Oncology-Anti-Metabolites

Oncology-Anti-Metabolites
I. Introduction to Anti-Metabolites

• Mechanism: Anti-metabolites disrupt normal nucleic acid metabolism, primarily during the S-phase of the cell cycle (Fig 5.1). They are widely used cytotoxic agents, not limited to cancer treatment.

II. Anti-Folates

• Folate Biochemistry: Understanding folate biochemistry is crucial. Thymidylate synthase (TS) is rate-limiting in thymidylate (dTTP) synthesis, converting dUMP to dTTP using CH2-FH4. Dihydrofolate reductase (DHFR) maintains the supply of reduced folate.

III. Methotrexate (MTX)

• Clinical Use: Widely used in various cancers (breast, osteosarcoma, GI, choriocarcinoma).
• Pharmacology: Well absorbed orally (<25mg/m²), usually administered IV. Hepatic metabolism to active 7-OH-MTX; 7-10% biliary excretion. Dose adjustments usually unnecessary with hepatic dysfunction. Fluid collections (ascites, pleural effusions) increase toxicity due to reduced clearance. Excretion inhibited by probenecid, penicillins/cephalosporins, NSAIDs.
• Toxicities: Mucositis, myelosuppression, nephrotoxicity.

IV. Thymidylate Synthase (TS) Inhibitors

• Direct vs. Indirect Inhibitors: New agents directly inhibit TS (e.g., Raltitrexed), unlike indirect inhibitors (e.g., 5-FU, MTX).
• Raltitrexed: Prolonged TS inhibition via polyglutamation. Triphasic elimination (renal excretion ~50%). Active in breast and colorectal cancers. Toxicities: myelosuppression, diarrhea, transaminitis. Unpredictable severe toxicities limit widespread use.

V. Fluoropyrimidines

• Mechanism: Prodrugs activated intracellularly, inhibiting pyrimidine synthesis.

A. Fluorouracil (5-FU)

• Clinical Use: Widely used, particularly in breast, GI, and head/neck cancers.
• Mechanism: Metabolized to FdUMP, forming a stable complex with TS in the presence of CH2-FH4, inhibiting TS. Also inhibits RNA synthesis and pre-ribosomal RNA processing.
• Pharmacology: IV administration (bolus or prolonged infusion). Short initial half-life; hepatic, renal, and lung clearance. Active metabolites (5dUMP, FUTP) have variable pharmacokinetics.
• Toxicities: Myelosuppression, stomatitis, diarrhea (longer administration). Prolonged infusion minimizes bone marrow effects but causes hand-foot syndrome, neurotoxicity, and cardiotoxicity.

B. Fluorouracil Prodrugs

• Tegafur (Uftoral®): Oral combination with uracil (1:4 molar ratio). Licensed in many countries (not the US). Active mainly in colorectal and other GI cancers.
• Capecitabine: Oral prodrug, preferentially activated in tumor and liver tissue. Potential replacement for prolonged 5-FU infusion. Active in various cancers; licensed for breast and GI cancers. Further clinical trials ongoing.
• Floxuridine: IV administration; metabolized to 5-FU and FdUMP. Primarily used in hepatic artery infusion for colon cancer due to lower toxicity than 5-FU. Not licensed in the UK.

C. Modulation of Fluorouracil

• Fluorouracil + Folinic Acid (FA): Mainstay colon cancer treatment. FA increases CH2-FH4 supply, potentiating 5-FU's interaction with TS. Higher response rate but increased toxicity compared to 5-FU alone.

VI. Anti-Purines

• Clinical Use: Treat leukemias, immunosuppressants (azathioprine), antivirals (aciclovir, ganciclovir).
• Pemetrexed: Novel TS inhibitor; also inhibits DHFR and GARFT. Licensed for mesothelioma and NSCLC. Toxicity reduced by B12 and folate supplementation.
• 6-Mercaptopurine (6-MP) & 6-Thioguanine (6-TG): Inhibit de novo purine synthesis; nucleotide products incorporated into DNA. Synergistic with MTX. Resistance develops due to HGPRT deficiency. Variable oral bioavailability.
• Pharmacology: Short half-life; primarily metabolized. 6-MP is a xanthine oxidase substrate (dose adjustments needed with allopurinol). Poor CSF penetration.
• Toxicities: Myelosuppression; 6-MP can cause hepatotoxicity; nausea, vomiting, mucositis (more common with 6-MP). Main indication: hematological malignancies (6-MP for ALL maintenance, 6-TG for AML).

VII. Cytosine Analogues
A. Cytarabine (Ara-C)

• Mechanism: Active transport; ara-CTP incorporated into DNA, inhibiting DNA polymerases and possibly phospholipid synthesis. Damaged DNA susceptible to repair.
• Clinical Use: Active in NHL and AML, not solid tumors. Renal excretion of deaminated compound. Continuous infusion improves activity due to rapid clearance.
• Toxicities: Emesis, alopecia, myelosuppression, “ara-C syndrome” (fevers, myalgias, rash, keratoconjunctivitis, arthralgias), rarely lung/pancreatic damage.

B. Gemcitabine (dF-CTP)

• Mechanism: Better membrane permeation and deoxycytidine kinase affinity than ara-C. Prolonged intracellular retention via self-potentiation (bi- and triphosphates facilitate phosphorylation and inhibit catabolism). dF-CTP incorporated into DNA, followed by only one normal nucleotide (“masked termination”), protecting DNA from repair. Schedule-dependent activity (usually weekly IV × 3 out of 4 weeks).
• Clinical Use: Wide range of cancers, notably pancreatic carcinoma (modest survival advantage).
• Toxicities: Flu-like symptoms, transaminitis, peripheral edema, myelosuppression, nephrotoxicity. Synergy with cisplatin (schedule-dependent).

VIII. Adenosine Analogues

• Clinical Use: Low-grade NHL, Waldenström’s macroglobulinemia, CLL. Interact with adenosine deaminase (ADA).
• Toxicities: Myelosuppression (lymphocytes), reduced NK cell activity.

A. Fludarabine:

• Resistant to ADA; actively transported, phosphorylated, incorporated into DNA/RNA; possible topo II inhibition. Can cause hemolytic anemia. Useful in CLL.

B. Pentostatin:

• High ADA affinity; stable complex, resulting in enzyme inhibition. Major indication: hairy cell leukemia. Inhibits DNA synthesis and repair.

C. Cladribine:

• Resistant to ADA; phosphorylated, incorporated into DNA. Used for hairy cell leukemia.

IX. Hydroxycarbamide

• Mechanism: Inhibits ribonucleotide reductase, reducing deoxynucleotide availability. Crosses blood-brain barrier.
• Clinical Use: Myeloproliferative disorders.
• Toxicities: Myelosuppression, GI toxicities, hyperpigmentation.