Antimetabolite Chemotherapy Agents

Antimetabolite chemotherapy agents belong to the cell-cycle–specific drugs, which act on a specific phase of the 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 occurs, thus inhibiting DNA synthesis of tumor cells. In this group, the drugs include antifolates (which block folic acid activity, an essential component of DNA and RNA precursors), pyrimidine and purine analogs (which interfere with the process of DNA 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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Overview

Cell-cycle kinetics

  • The 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
    • S phase: DNA replication
    • G2 phase: further cell growth (e.g., replication of organelles) in preparation for mitosis 
    • M phase: duplicated DNA 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):
    • Effective against cells cycling at a rapid rate (moving through the cell cycle)
    • Analogs for the units of DNA and RNA, which when incorporated, stop DNA and RNA synthesis.
    • Target the S phase of the cell cycle → inhibit normal DNA and RNA 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 
    • ↑ Activity of tumor cell enzymes, which inactivate anticancer drugs
    • Change in the sensitivity of the target enzyme to the drug
    • ↓ Conversion of prodrugs by tumor cell 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 or folic acid is essential in providing methyl groups for precursors of DNA and RNA.
  • Medications in this drug class inhibit dihydrofolate reductase, in general:
    • Methotrexate 
    • Pemetrexed
    • Pralatrexate 
    • Proguanil (antimalarial)
    • Trimethoprim (antibiotic/antibacterial)

Methotrexate (MTX)

  • Folic acid analog 
  • Mechanism of action:
    • Binds to dihydrofolate reductase (DHFR) → inhibits the formation of tetrahydrofolate (FH₄) → ↓ DNA 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
      • ALL
      • Head and neck cancer
      • Cutaneous T-cell lymphoma
      • Gestational trophoblastic neoplasia
      • Non-Hodgkin lymphoma
      • Osteosarcoma
    • Nonneoplastic:
      • Rheumatoid arthritis
      • Psoriasis
      • Juvenile idiopathic arthritis
  • Adverse effects:
    • Myelosuppression: anemia, neutropenia, and thrombocytopenia
    • Hepatotoxicity: ↑ liver enzymes
    • Immunosuppression
    • GI: stomatitis, diarrhea, nausea, vomiting 
    • Nephrotoxicity: crystal nephropathy and direct tubular toxicity
    • Neurotoxicity
    • Pulmonary toxicity: interstitial pneumonitis
    • Dermatologic: Stevens-Johnson syndrome (SJS), 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 (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:
      • 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 
    • Non–small cell lung cancer 
  • Adverse effects:
    • Myelosuppression
    • Skin rash
    • Nephrotoxicity
    • Pulmonary toxicity
    • GI: nausea, vomiting, diarrhea, stomatitis
  • Precautions: prophylactic folic acid and vitamin B12 to ↓ hematologic and GI toxicity
  • Contraindications: hypersensitivity to any antifolate drugs
  • Pregnancy 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, leukopenia, thrombocytopenia 
    • GI: nausea, abdominal pain, diarrhea, stomatitis
    • Fatigue
    • Edema
  • Contraindications: hypersensitivity to any antifolate drugs
  • Pregnancy 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
AgentMechanism of actionLabeled indicationsAdverse effectsAdditional considerations
MethotrexateInhibit DHFR
  • ALL
  • Breast cancer
  • Gestational trophoblastic neoplasia
  • Head and neck cancer
  • Non-Hodgkin lymphoma
  • Cutaneous T-cell lymphoma
  • Osteosarcoma
  • Myelosuppression
  • Immunosuppression
  • Nephrotoxicity
  • Hepatotoxicity
  • Neurotoxicity
  • Pulmonary toxicity
  • GI side effects
  • Pregnancy: neural tube defects
Add leucovorin to rescue cells from toxicity.
PemetrexedInhibit:
  • Thymidylate synthetase
  • DHFR
  • GARFT
  • AICARFT
  • NSCLC
  • 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

