeled):
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer (metastatic)
    • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer
  • Adverse effects:
    • Myelosuppression
    • GI toxicity:
      • Mucositis
      • Nausea, vomiting
      • Diarrhea: may be dose-limiting because of severity 
    • Cardiotoxicity: ischemia, arrhythmia, cardiac failure
    • Hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand-and-foot syndrome
    • Hepatotoxicity (↑ bilirubin)
    • Neurotoxicity:
      • Headache
      • Encephalopathy
      • Ataxia
      • Neuropathy
  • Precautions: dihydropyrimidine dehydrogenase deficiency: 
    • Enzyme is important in detoxification.
    • Deficiency will lead to an increased risk of toxicity. 
  • Contraindications: hypersensitivity to capecitabine
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Inactivated vaccines: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
    • Warfarin: ↑ risk of bleeding 
Structure of capecitabine

Structure of capecitabine

Image: “Capecitabine Structure” by JoeyChen. License: CC BY-SA 4.0

Cytarabine

  • Cytarabine (also called cytosine arabinoside (ara-C)) is a cytosine base combined with an arabinose sugar, instead of deoxyribose.
  • Deoxycytidine analog
  • Mechanism of action:
    • In the cell, cytarabine → ara-cytidine monophosphate (ara-CMP) via deoxycytidine kinase (dCK) → ara-cytidine triphosphate (ara-CTP)
    • Ara-CTP is in competition with deoxy-CTP to be incorporated into DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure by DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase.
    • When ara-CTP is incorporated, termination of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure chain elongation occurs. 
    • Cell cycle does not continue → DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure breaks → cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death
  • Mechanism of resistance:
    • Loss of dCK 
    • Up-regulation of cytidine deaminase (CDA; converts ara-C to the nontoxic metabolite ara-uridine)
  • Pharmacokinetics:
    • Absorption: 
      • IV administration
      • With ↑ CDA in the GI tract, oral absorption is poor.
    • Distribution: readily enters cells, crosses blood–brain barrier
    • Metabolism and excretion: 
      • Metabolized in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
      • Primarily renally excreted (90% as metabolite uracil arabinoside) 
  • Indications:
    • ALL
    • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
    • CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
    • Meningeal leukemia
  • Adverse effects:
    • Main toxic effect: myelosuppression ( neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, leukopenia)
    • Others:
      • GI: mucositis, nausea, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, pancreatitis
      • Hepatotoxicity: ↑ transaminases
      • Dizziness, headache, neurotoxicity
      • Cardiotoxicity: angina, pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis
      • Hyperuricemia
      • Cytarabine syndrome (6–12 hours after administration): fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, myalgia, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, rash, conjunctivitis Conjunctivitis Conjunctivitis is a common inflammation of the bulbar and/or palpebral conjunctiva. It can be classified into infectious (mostly viral) and noninfectious conjunctivitis, which includes allergic causes. Patients commonly present with red eyes, increased tearing, burning, foreign body sensation, and photophobia. Conjunctivitis, malaise
  • Precautions: dose adjustment in hepatic and renal impairment
  • Contraindications: hypersensitivity to cytarabine
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Inactivated vaccines: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
Deoxycytidine and analogs

Deoxycytidine and analogs:
Gemcitabine (difluoro analog) and cytarabine (cytosine arabinoside)

Image: “Structural formulae of deoxycytidine, gemcitabine, cytarabine, troxacitabine and PMEA” by Godefridus J Peters, et al. License: CC BY 4.0, cropped by Lecturio.

