Alkylating Agents and Platinum

Alkylating agents are 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–independent antineoplastic drugs that work primarily by binding alkyl groups to various parts 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. The overall action produces cross-linking 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, leading to inhibition of 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 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 damage. The general effect is cancer (CA) 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. The subgroups of drugs are nitrogen mustards, nitrosoureas, alkyl sulfonates, triazines, ethylenimines, and methylmelamines. Platinum coordination complexes belong to the group of alkylating agents by producing the same effect, but their mechanism is via formation of covalent metal adducts with 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. Myelosuppression and toxicity to organ systems such as the 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, 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, and lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs are common adverse reactions.

Last update:

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Alkylating agents

Alkylating agents are antineoplastic drugs that attach an alkyl group onto 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 to cause cancer (CA) 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.

  • Have a cytotoxic effect on cells via addition of an alkyl group to various cellular constituents:
    • A major site of alkyl group: N7 position of guanine
    • 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 code is misread with alkylation process → 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 breakage → inhibited 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, 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, and protein synthesis
    • Alkylating agents are not 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 specific, but they are most effective in late G1 and S phase.
  • Platinum coordination complexes:
    • Classified under alkylating agents, though their action is not the alkylation 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
    • These agents form covalent metal adducts with 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, producing an effect similar to that of alkylating agents. 
  • Alkylating agents affect all cells, primarily those that are rapidly dividing. 
    • CA cells are one of the most rapidly dividing cells.
    • Other, normal cells that undergo frequent cell division are adversely affected, as seen in:
      • Hematopoietic cells → 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, pancytopenia
      • Reproductive cells → amenorrhea, ↓ spermatogenesis
      • Hair cells → alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia
      • GI tract → damaged intestinal mucosa

Types of alkylating agents

  • Nitrogen mustards
  • Nitrosoureas
  • Alkyl sulfonates
  • Triazenes
  • Ethylenimine and methylmelamines
  • Platinum coordination complexes

Nitrogen Mustards

General description

  • Nitrogen mustards contain chloroethylamine groups.
  • Drugs in this class:
    • Chlorambucil
    • Cyclophosphamide
    • Ifosfamide
    • Melphalan
    • Bendamustine
  • Mechanism of action: forms 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 cross-links, leading to 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 function

Chlorambucil

  • Pharmacokinetics:
    • Rapid GI absorption (↓ with food)
    • 99% protein bound
    • Hepatic metabolism to phenylacetic acid mustard
    • Half-life: approximately 1.5 hours
    • Excretion: urine
  • Indications (labeled):
    • 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
    • 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 (HL)
    • 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 (NHL)
  • Adverse effects:
    • Myelosuppression
    • Immunosuppression
    • Nausea, vomiting
    • Hepatotoxicity
    • Pulmonary toxicity
    • 2-degree malignancy
    • Infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility
    • Teratogenicity
    • 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

Cyclophosphamide

  • Pharmacokinetics:
    • Oral, IV
    • Good oral absorption
    • 20% protein binding
    • Hepatic metabolism
    • Half-life: 3–12 hours IV
    • Excretion: urine
  • Indications (labeled):
    • 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
    • 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, 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
    • HL
    • NHL
    • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma (MM)
    • Breast and ovarian CA
    • Neuroblastoma Neuroblastoma Neuroblastoma is a malignancy that arises from the neural crest cell derivatives along the sympathetic chain (neuroblasts) and is most commonly located in the adrenal medulla. The tumor often presents in childhood with a flank mass that crosses the midline. Neuroblastoma, retinoblastoma Retinoblastoma Retinoblastoma is a rare tumor but the most common primary intraocular malignancy of childhood. It is believed that the condition arises from a neuronal progenitor cell. Retinoblastoma can be heritable or nonheritable. Retinoblastoma
    • Nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephrotic Syndrome
  • Adverse effects:
    • Nausea, vomiting
    • Myelosuppression
    • Immunosuppression
    • Hepatotoxicity
    • Pulmonary toxicity
    • 2-degree malignancy
    • Infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility
    • Teratogenicity
    • Cardiotoxicity
    • Renal toxicity
    • Bladder toxicity (to ↓ hemorrhagic cystitis: ↑ hydration + mesna)
    • Alopecia
    • SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
Chemical structure of cyclophosphamide

