Antimetabolites

Introduction

Antimetabolites are a major class of chemotherapeutic agents primarily used in the treatment of cancer and certain autoimmune diseases. They exert their pharmacological effects by interfering with essential biochemical pathways required for DNA and RNA synthesis, cell replication, and proliferation. Because cancer cells typically divide more rapidly than normal cells, they are particularly susceptible to these agents, making antimetabolites essential in oncology. Beyond cancer, antimetabolites also serve in managing inflammatory and autoimmune disorders, as well as in organ transplantation.

The development of antimetabolites dates back to the mid-20th century, following observations that structurally similar compounds could act as analogs to natural metabolites and thereby disrupt cellular functions. Their discovery represented a turning point in rational drug design, focusing on targeting specific enzymes or nucleotide pathways.

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Mechanism of Action

Antimetabolites work by mimicking or inhibiting natural metabolites involved in nucleotide and nucleic acid synthesis. Their mechanisms include:

1. Folate Antagonism

   • Some antimetabolites block folic acid metabolism, a cofactor critical for thymidylate and purine synthesis. Inhibition leads to impaired DNA synthesis and cell cycle arrest at the S-phase.

   • Example: Methotrexate inhibits dihydrofolate reductase (DHFR), preventing the regeneration of tetrahydrofolate required for purine and thymidylate synthesis.

2. Pyrimidine Analogs

   • These resemble natural pyrimidines (cytosine, thymine, uracil) and are incorporated into DNA or RNA, leading to chain termination or inhibition of key enzymes.

   • Example: 5-Fluorouracil (5-FU) is converted into FdUMP, which irreversibly inhibits thymidylate synthase, blocking dTMP production.

3. Purine Analogs

   • These interfere with enzymes involved in purine synthesis or are incorporated into nucleic acids to induce faulty DNA/RNA.

   • Example: 6-Mercaptopurine (6-MP) inhibits amidophosphoribosyl transferase, blocking de novo purine synthesis.

4. Cytidine Analogs

   • Substitution of cytidine analogs disrupts DNA replication and repair.

   • Example: Cytarabine is incorporated into DNA, inhibiting DNA polymerase and halting elongation.

5. Inhibition of DNA Methylation

   • Certain antimetabolites act as hypomethylating agents, reactivating tumor suppressor genes.

   • Example: Azacitidine and Decitabine inhibit DNA methyltransferases.

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Classification of Antimetabolites

Antimetabolites are categorized based on the metabolic pathway or nucleotide analog they target:

1. Folate Antagonists

• Methotrexate – Inhibits DHFR, used in leukemia, lymphoma, breast cancer, rheumatoid arthritis, and psoriasis.

• Pemetrexed – A multitargeted antifolate inhibiting thymidylate synthase, DHFR, and GARFT; used in mesothelioma and non-small cell lung cancer (NSCLC).

• Pralatrexate – A folate analog metabolic inhibitor used in relapsed or refractory peripheral T-cell lymphoma.

• Raltitrexed – A thymidylate synthase inhibitor used mainly in colorectal cancer.

2. Pyrimidine Analogs

• 5-Fluorouracil (5-FU) – Used in colorectal, breast, gastric, pancreatic cancers; often combined with leucovorin to enhance binding to thymidylate synthase.

• Capecitabine – Oral prodrug of 5-FU, used in breast and colorectal cancers.

• Tegafur – Another oral prodrug of 5-FU, often used in combination regimens (e.g., tegafur-uracil).

• Cytarabine (Ara-C) – Used in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and lymphoma.

• Gemcitabine – Incorporated into DNA, causing chain termination; used in pancreatic, bladder, breast, and NSCLC.

• Azacitidine – A hypomethylating agent for myelodysplastic syndrome (MDS) and acute myeloid leukemia.

• Decitabine – Similar to azacitidine, inhibits DNA methyltransferases, used in AML and MDS.

• Floxuridine – Used for hepatic arterial infusion in metastatic colorectal cancer.

3. Purine Analogs

• 6-Mercaptopurine (6-MP) – Used in acute lymphoblastic leukemia; metabolized by HGPRT to inhibit purine synthesis.

• Azathioprine – A prodrug of 6-MP, used in autoimmune diseases and organ transplantation.

• 6-Thioguanine (6-TG) – Similar mechanism to 6-MP, used in leukemia.

• Fludarabine – Purine analog inhibiting DNA polymerase and ribonucleotide reductase; used in chronic lymphocytic leukemia (CLL) and lymphomas.

• Cladribine – Resistant to adenosine deaminase, causes DNA strand breaks; used in hairy cell leukemia, multiple sclerosis.

• Clofarabine – Next-generation purine analog used in pediatric ALL.

• Pentostatin – Adenosine deaminase inhibitor; used in hairy cell leukemia and T-cell malignancies.