Gemcitabine

  • Difluoro analog of deoxycytidine
  • Mechanism of action:
    • Gemcitabine is phosphorylated by dCK into gemcitabine monophosphate → gemcitabine diphosphate → gemcitabine triphosphate
    • Gemcitabine diphosphate inhibits ribonucleotide reductase (which converts ribonucleotides to deoxyribonucleotides) → ↓ DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis
    • Gemcitabine triphosphate (structurally similar to deoxycytidine triphosphate) is incorporated into DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure.
    • Incorporation into DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase inhibited → cessation of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis → cellular death
  • Pharmacokinetics:
    • Absorption: IV administration
    • Distribution: widely distributed, minimal protein binding
    • Metabolism: metabolized intracellularly (into diphosphates and triphosphates) by kinases 
    • Excretion: renal (> 92%)
  • Indications (labeled):
    • Non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
    • Pancreatic cancer
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
    • Ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer
  • Adverse effects:
    • Myelosuppression
    • Capillary leak syndrome (potentially lethal sudden capillary hyperpermeability → edema, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, ↓ albumin)
    • GI: mucositis, nausea, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Hepatotoxicity: ↑ transaminases
    • Hemolytic uremic syndrome
    • Pulmonary toxicity
  • Precautions: discontinue if severe renal or hepatic toxicity occurs
  • Contraindications: hypersensitivity to gemcitabine
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Inactivated vaccines: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
    • Coadministration with anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants increases the risk of bleeding.

Comparison of pyrimidine analogs

Table: Comparison of pyrimidine analogs
Agent Mechanism of action Labeled indications Adverse effects Additional considerations
5-FU Inhibits thymidylate synthetase
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer
  • Gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer
  • Pancreatic cancer
  • Myelosuppression
  • CV toxicity
  • Neurotoxicity
  • Rash
  • Hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand-foot syndrome
  • ↑ Ammonia
  • ↑ Bleeding with warfarin
In DPD: ↑ toxicity
Capecitabine Prodrug of 5-FU (inhibits thymidylate synthetase)
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer
  • Myelosuppression
  • CV toxicity
  • Neurotoxicity
  • GI toxicity
  • Hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand-foot syndrome
  • ↑ Bleeding with warfarin
In DPD: ↑ toxicity
Cytarabine Inhibits DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase
  • ALL
  • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
  • CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
  • Meningeal leukemia
  • Myelosuppression
  • Ara-C syndrome
  • GI toxicity
  • Hepatotoxicity
  • Pancreatitis
  • Hyperuricemia
Gemcitabine Inhibits DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase and ribonucleotide reductase
  • NSCLC
  • Pancreatic cancer
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer
  • Myelosuppression
  • Capillary leak syndrome
  • HUS
  • Pulmonary toxicity
  • ↑ Bleeding with warfarin
5-FU: 5-fluorouracil
CV: cardiovascular
HUS: hemolytic uremic syndrome
NSCLC: non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer

Purine Analogs

Analogs of adenine or guanine

  • These antimetabolites interfere or compete with nucleoside triphosphates in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and/or RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure synthesis. 
  • Generally possess excellent activity against leukemias and lymphomas
  • Medication in this drug class:
    • Thiopurines (inhibit de novo purine synthesis): 
      • 6-Mercaptopurine (6-MP): antineoplastic and immunosuppressive agent
      • 6-Thioguanine
      • Azathioprine (immunosuppressant): undergoes nonenzymatic reduction into 6-MP 
    • Fludarabine
    • Cladribine

6-Mercaptopurine

  • Mechanism of action:
    • Metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) into a metabolite thioinosine monophosphate (TIMP).
    • TIMP:
      • Outcompetes purine derivatives
      • Because TIMP is a poor substrate for guanylyl kinase, it accumulates in the cell, inhibiting enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes in the purine synthesis.
      • Metabolized to the triphosphate form → incorporated into DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure
  • Mechanism of resistance:
    • Lack of HGPRT
    • ↑ Alkaline phosphatase activity
  • Pharmacokinetics:
    • Absorption:
      • Oral absorption reduced by food and antibiotics.
      • Oral absorption improved by MTX.
      • IV dose half-life: approximately 1 hour
    • Distribution: poor CNS distribution
    • Metabolism: 
      • Hepatic metabolism via xanthine oxidase
      • Methylation by thiopurine methyltransferase (TPMT), in which a methyl group is attached to the thiopurine ring
    • Excretion: renal
  • Indication: ALL
  • Adverse effects:
    • Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow suppression
    • Hepatotoxicity
    • Immunosuppression
    • Photosensitivity
    • Secondary malignancy
    • Macrophage activation syndrome or hemophagocytic lymphohistiocytosis (↑ risk in autoimmune disorders)
  • Precautions: 
    • Oral doses of 6-MP should be reduced when receiving the xanthine oxidase inhibitor allopurinol, which can ↑ 6-MP.
    • Consider testing for deficiency of TPMT and nudix hydrolase 15 (nucleotide diphosphatase (NUDT15)): ↑ risk for severe toxicity 
  • Contraindications: hypersensitivity to 6-MP
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Inactivated vaccines: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
    • Allopurinol: ↑ 6-MP
    • MTX: ↑ 6-MP
    • ↓ Effect of warfarin
Structure of 6-mercaptopurine