Pyrimidine Analogs

Pyrimidine antimetabolites

  • Cytotoxic chemotherapy agents that inhibit DNA synthesis through the effects of precursor analogs entering tumor cells.
  • Background:
    • 4 bases that are precursors: 
      • 2 pyrimidines: cytosine and thymine (in RNA: 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.
    • 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 and protein synthesis
  • Mechanism of resistance:
    • ↓ Activity of activating enzymes of 5-FU
    • Amplification or mutation of TS
  • Pharmacokinetics: 
    • Absorption: administered IV (poor oral absorption)
    • Distribution: well distributed throughout, including in CSF
    • Metabolism: hepatic
    • Excretion: renal 
  • Indications (labeled):
    • Breast cancer
    • Colorectal cancer
    • Gastric cancer
    • Pancreatic cancer
  • Adverse effects:
    • Myelosuppression
    • Cardiovascular toxicity: angina, arrhythmia, cardiac failure
    • Neurotoxicity: headache, confusion, disorientation
    • Rash, SJS, TEN
    • Hand-and-foot syndrome (painful, erythematous swelling of the hands and feet)
    • Hyperammonemic encephalopathy
    • Stomatitis, anorexia, 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 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 (metastatic)
    • Colorectal cancer
  • Adverse effects:
    • Myelosuppression
    • GI toxicity:
      • Mucositis
      • Nausea, vomiting
      • Diarrhea: may be dose-limiting because of severity 
    • Cardiotoxicity: ischemia, arrhythmia, cardiac failure
    • 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 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 by DNA polymerase.
    • When ara-CTP is incorporated, termination of DNA chain elongation occurs. 
    • Cell cycle does not continue → DNA breaks → cell 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
      • Primarily renally excreted (90% as metabolite uracil arabinoside) 
  • Indications:
    • ALL
    • AML
    • CML
    • Meningeal leukemia
  • Adverse effects:
    • Main toxic effect: myelosuppression (neutropenia, thrombocytopenia, leukopenia)
    • Others:
      • GI: mucositis, nausea, diarrhea, abdominal pain, pancreatitis
      • Hepatotoxicity: ↑ transaminases
      • Dizziness, headache, neurotoxicity
      • Cardiotoxicity: angina, pericarditis
      • Hyperuricemia
      • Cytarabine syndrome (6–12 hours after administration): fever, myalgia, bone pain, rash, conjunctivitis, malaise
  • Precautions: dose adjustment in hepatic and renal impairment
  • Contraindications: hypersensitivity to cytarabine
  • Pregnancy 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 synthesis
    • Gemcitabine triphosphate (structurally similar to deoxycytidine triphosphate) is incorporated into DNA.
    • Incorporation into DNA → DNA polymerase inhibited → cessation of DNA 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
    • Pancreatic cancer
    • Breast cancer
    • Ovarian cancer
  • Adverse effects:
    • Myelosuppression
    • Capillary leak syndrome (potentially lethal sudden capillary hyperpermeability → edema, hypotension, ↓ albumin)
    • GI: mucositis, nausea, diarrhea, abdominal pain
    • Hepatotoxicity: ↑ transaminases
    • Hemolytic uremic syndrome
    • Pulmonary toxicity
  • Precautions: discontinue if severe renal or hepatic toxicity occurs
  • Contraindications: hypersensitivity to gemcitabine
  • Pregnancy 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 increases the risk of bleeding.

Comparison of pyrimidine analogs

Table: Comparison of pyrimidine analogs
AgentMechanism of actionLabeled indicationsAdverse effectsAdditional considerations
5-FUInhibits thymidylate synthetase
  • Breast cancer
  • Colorectal cancer
  • Gastric cancer
  • Pancreatic cancer
  • Myelosuppression
  • CV toxicity
  • Neurotoxicity
  • Rash
  • Hand-foot syndrome
  • ↑ Ammonia
  • ↑ Bleeding with warfarin
In DPD: ↑ toxicity
CapecitabineProdrug of 5-FU (inhibits thymidylate synthetase)
  • Breast cancer
  • Colorectal cancer
  • Myelosuppression
  • CV toxicity
  • Neurotoxicity
  • GI toxicity
  • Hand-foot syndrome
  • ↑ Bleeding with warfarin
In DPD: ↑ toxicity
CytarabineInhibits DNA polymerase
  • ALL
  • AML
  • CML
  • Meningeal leukemia
  • Myelosuppression
  • Ara-C syndrome
  • GI toxicity
  • Hepatotoxicity
  • Pancreatitis
  • Hyperuricemia
GemcitabineInhibits DNA polymerase and ribonucleotide reductase
  • NSCLC
  • Pancreatic cancer
  • Breast cancer
  • 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