Chemical structure of cyclophosphamide

Image: “Cyclophosphamide structure” by Mysid. License: Public Domain

Ifosfamide

  • Pharmacokinetics:
    • Minimal protein binding
    • Hepatic metabolism
    • Half-life: approximately 15 hours (high dose)
    • Excretion: urine
  • Indication (labeled): testicular CA
  • Adverse effects:
    • Nausea, vomiting
    • Myelosuppression
    • Immunosuppression
    • Hepatotoxicity
    • Pulmonary toxicity
    • 2-degree malignancy
    • Infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility
    • Teratogenicity
    • CNS toxicity
    • Cardiotoxicity
    • Hemorrhagic cystitis (↓ by mesna)
    • Nephrotoxicity

Melphalan

  • Pharmacokinetics:
    • Oral absorption is 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.
    • Up to 60% bound to albumin
    • Hepatic metabolism
    • Half-life: 
      • Approximately 75 mins (IV)
      • 1.5 hours (oral)
    • Excretion: 
      • Oral through feces
      • IV through urine
  • Indications (labeled):
    • MM
    • Ovarian CA
  • Adverse effects:
    • Myelosuppression
    • Nausea, vomiting, and other GI toxicities
    • Hepatotoxicity
    • Pulmonary toxicity
    • Secondary malignancy
    • Extravasation

Bendamustine

  • Produces single- and double-stranded 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
  • Pharmacokinetics:
    • IV
    • Up to 96% protein bound
    • Hepatic metabolism
    • Excretion: feces, urine
  • Indications (labeled):
    • 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
    • NHL
  • Adverse effects:
    • Myelosuppression
    • Nausea, vomiting
    • Hepatotoxicity
    • Extravasation
    • Dermatologic toxicity
    • 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 (TLS)

Contraindications and drug interactions

  • General contraindications:
    • Hypersensitivity to the agent is a common contraindication.
    • Due to the toxic effects of the drugs, they are not advised when adverse effects are severe.
    • Active infection
    • Severe myelosuppression
    • In some cases, severe hepatic or renal impairment
  • General drug interactions with vaccines:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)
  • Specific drug interactions:
    • Cyclophosphamide:
      • ↑ Pulmonary toxicity of amiodarone
      • ↑ Cardiotoxicity with pentostatin
      • ↑ Cardiotoxic effects of anthracyclines
    • Ifosfamide: ↑ anticoagulant effect of vitamin K antagonists
    • Melphalan: ↑ pulmonary toxicity of carmustine

Nitrosoureas

General description

  • Nitrosoureas are chemotherapy agents that include a nitroso and urea group.
  • Agents undergo transformation to metabolites with alkylating and carbamyolating properties.
  • Highly lipid soluble: can cross the blood–brain barrier (BBB), making this class of medications useful in treating CNS malignancies
  • Drugs in this class:
    • Carmustine
    • Lomustine
  • Mechanism of action: forms 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 cross-links
    • Alkylation on the N7 position of guanine 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 on the O6 position of guanine
    • Prevents 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 and transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription

Carmustine

  • Pharmacokinetics:
    • IV, implant
    • Crosses BBB, reaching > 50% of plasma levels
    • Hepatic metabolism
    • Excretion: urine
  • Indications (labeled):
    • Brain tumors
    • NHL
    • HL
    • MM
  • Adverse effects:
    • Myelosuppression
    • Cardiovascular: arrhythmia, tachycardia
    • GI: nausea, vomiting, mucositis
    • Hepatic: ↑ transaminases, ↑ alkaline phosphatase (ALP)
    • Renal: azotemia, renal failure
    • Respiratory: interstitial pneumonitis
    • Secondary malignancy
Chemical structure of carmustine

Chemical structure of carmustine

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

Lomustine

  • Pharmacokinetics:
    • Oral
    • Crosses BBB
    • Hepatic metabolism
    • Excretion: urine
  • Indications (labeled):
    • Brain CA
    • HL
  • Adverse effects:
    • Myelosuppression
    • GI: nausea, vomiting, mucositis
    • Hepatic: ↑ transaminases, ↑ ALP
    • Renal: azotemia, renal failure
    • Respiratory: pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis
    • Secondary malignancy
Chemical structure of lomustine

Chemical structure of lomustine

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

Contraindications and drug interactions

  • General contraindications:
    • Hypersensitivity to the agent is a common contraindication.
    • Due to toxic effects of the drugs, they are not advised when adverse effects are severe.
  • General drug interactions with vaccines:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)

