Anticancer Drugs — Classification, Cell-Cycle Specificity, Signature Toxicities and Protective Agents

Classic cytotoxic drugs are grouped by how they damage the tumour cell. Almost all share myelosuppression, mucositis, nausea and alopecia, because they hit every rapidly dividing tissue; exams therefore focus on each drug's unique (signature) toxicity.

The cell cycle runs G1 → S (DNA synthesis) → G2 → M (mitosis). Cell-cycle (phase) specific drugs act on cells in one particular phase. Cell-cycle non-specific drugs damage DNA whatever phase the cell is in. Cytotoxic drugs as a group do the most damage in S phase, when DNA is being copied.

Cisplatin acts by cell cycle–nonspecific covalent binding of platinum to the N7 position of guanine and adenine, forming intrastrand and interstrand cross-links that break DNA.

• Nephrotoxicity: a major toxicity — prevent with hydration and magnesium supplementation.
• Ototoxicity: hearing loss; sodium thiosulfate is FDA-approved to prevent cisplatin hearing loss in children.
• Peripheral neuropathy and myelosuppression; gonadal toxicity.
• Vomiting: cisplatin is highly emetogenic; guidelines use a four-drug combination of olanzapine, an NK1 antagonist, a 5-HT3 antagonist and dexamethasone — see anti-emetic drugs.

Doxorubicin (an anthracycline) inhibits topoisomerase II, causing DNA damage and apoptosis. Bound to iron, it also produces free radicals — the main reason for its heart damage.

• Type 1 cardiotoxicity: dose-dependent, cumulative and irreversible cardiomyocyte death leading to dilated cardiomyopathy and heart failure.
• Cumulative dose limit: a maximum lifetime cumulative dose of 550 mg/m² is quoted for conventional doxorubicin.
• Pegylated liposomal doxorubicin has comparable efficacy with less cardiotoxicity.
• Dexrazoxane is an iron chelator that limits doxorubicin–iron binding and free-radical formation; it is approved as a cardioprotectant and to limit tissue damage after anthracycline extravasation.
• Other risks: myelosuppression, extravasation injury (vesicant), secondary malignancies.

Bleomycin forms complexes that generate reactive oxygen species, causing single- and double-strand DNA breaks and arrest in G2. It is used for testicular cancer, Hodgkin lymphoma and head and neck cancers. The low level of the inactivating hydrolase enzyme in skin and lung is thought to explain why these organs are the ones damaged.

• Bleomycin pulmonary toxicity: the most common serious effect; inflammation within a week and fibrosis by about three weeks in experimental exposure — chronic and irreversible.
• Risk factors: high cumulative dose, raised creatinine or low GFR, older age and supplemental oxygen.
• Skin: pigmentation changes and itching; also loss of taste, nausea and weight loss.

Vincristine binds tubulin and prevents its polymerisation into microtubules, so the mitotic spindle cannot form and cells arrest in mitosis.

• Neurotoxicity is the most common and dose-limiting effect — peripheral neuropathy affecting sensory, motor and autonomic nerves; constipation is also common.
• Route: vincristine must be given intravenously only; giving it by any other route, especially intrathecally, can be fatal.

Cyclophosphamide is a prodrug. Liver cytochrome P450 enzymes convert it to aldophosphamide, which splits into the active alkylating agent phosphoramide mustard and acrolein. Acrolein has no antitumour effect but concentrates in the bladder, where it releases inflammatory mediators that cause vascular dilatation, mucosal oedema and bleeding — haemorrhagic cystitis. Ifosfamide shares this toxicity.

• Prevention: generous hydration with a urine output of at least 100 mL/hour during therapy.
• Mesna is a sulfhydryl (thiol) donor; it is reactivated in the bladder and binds acrolein into an inactive conjugate.
• Cyclophosphamide is not cell-cycle phase-specific; it is part of regimens such as R-CHOP for lymphoma.

Methotrexate and its polyglutamates inhibit dihydrofolate reductase (DHFR), which converts dihydrofolate to tetrahydrofolate — the active folate needed to make purines and thymidylate. Leucovorin (folinic acid) is an already-reduced folate, so it bypasses the DHFR block and rescues normal cells.

• Leucovorin rescue after high-dose methotrexate (for example in osteosarcoma) protects against myelosuppression, gut toxicity and neurotoxicity; the three main treatments for methotrexate toxicity are leucovorin, thymidine and glucarpidase.
• Other measures: hydration and urine alkalinisation to keep methotrexate soluble.
• Methotrexate toxicity: hepatotoxicity (the most significant adverse effect), myelosuppression, mucositis, renal impairment, interstitial pneumonitis; it is teratogenic.

5-Fluorouracil is converted to FdUMP, which locks thymidylate synthase in a complex and stops dTMP production; it also misincorporates into RNA and DNA. Here leucovorin works the opposite way: as 5,10-methylenetetrahydrofolate it stabilises the FdUMP–thymidylate synthase complex, enhancing 5-FU's effect — so the two are given together in colorectal cancer.

• 5-FU toxicities: diarrhoea (the most common), mucositis, myelosuppression, hand–foot syndrome (dose-limiting with capecitabine), and cardiotoxicity — angina, myocardial infarction, heart failure.
• DPD deficiency: dihydropyrimidine dehydrogenase normally breaks down over 80% of 5-FU; deficiency causes life-threatening toxicity and is a contraindication.
• Antidote: uridine triacetate for 5-FU overdose or severe toxicity.