Structure of 6-mercaptopurine

Image: “Mercaptopurine” by Fvasconcellos. License: Public Domain

6-Thioguanine

  • Mechanism of action:
    • Analog of guanine
    • Incorporates in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure → inhibits synthesis of purine nucleotides
  • Pharmacodynamics:
    • Absorption: approximately 30% ( variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables)
    • Distribution: does not reach significant levels in CSF
    • Metabolism: hepatic via TPMT
    • Excretion: renal
  • Indication: AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
  • Adverse effects:
    • Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow suppression
    • Hepatotoxicity
    • Secondary malignancy
    • Tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome
    • Photosensitivity
  • Precautions: consider testing for deficiency of TPMT and NUDT15: ↑ risk for severe toxicity 
  • Contraindications: hypersensitivity to 6-thioguanine
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Inactivated vaccines: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
Structure of 6-thioguanine

Structure of 6-thioguanine

Image: “6-Thioguanin” by NEUROtiker. License: Public Domain

Fludarabine

  • Mechanism of action:
    • Dephosphorylated in the plasma → enters cells → rephosphorylated into the active triphosphate
    • Inhibits DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase, ribonucleotide reductase, DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure primase, and DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure ligase I
    • When incorporated into DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure → chain termination
    • When incorporated into RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure → inhibition of RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure processing and translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation
  • Pharmacokinetics:
    • Absorption: oral and IV
    • Distribution: peak concentration in plasma within 1.5 hours (with oral administration) 
    • Metabolism: dephosphorylated in plasma into the active metabolite, which enters the cells
    • Excretion: renal
  • Indications: CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia
  • Adverse effects:
    • Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow suppression
    • Autoimmunity Autoimmunity Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. Autoimmunity
    • Neurotoxicity (confusion, agitation, coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures)
    • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
    • Infections
    • Diarrhea, nausea, vomiting
    • Tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome
  • Precautions: dose adjustment in renal impairment
  • Contraindications:
    • Hypersensitivity to fludarabine
    • Coadministration with pentostatin → severe pulmonary toxicity
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Pentostatin: pulmonary toxicity
    • Inactivated vaccines: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
Structure of fludarabine

Structure of fludarabine

Image: “Fludarabine” by Yikrazuul. License: Public Domain

Cladribine

  • Mechanism of action:
    • Purine nucleoside analog 
    • Prodrug that is converted to cladribine adenosine triphosphate (Cd-ATP).
    • Incorporates into DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure strand breaks → inhibition of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis and repair
  • Pharmacokinetics: 
    • Absorption: 
      • Administered orally and IV
      • Oral administration delayed by food
    • Distribution: 
      • 20% protein-bound
      • Penetrates CSF
    • Metabolism: prodrug (intracellular kinases phosphorylate the drug)
    • Excretion: renal
  • Indications (labeled): 
    • Hairy cell leukemia Hairy cell leukemia Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia
    • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
  • Adverse effects:
    • Myelosuppression
    • GI disturbances
    • Hepatotoxicity
    • Secondary malignancy
    • Opportunistic infections
    • Tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome
    • Renal toxicity
    • Neurotoxicity
  • Precautions: dose adjustment in renal and hepatic impairment
  • Contraindications:
    • Hypersensitivity to cladribine
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care (teratogenic)
  • Drug interactions:
    • Inactivated vaccines: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
Structure of cladribine