Alkyl Sulfonates

General description

  • Alkyl sulfonates are alkyl esters of sulfonic acid.
  • Drug in this class: busulfan
  • Mechanism of action: forms 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 cross-links 
    • Alkylation on the N7 position of guanine
    • 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 function

Busulfan

  • Pharmacokinetics:
    • IV and oral
    • Rapid absorption
    • Crosses BBB
    • Hepatic metabolism
    • Half-life: 2.5 hours
    • Excretion: majority through the urine
  • 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
  • Adverse effects:
    • Myelosuppression
    • Cardiovascular: hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain, cardiac tamponade Cardiac tamponade Pericardial effusion is the accumulation of excess fluid in the pericardial space around the heart. The pericardium does not easily expand; thus, rapid fluid accumulation leads to increased pressure around the heart. The increase in pressure restricts cardiac filling, resulting in decreased cardiac output and cardiac tamponade. Pericardial Effusion and Cardiac Tamponade
    • GI: nausea, vomiting
    • Hepatic sinusoidal obstruction syndrome
    • Pulmonary: bronchopulmonary dysplasia with pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis (“busulfan lung”: cough, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, ↓ pulmonary capacity) 
    • Secondary malignancy
    • Hyperpigmentation
    • Adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease
  • Contraindications: 
    • Hypersensitivity to the drug
    • Without confirmed 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
  • Drug Interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)
    • Acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen: ↓ busulfan clearance
    • Phenytoin: ↑ busulfan clearance
Chemical structure of busulfan

Chemical structure of busulfan

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

Triazines

General description

  • Triazines are nitrogen heterocycles used as chemotherapy, frequently in the treatment of brain CA or lymphoma.
  • Drugs in this drug class:
    • Procarbazine
    • Dacarbazine 
    • Temozolomide
  • Mechanism of action: 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 function by alkylation 

Procarbazine

  • In addition to alkylation, procarbazine inhibits transmethylation of methionine into tRNA.
  • Pharmacokinetics:
    • Oral
    • Rapid absorption
    • Crosses BBB
    • Hepatic metabolism
    • Half-life: approximately 1 hour
    • Excretion: urine
  • Indication (labeled): HL
  • Adverse effects:
    • Myelosuppression
    • CNS toxicity (confusion, neuropathies)
    • Pulmonary toxicity
    • Hepatotoxicity
    • Nausea, vomiting
    • Disulfiram-like reaction
    • Hemolysis
    • Hemorrhage
    • Secondary malignancy
    • Infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility
  • Contraindications:
    • Hypersensitivity to the drug
    • Severe myelosuppression
    • Alcohol intake (disulfiram effect)
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)
    • Avoid the following, as procarbazine metabolite is a weak monoamine oxidase inhibitor (MAOI) (an interaction such as acute hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension can occur): 
      • MAOIs
      • Sympathomimetic Sympathomimetic Sympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (α, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate). Sympathomimetic Drugs agents
      • Antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
      • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants (TCAs)
      • Foods high in tyramine content
Chemical structure of procarbazine

Chemical structure of procarbazine

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

Dacarbazine

  • Alkylation (methylation) leads to 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 double strand breaks.
  • Pharmacokinetics:
    • IV
    • Hepatic metabolism
    • Excretion: urine
  • Indications (labeled):
    • HL
    • Metastatic melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
  • Adverse effects:
    • Myelosuppression
    • Hepatotoxicity
    • Secondary malignancy
    • Teratogenicity
    • Alopecia
    • Nausea, vomiting
  • Contraindications: hypersensitivity to the drug
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)

