## Antimetabolite Activation and Metabolism in ALL ### Mechanism of Action and Activation **Key Point:** Most antimetabolites require enzymatic activation to exert their cytotoxic effects. The specific enzyme and product vary by drug. | Agent | Enzyme | Product | Mechanism | |-------|--------|---------|----------| | Methotrexate | — | Polyglutamates | Inhibits DHFR; blocks folate metabolism | | Mercaptopurine | HGPRT | 6-MP-RMP (not GMPR) | Converted to nucleotides; DNA incorporation | | Cytarabine | Deoxycytidine kinase | Ara-CTP | Inhibits DNA polymerase; chain termination | | Thioguanine | HGPRT | TG-nucleotides | DNA incorporation; cell death | ### Why the Incorrect Option is Wrong **Mercaptopurine is activated by HGPRT to form 6-mercaptopurine ribonucleotide (6-MP-RMP), NOT GMPR (guanosine monophosphate ribose).** GMPR is not a recognized metabolite of mercaptopurine. The correct product is 6-MP-RMP, which is then further phosphorylated to the triphosphate form (6-MP-RTP) for incorporation into DNA and RNA. **High-Yield:** The HGPRT enzyme (hypoxanthine-guanine phosphoribosyltransferase) is critical for purine antagonist activation. Genetic deficiency of HGPRT (Lesch-Nyhan syndrome) results in resistance to mercaptopurine and thioguanine. **Mnemonic:** **HGPRT** = **H**ypoxanthine-**G**uanine **P**hosphoribosyl**T**ransferase — activates purine antagonists (6-MP, 6-TG) to their ribonucleotide forms. ### Thiopurine Methyltransferase (TPMT) Polymorphism **Clinical Pearl:** TPMT deficiency is a critical pharmacogenetic consideration. Patients with low or absent TPMT activity accumulate toxic metabolites of mercaptopurine and thioguanine, leading to severe myelosuppression, hepatotoxicity, and GI toxicity. TPMT genotyping or phenotyping should be performed before initiating thiopurine therapy. [cite:KD Tripathi 8e Ch 65]
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