Structure of cladribine

Image: “Cladribine” by Yikrazuul. License: Public Domain

Pentostatin

  • 2′-deoxycoformycin
  • Analog of the intermediate in the adenosine deaminase (ADA) reaction 
  • Mechanism of action:
    • Inhibits ADA → adenosine not deaminated to inosine
    • Effects: ↑ intracellular adenosine and deoxyadenosine nucleotides → block DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis
  • Pharmacodynamics:
    • Absorption: IV administration
    • Distribution: approximately 4% protein-bound
    • Metabolism and excretion: eliminated via kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys 
  • Indication: hairy cell leukemia
  • Adverse effects:
    • Myelosuppression
    • Neurotoxicity
    • Hepatotoxicity
    • Dermatologic toxicity (severe rashes Rashes Rashes are a group of diseases that cause abnormal coloration and texture to the skin. The etiologies are numerous but can include irritation, allergens, infections, or inflammatory conditions. Rashes that present in only 1 area of the body are called localized rashes. Generalized rashes occur diffusely throughout the body. Generalized and Localized Rashes)
    • Pulmonary toxicity
    • Renal toxicity
    • Worsening infections
  • Contraindications:
    • Hypersensitivity to pentostatin
    • Coadministration with fludarabine → severe pulmonary toxicity
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions: 
    • Fludarabine: pulmonary toxicity
    • Inactivated vaccines: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
Structure of pentostatin

Structure of pentostatin

Image: “Pentostatin” by Fvasconcellos. License: Public Domain

Comparison of purine analogs

Table: Comparison of purine analogs
Agent Mechanism of action Labeled indications Adverse effects Additional considerations
6-MP Purine antagonist (inhibits purine nucleotide synthesis) ALL
  • Myelosuppression
  • Immunosuppression
  • Hepatotoxicity
  • Secondary malignancy
  • Photosensitivity
  • MAS
  • ↓ Effect of warfarin
↓ Dose if taking allopurinol
6-TG Purine antagonist AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
  • Myelosuppression
  • Hepatotoxicity
  • Photosensitivity
  • Secondary malignancy
  • Tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome
Fludarabine Inhibits:
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase
  • Ribonucleotide reductase
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure primase
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure ligase I
CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia
  • Myelosuppression
  • Autoimmunity Autoimmunity Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. Autoimmunity
  • Infections
  • Neurotoxicity
Avoid pentostatin (↑ pulmonary toxicity)
Cladribine Inhibits:
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis (producing DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure strand breaks)
  • Ribonucleotide reductase
Hairy cell leukemia Hairy cell leukemia Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia
  • Myelosuppression
  • Cardiotoxicity
  • Hepatotoxicity
  • Neurotoxicity
  • Nephrotoxicity
  • Tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome
  • Infections
  • Secondary malignancy
Pentostatin Inhibits adenosine deaminase (↓ DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis) Hairy cell leukemia Hairy cell leukemia Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia
  • Myelosuppression
  • Neurotoxicity
  • Pulmonary toxicity
  • Renal toxicity
  • Dermatologic toxicity
  • Hepatotoxicity
  • Infections
Avoid fludarabine (↑ pulmonary toxicity)
MAS: macrophage activation syndrome
6-TG: 6-thioguanine

Hydroxyurea

  • Also known as hydroxycarbamide
  • Hydroxylated analog of urea
  • Used to treat solid tumors and myeloproliferative diseases
  • Mechanism of action:
    • Inhibition of the enzyme ribonucleotide reductase (RR) 
    • RR mediates conversion ribonucleotides to deoxyribonucleotides ( DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure precursors)
    • ↓ Production of deoxyribonucleotides → ↓ DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis and cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle replication
    • S-phase–specific cytotoxic effect on cells
  • Pharmacokinetics: 
    • Absorption: oral administration, absorbed rapidly
    • Distribution: wide distribution (including the brain)
    • Metabolism: liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver (60%), GI tract 
    • Excretion: renal
  • Indications (labeled):
    • CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
    • Noncancer indication: sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease
  • Adverse effects:
    • Myelosuppression
    • Secondary malignancy
    • Cutaneous vasculitic toxicities (ulcerations and gangrene)
    • Pulmonary toxicity
    • Hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia
    • Macrocytosis
    • Bacterial and viral infections
    • Mucositis, nausea
  • Contraindications:
    • Hypersensitivity to hydroxyurea
    • Severe myelosuppression
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care (potential teratogenicity)
  • Drug interactions:
    • Antiretroviral drugs (didanosine and stavudine): pancreatitis, peripheral neuropathy, hepatotoxicity
    • Inactivated vaccines: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
Structure of hydroxyurea