Temozolomide

  • Temozolomide is less effective against tumors that express the MGMT gene (codes for an alkyltransferase protein that can repair sites of alkylation/methylation).
  • Conversely, silencing of the MGMT gene makes temozolomide active against the tumor cells. 
  • Also a weak MAOI
  • Pharmacokinetics:
    • IV, oral
    • Metabolism: hydrolysis
    • Half-life: 1.8 hours
    • Excretion: urine
  • Indications (labeled):
    • Anaplastic astrocytoma Astrocytoma Astrocytomas are neuroepithelial tumors that arise from astrocytes, which are star-shaped glial cells (supporting tissues of the CNS). Astrocytomas are a type of glioma. There are 4 grades of astrocytomas. Astrocytoma
    • Glioblastoma multiforme Glioblastoma multiforme Glioblastoma multiforme is a high-grade astrocytoma, an aggressive brain tumor arising from astrocytes, with an unknown cause and a poorly understood link to risk factors. There are two main types: primary, a more aggressive form seen more commonly in older patients, and secondary, developing from lower-grade astrocytomas and seen more commonly in younger patients. Glioblastoma Multiforme (GBM)
  • Adverse effects:
    • Myelosuppression
    • Hepatotoxicity
    • Secondary malignancy
    • Pneumocystis pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia ( PCP PCP Pneumocystis jiroveci is a yeast-like fungus causing pneumocystis pneumonia (PCP) in immunocompromised patients. Pneumocystis pneumonia is spread through airborne transmission and classically affects patients with AIDS, functioning as an AIDS-defining illness. Patients may present with insidious onset of fever, chills, dry cough, chest pain, and shortness of breath. Pneumocystis jiroveci/Pneumocystis Pneumonia (PCP)): Provide prophylaxis.
    • Hepatotoxicity
    • Nephrotoxicity
  • Contraindications:
    • Hypersensitivity
    • Severe myelosuppression
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines
    • Avoid the following (given weak MAOI activity):
      • Sympathomimetic drugs Sympathomimetic drugs Sympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (α, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate). Sympathomimetic Drugs 
      • TCAs
      • Antidepressants

Ethylenimines and Methylmelamines

General description

  • Medications in this drug class:
    • Thiotepa 
    • Altretamine
  • Mechanism of action: forms 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 cross-links via alkylation reaction
    • 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 function
    • Major site of alkyl group: N7 position of guanine

Thiotepa

  • Contains 3 ethylenimine groups 
  • Pharmacokinetics:
    • IV, intrathecal
    • Metabolism: hepatic via the cytochrome P450 system
    • Excretion: urine
  • Indications (labeled): 
    • Beta thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia
    • Off-label: conditioning regimen before stem cell transplantation, leptomeningeal metastasis
  • Adverse effects:
    • Myelosuppression 
    • Nausea and vomiting
    • Hepatotoxicity
    • CNS toxicity (e.g., headache, confusion, encephalopathy)
    • Dermatologic toxicity (e.g., pruritus, discoloration, blistering)
    • Hepatic sinusoidal obstruction syndrome
    • Secondary malignancy
  • Contraindications: hypersensitivity to the drug
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)
Chemical structure of thiotepa

Chemical structure of thiotepa

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

Altretamine

  • Similar to triethylenemelamine in structure
  • Pharmacokinetics:
    • Oral
    • Hepatic metabolism
    • Half-life: 4–10 hours
    • Excretion: urine
  • Indication (labeled): ovarian CA
  • Adverse effects:
    • Myelosuppression
    • GI: nausea, vomiting
    • CNS toxicity and peripheral neuropathy
  • Contraindications:
    • Hypersensitivity to the drug
    • Severe neurologic toxicity
    • Myelosuppression
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)
    • Intake with MAOIs can cause orthostatic 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.

Platinum Coordination Complexes

General description

  • Cell cycle–nonspecific drugs with broad anticancer activity
  • Medications in this drug class:
    • Cisplatin 
    • Carboplatin 
    • Oxaliplatin
  • Mechanism of action:
    • Covalently binds 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 (forming intrastrand and interstrand cross-links), with cytotoxic effects similar to alkylating agents
    • Inhibits 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

Cisplatin

  • Pharmacokinetics:
    • IV
    • 90% proteinbinding
    • Half-life: 20–30 minutes in adults
    • Excretion: renal
  • Indications (labeled):
    • Bladder CA
    • Ovarian CA
    • Testicular CA
  • Adverse effects:
    • Myelosuppression
    • Nausea, vomiting
    • Peripheral neuropathy
    • Nephrotoxicity (prehydration advised to ↓ risk of kidney damage)
    • Secondary malignancy 
    • ↑ 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
    • Ototoxicity
    • TLS
    • May exacerbate myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis (MG)
  • Contraindications: hypersensitivity to the drug
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines
    • Loop diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics: ↑ nephrotoxicity of cisplatin
Chemical structure of cisplatin