Purine Analogs

Analogs of adenine or guanine

  • These antimetabolites interfere or compete with nucleoside triphosphates in DNA and/or RNA 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 in the purine synthesis.
      • Metabolized to the triphosphate form → incorporated into DNA and RNA
  • 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 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 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 and RNA → inhibits synthesis of purine nucleotides
  • Pharmacodynamics:
    • Absorption: approximately 30% (variable)
    • Distribution: does not reach significant levels in CSF
    • Metabolism: hepatic via TPMT
    • Excretion: renal
  • Indication: AML
  • Adverse effects:
    • Bone marrow suppression
    • Hepatotoxicity
    • Secondary malignancy
    • Tumor lysis syndrome
    • Photosensitivity
  • Precautions: consider testing for deficiency of TPMT and NUDT15: ↑ risk for severe toxicity 
  • Contraindications: hypersensitivity to 6-thioguanine
  • Pregnancy 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 polymerase, ribonucleotide reductase, DNA primase, and DNA ligase I
    • When incorporated into DNA → chain termination
    • When incorporated into RNA → inhibition of RNA processing and 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
  • Adverse effects:
    • Bone marrow suppression
    • Autoimmunity
    • Neurotoxicity (confusion, agitation, coma, seizures)
    • Edema
    • Infections
    • Diarrhea, nausea, vomiting
    • Tumor lysis syndrome
  • Precautions: dose adjustment in renal impairment
  • Contraindications:
    • Hypersensitivity to fludarabine
    • Coadministration with pentostatin → severe pulmonary toxicity
  • Pregnancy 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 strand breaks → inhibition of DNA 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
    • AML
  • Adverse effects:
    • Myelosuppression
    • GI disturbances
    • Hepatotoxicity
    • Secondary malignancy
    • Opportunistic infections
    • Tumor lysis syndrome
    • Renal toxicity
    • Neurotoxicity
  • Precautions: dose adjustment in renal and hepatic impairment
  • Contraindications:
    • Hypersensitivity to cladribine
    • Pregnancy (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 synthesis
  • Pharmacodynamics:
    • Absorption: IV administration
    • Distribution: approximately 4% protein-bound
    • Metabolism and excretion: eliminated via kidneys 
  • Indication: hairy cell leukemia
  • Adverse effects:
    • Myelosuppression
    • Neurotoxicity
    • Hepatotoxicity
    • Dermatologic toxicity (severe rashes)
    • Pulmonary toxicity
    • Renal toxicity
    • Worsening infections
  • Contraindications:
    • Hypersensitivity to pentostatin
    • Coadministration with fludarabine → severe pulmonary toxicity
  • Pregnancy 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
AgentMechanism of actionLabeled indicationsAdverse effectsAdditional considerations
6-MPPurine antagonist (inhibits purine nucleotide synthesis)ALL
  • Myelosuppression
  • Immunosuppression
  • Hepatotoxicity
  • Secondary malignancy
  • Photosensitivity
  • MAS
  • ↓ Effect of warfarin
↓ Dose if taking allopurinol
6-TGPurine antagonistAML
  • Myelosuppression
  • Hepatotoxicity
  • Photosensitivity
  • Secondary malignancy
  • Tumor lysis syndrome
FludarabineInhibits:
  • DNA polymerase
  • Ribonucleotide reductase
  • DNA primase
  • DNA ligase I
CLL
  • Myelosuppression
  • Autoimmunity
  • Infections
  • Neurotoxicity
Avoid pentostatin (↑ pulmonary toxicity)
CladribineInhibits:
  • DNA synthesis (producing DNA strand breaks)
  • Ribonucleotide reductase
Hairy cell leukemia
  • Myelosuppression
  • Cardiotoxicity
  • Hepatotoxicity
  • Neurotoxicity
  • Nephrotoxicity
  • Tumor lysis syndrome
  • Infections
  • Secondary malignancy
PentostatinInhibits adenosine deaminase (↓ DNA synthesis)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 precursors)
    • ↓ Production of deoxyribonucleotides → ↓ DNA synthesis and cell cycle replication
    • S-phase–specific cytotoxic effect on cells
  • Pharmacokinetics: 
    • Absorption: oral administration, absorbed rapidly
    • Distribution: wide distribution (including the brain)
    • Metabolism: liver (60%), GI tract 
    • Excretion: renal
  • Indications (labeled):
    • CML
    • Noncancer indication: sickle cell disease
  • Adverse effects:
    • Myelosuppression
    • Secondary malignancy
    • Cutaneous vasculitic toxicities (ulcerations and gangrene)
    • Pulmonary toxicity
    • Hemolytic anemia
    • Macrocytosis
    • Bacterial and viral infections
    • Mucositis, nausea
  • Contraindications:
    • Hypersensitivity to hydroxyurea
    • Severe myelosuppression
    • Pregnancy (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 dependent chemotherapy drugs
Drug classCell cycle phase affectedMechanism of action
AntifolatesCell cycle arrest at S phaseInhibit:
  • Dihydrofolate reductase
  • Thymidylate synthase
FluoropyrimidinesCell cycle arrest at S phaseInhibit thymidylate synthase
Deoxycytidine analogsCell cycle arrest at S phaseInhibit:
  • DNA polymerase
  • Ribonucleotide reductase
Purine analogsCell cycle arrest at S phaseInhibition of de novo purine synthesis
Topoisomerase II inhibitorsCell cycle arrest at S and G2 phasesInhibit topoisomerase II
TaxanesCell cycle arrest at metaphase of the M phaseHyper-stabilization of microtubules
Vinca alkaloidsCell arrest during metaphase of the M phaseBinds to beta-tubulin and prevents microtubule polymerization
Chemotherapy comparison

Various chemotherapy drugs and their effects on the 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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