Cell Cycle Specific Anticancer Drugs

Cell cycle specific drugs kill cells only in a particular phase of the cycle. Because the fraction of cells in any one phase is limited, killing reaches a plateau as the dose rises, and the effect depends on the duration of exposure more than on the peak concentration. They are therefore given by prolonged infusion, frequent short schedules, or repeated cycles.

Classification. By phase of action:

• S phase: antimetabolites (methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine), and topoisomerase I inhibitors.
• G2 phase: bleomycin, topoisomerase II inhibitors (etoposide).
• M phase: vinca alkaloids and taxanes (microtubule inhibitors).
• G1 phase: asparaginase.

Pharmacodynamics. Time over a threshold concentration predicts kill. Tumours with a high growth fraction (leukaemia, lymphoma, germ cell tumour) respond best; slow-growing tumours with a large resting fraction respond poorly.

• Methotrexate 3 to 12 g/m2 over 4 to 24 hours with folinic acid rescue in high-dose regimens; 12 mg intrathecally.
• Fluorouracil 400 mg/m2 intravenous bolus then 2,400 mg/m2 over 46 hours every 2 weeks.
• Cytarabine 100 to 200 mg/m2 daily by continuous infusion for 7 days (induction); 1 to 3 g/m2 every 12 hours for consolidation.
• Gemcitabine 1,000 mg/m2 on days 1, 8 and 15 of a 28-day cycle.
• Vincristine 1.4 mg/m2 (maximum 2 mg) intravenously every 1 to 3 weeks.
• Paclitaxel 175 mg/m2 over 3 hours every 3 weeks, or 80 mg/m2 weekly.
• Etoposide 100 mg/m2 on days 1 to 3, or 50 mg/m2 orally for 14 days.
• Bleomycin 10 to 20 units/m2 weekly.

Differences. Antimetabolites cause marrow and mucosal toxicity; microtubule inhibitors cause neuropathy; bleomycin spares marrow but injures lung and skin. Schedule changes outcome and toxicity: bolus fluorouracil causes more neutropenia, infusional fluorouracil more hand and foot syndrome.

• Leukaemia and lymphoma: schedule-dependent drugs in repeated cycles give the highest cure rates.
• Solid tumours: combine a phase-specific drug with a non-specific drug to widen kill.
• Sequencing: a drug that recruits cells into cycle can sensitise them to a phase-specific drug (for example, giving cytarabine before an anthracycline in acute leukaemia); sequence-dependent interactions are built into regimens and must not be reversed.
• Schedule choice: weekly or continuous schedules lower peak toxicity for some drugs, but cure-intent regimens keep the planned interval.

Selection. Choose by tumour type and chemosensitivity; palliative treatment may use oral continuous drugs (capecitabine, etoposide, mercaptopurine) to limit hospital visits.

Contraindications. Drug specific: severe marrow failure, severe liver or kidney impairment for renally cleared drugs, pregnancy in the first trimester.

Adverse effects. Myelosuppression (nadir 7 to 14 days), mucositis, diarrhoea, alopecia, peripheral neuropathy (vinca alkaloids and taxanes), hypersensitivity (paclitaxel), cerebellar toxicity (high-dose cytarabine), pulmonary fibrosis (bleomycin).

Interactions. Allopurinol raises mercaptopurine levels; NSAIDs, penicillins, proton pump inhibitors and co-trimoxazole raise methotrexate levels; azole antifungals and boosted antiretroviral regimens raise vinca alkaloid levels.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: tolerate higher doses by surface area; use specialist regimens.
• Older adults: reduce vinca alkaloid and taxane doses with neuropathy.
• Kidney impairment: reduce or avoid methotrexate and fludarabine.
• Liver impairment: reduce vinca alkaloids and taxanes by bilirubin.

Monitoring. Full blood count before each cycle, renal and liver function, neurological assessment, and cumulative bleomycin dose.

Referral and escalation. Neutropenic fever, severe mucositis, intrathecal vincristine error, extravasation, or sudden dyspnoea on bleomycin need emergency care.