Chemical structure of cisplatin

Image: “Cisplatin-stereo” by Benrr101. License: Public Domain

Carboplatin

  • 2nd-generation platinum analog, carrying less GI and renal toxicity than cisplatin
  • Pharmacokinetics:
    • IV
    • Minimal hepatic metabolism
    • Half-life: 3–6 hours (normal renal function)
    • Excretion: urine (approximately 70% as carboplatin)
  • Indication (labeled): ovarian CA
  • Adverse effects:
    • Myelosuppression
    • Nausea, vomiting
    • Peripheral neuropathy
    • Nephrotoxicity
    • Secondary malignancy 
    • ↑ 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
    • Ototoxicity
    • Vision loss (high doses)
  • Contraindications:
    • Hypersensitivity to the drug
    • Severe myelosuppression
    • Preexisting renal impairment
    • Bleeding
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines
Chemical structure of carboplatin

Chemical structure of carboplatin

Image: “Carboplatin-skeletal” by catclock. License: Public Domain

Oxaliplatin

  • 3rd-generation platinum analog
  • Pharmacokinetics:
    • IV
    • > 90% protein binding
    • Enzymatic metabolism
    • Excretion: urine
  • Indications: colorectal CA (CRC)
  • Adverse effects:
    • Myelosuppression
    • Nausea, vomiting
    • Nephrotoxicity
    • Neuropathy
    • Cardiotoxicity
    • Hepatotoxicity
    • Bleeding
    • Pulmonary toxicity
    • Rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis 
  • Contraindications: 
    • Hypersensitivity to the drug
    • Preexisting peripheral neuropathy with impaired function
Chemical structure of oxaliplatin

Chemical structure of oxaliplatin

Image: “Oxaliplatin-2D-skeletal” by Benjah-bmm27. License: Public Domain

Comparison with Other Chemotherapeutic Agents

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.
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–independent chemotherapy drugs
Drug class Mechanism
Antitumor antibiotics Antitumor Antibiotics Antitumor antibiotics, also known as antineoplastic antibiotics, are the product of soil microbes, Streptomyces bacteria. The commonly used types of antitumor antibiotics (bleomycin, dactinomycin, and anthracyclines) have a wide spectrum of activity against hematologic malignancies and solid tumors. Antitumor Antibiotics:
  • Dactinomycin
  • Mitomycin
Intercalation between bases leading to blockage 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 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, and prevention of 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
Anthracyclines
  • Inhibition of topoisomerase II
  • 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 intercalation, leading to 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 inhibition
  • Promotion of reactive oxygen species formation
Alkylating agents
  • 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 due to alkylation 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
  • 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, protein synthesis

References

  1. Chu, E. (2021). Cancer chemotherapy. In Katzung, BG., & Vanderah, TW (Eds.), Basic & Clinical Pharmacology, 15e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250603422
  2. Gold, JM, & Raja, A. (2021). Cisplatin. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK547695/
  3. Katzung, B, & Trevor, A. (2020). Basic and Clinical Pharmacology, 15e. McGraw-Hill Education. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250593594
  4. Ogino, MH, & Tadi, P. (2021). Cyclophosphamide. StatPearl. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK553087/
  5. Patel, R, & Tadi, P. (2021). Busulfan. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK555986/
  6. Altretamine. (2021). UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/altretamine-drug-information
  7. Bendamustine. (2021). Bendamustine. UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/bendamustine-drug-information
  8. Busulfan. (2021). UpToDate. Retrieved Sept 19, 2021 from, https://www.uptodate.com/contents/busulfan-drug-information
  9. Carboplatin. (2021). UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/carboplatin-drug-information
  10. Cisplatin. (2021). UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/cisplatin-drug-information
  11. Cyclophosphamide. (2021). UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/cyclophosphamide-drug-information
  12. Oxaliplatin. (2021). UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/oxaliplatin-drug-information
  13. Thiotepa. (2021). UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/thiotepa-drug-information
  14. Wellstein, A, Giaccone, G, Atkins, MB, & Sausville, EA. (2017). Cytotoxic drugs. In Brunton, LL, Hilal-Dandan, R, & Knollmann, BC (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172486857

USMLE™ is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). MCAT is a registered trademark of the Association of American Medical Colleges (AAMC). NCLEX®, NCLEX-RN®, and NCLEX-PN® are registered trademarks of the National Council of State Boards of Nursing, Inc (NCSBN®). None of the trademark holders are endorsed by nor affiliated with Lecturio.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

User Reviews

0.0

()

¡Hola!

Esta página está disponible en Español.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details