Structure of hydroxyurea

Image: “Hydroxyurea-2D-skeletal” by Chem Sim 2001. License: Public Domain

Comparison with Other Chemotherapeutic Agents

Table: Comparison of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle dependent chemotherapy drugs
Drug class Cell cycle phase affected Mechanism of action
Antifolates Cell cycle arrest at S phase Inhibit:
  • Dihydrofolate reductase
  • Thymidylate synthase
Fluoropyrimidines Cell cycle arrest at S phase Inhibit thymidylate synthase
Deoxycytidine analogs Cell cycle arrest at S phase Inhibit:
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase
  • Ribonucleotide reductase
Purine analogs Cell cycle arrest at S phase Inhibition of de novo purine synthesis
Topoisomerase II inhibitors Cell cycle arrest at S and G2 phases Inhibit topoisomerase II
Taxanes Cell cycle arrest at metaphase of the M phase Hyper-stabilization of microtubules
Vinca alkaloids Cell arrest during metaphase of the M phase Binds to beta-tubulin and prevents microtubule polymerization
Chemotherapy comparison

Various chemotherapy drugs and their effects on the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle

Image by Lecturio.

References

  1. Katzung, B.G., Kruidering-Hall, M., Tuan, R., Vanderah, T.W., Trevor, A.J. (2021). Cancer chemotherapy. Chaper 54 of Katzung & Trevor’s Pharmacology: Examination & Board Review, 13th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=3058&sectionid=255307933
  2. Parker, W. B. (2009). Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chemical Reviews 109:2880–2893. https://doi.org/10.1021/cr900028p
  3. UpToDate. (2021). Methotrexate. UpToDate. Retrieved Sept 8, 2021, from https://www.uptodate.com/contents/methotrexate-drug-information
  4. UpToDate. (2021). Pemetrexed. UpToDate. Retrieved Sept 8, 2021, from https://www.uptodate.com/contents/pemetrexed-drug-information
  5. UpToDate. (2021). Thioguanine. UpToDate. Retrieved Sept 8, 2021, from https://www.uptodate.com/contents/thioguanine-drug-information
  6. UpToDate. (2021). Mercaptopurine. UpToDate. Retrieved Sept 8, 2021, from https://www.uptodate.com/contents/mercaptopurine-drug-information
  7. UpToDate, Inc. (2021). Hydroxyurea. UpToDate. Retrieved Sept 9, 2021, from https://www.uptodate.com/contents/hydroxyurea-hydroxycarbamide-drug-information
  8. UpToDate. (2021). Cytarabine. UpToDate. Retrieved Sept 8, 2021, from https://www.uptodate.com/contents/cytarabine-conventional-drug-information
  9. UpToDate. (2021). Gemcitabine. UpToDate. Retrieved Sept 8, 2021, from https://www.uptodate.com/contents/gemcitabine-drug-information
  10. UpToDate. (2021). Capecitabine. UpToDate. Retrieved Sept 8, 2021, from https://www.uptodate.com/contents/capecitabine-drug-information
  11. UpToDate. (2021). Pralatrexate. UpToDate. Retrieved Sept 8, 2021, from https://www.uptodate.com/contents/pemetrexed-drug-information
  12. UpToDate. (2021). Fluorouracil. UpToDate. Retrieved Sept 8, 2021, from https://www.uptodate.com/contents/fluorouracil-systemic-drug-information
  13. UpToDate. (2021). Pentostatin. UpToDate. Retrieved Sept 9, 2021, from https://www.uptodate.com/contents/pentostatin-drug-information
  14. Wellstein, A., Giaccone, G., Atkins, M.B., Sausville, E.A. (2017). Cytotoxic drugs. Chapter 66 of Brunton, L.L., Hilal-Dandan, R., Knollmann, B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172486857

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