Antimetabolites in Cancer Therapy
Antimetabolites are structural analogs of natural nucleotides and folate cofactors that disrupt DNA synthesis and cellular metabolism in cancer cells.
## Overview
Antimetabolites are structurally similar to naturally occurring metabolites required for DNA and RNA synthesis. They interfere with nucleotide biosynthesis and incorporation, selectively targeting rapidly dividing cells. These agents are cell cycle S-phase specific, making scheduling and timing critical for maximal effect.
## Folate Antagonists
**Methotrexate (MTX)** inhibits dihydrofolate reductase (DHFR), depleting tetrahydrofolate needed for thymidylate and purine synthesis. High-dose MTX requires leucovorin (folinic acid) rescue to protect normal cells. MTX is used in ALL, osteosarcoma, lymphoma, and breast cancer. Leucovorin is administered after a defined interval to "rescue" non-tumor cells that were exposed to MTX.
**Pemetrexed** inhibits multiple folate-dependent enzymes including DHFR, thymidylate synthase, and GARFT. Used in mesothelioma and non-squamous NSCLC. Folic acid and B12 supplementation reduces toxicity without reducing antitumor effect.
## Pyrimidine Analogs
**5-Fluorouracil (5-FU)** is converted intracellularly to FdUMP, which inhibits thymidylate synthase (TS), blocking dTMP synthesis. Leucovorin stabilizes the FdUMP-TS complex, enhancing efficacy (FOLFOX, FOLFIRI regimens). Capecitabine is an oral prodrug of 5-FU, activated by thymidine phosphorylase.
**Gemcitabine** is incorporated into DNA and inhibits ribonucleotide reductase. Used in pancreatic, lung, breast, and bladder cancers. Self-potentiating: it inhibits its own degradation.
**Cytarabine (Ara-C)** is incorporated into DNA and inhibits DNA polymerase. Standard induction therapy for AML. High-dose ara-C is used for consolidation.
## Purine Analogs
**6-Mercaptopurine (6-MP)** and **6-thioguanine** are incorporated into DNA/RNA as fraudulent purines, inhibiting de novo purine synthesis. Used in ALL maintenance therapy. TPMT (thiopurine methyltransferase) polymorphisms affect metabolism; TPMT-deficient patients require dose reduction to avoid myelosuppression.
**Fludarabine** is highly active in CLL and indolent lymphomas. It inhibits DNA polymerase and induces apoptosis.
## Key Takeaways
- Antimetabolites are S-phase specific; prolonged infusions increase tumor cell exposure
- Methotrexate inhibits DHFR; leucovorin rescue protects normal tissues
- 5-FU inhibits thymidylate synthase; leucovorin enhances binding to TS
- TPMT genotyping guides 6-MP dosing in ALL to prevent severe toxicity