• Nelarabine – Prodrug of ara-GTP, toxic to T-cells; used in T-cell acute lymphoblastic leukemia and lymphoma.

4. Other Cytidine Analogues / Hypomethylating Agents

• Trifluridine/Tipiracil – Combination used in metastatic colorectal cancer and gastric cancer.

• Sapacitabine – Investigational cytidine analog with potential in AML.

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Therapeutic Uses

1. Oncology

Antimetabolites are foundational in cancer chemotherapy, either as monotherapy or in combination regimens.

• Acute Leukemias (ALL, AML): Cytarabine, 6-MP, 6-TG, methotrexate.

• Lymphomas: Methotrexate, fludarabine, cladribine.

• Solid Tumors:

  • Breast cancer: 5-FU, capecitabine, methotrexate.

  • Colorectal cancer: 5-FU, capecitabine, raltitrexed.

  • Pancreatic cancer: Gemcitabine, 5-FU.

  • NSCLC: Pemetrexed, gemcitabine.

  • Ovarian cancer: Gemcitabine, 5-FU combinations.

  • Mesothelioma: Pemetrexed with cisplatin.

2. Autoimmune and Inflammatory Disorders

• Methotrexate – Rheumatoid arthritis, psoriasis, Crohn’s disease.

• Azathioprine – Systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease.

3. Transplant Medicine

• Azathioprine – Used as an immunosuppressant in renal, liver, and cardiac transplantation.

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Dosage Overview (General)

• Methotrexate:

  • Oncology: 20–500 mg/m² IV weekly (varies widely by regimen).

  • Autoimmune: 7.5–25 mg orally or subcutaneously weekly.

• 5-Fluorouracil (5-FU):

  • IV bolus 500 mg/m² weekly, or continuous infusion 1000 mg/m²/day for 4–5 days (regimen-dependent).

• Capecitabine:

  • Oral: 1250 mg/m² twice daily for 14 days, followed by 7 days rest.

• Cytarabine:

  • Standard: 100–200 mg/m²/day continuous IV infusion for 7 days.

  • High-dose: 2–3 g/m² every 12 hours for 6–12 doses.

• Gemcitabine:

  • IV: 1000 mg/m² over 30 minutes once weekly for 7 weeks, followed by 1 week rest.

• Azathioprine:

  • Autoimmune/transplant: 1–3 mg/kg/day orally.

• 6-Mercaptopurine:

  • 2.5 mg/kg/day orally for ALL.

• Fludarabine:

  • IV: 25 mg/m² daily for 5 days, repeated every 28 days.

(Doses vary by protocol, indication, and combination regimen; always individualized.)

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Contraindications

• Hypersensitivity to the drug or excipients.

• Pregnancy and breastfeeding (teratogenic, category D/X depending on drug).

• Severe hepatic or renal impairment (relative contraindication for many).

• Bone marrow suppression or active infection.

• Concomitant live vaccines.

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Adverse Effects

1. Hematological Toxicity

   • Myelosuppression (neutropenia, thrombocytopenia, anemia).

   • Risk of infection and bleeding.

2. Gastrointestinal Toxicity

   • Mucositis, stomatitis, diarrhea, nausea, vomiting.

   • Hepatotoxicity (especially with methotrexate and azathioprine).

3. Neurological Effects

   • High-dose cytarabine: cerebellar toxicity, confusion, seizures.

   • Methotrexate: leukoencephalopathy with intrathecal use.

4. Dermatological

   • Alopecia, skin rashes, photosensitivity.

5. Other

   • Pulmonary toxicity (methotrexate, gemcitabine).

   • Cardiotoxicity (5-FU: coronary vasospasm).

   • Immunosuppression leading to opportunistic infections.

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Precautions

• Renal and Hepatic Monitoring – Many agents require dose adjustment in organ impairment.

• Folinic Acid Rescue (Leucovorin) – Used with high-dose methotrexate to prevent severe toxicity.

• Drug Level Monitoring – Methotrexate levels must be monitored in high-dose therapy.

• Vaccination – Avoid live vaccines during and shortly after treatment.

• Pregnancy – Strict contraception required during and after therapy.

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Drug Interactions

• Methotrexate: Interacts with NSAIDs, penicillins, proton pump inhibitors, sulfonamides (increase toxicity).

• 6-Mercaptopurine/Azathioprine: Interaction with allopurinol and febuxostat (xanthine oxidase inhibitors) – requires major dose reduction to avoid toxicity.

• 5-FU/Capecitabine: Interacts with warfarin (increased INR/bleeding risk).

• Gemcitabine: May enhance toxicity of radiation therapy.

• Fludarabine/Cladribine: Risk of severe immunosuppression when combined with other immunosuppressants.