Cytoprotective & Ameliorative Agents in Cancer Chemotherapy

Cytoprotective & Ameliorative Agents in Cancer Chemotherapy

1. The therapeutic-index problem that creates the need for cytoprotection

• Few drug categories have a narrower therapeutic index or greater potential for harm than anticancer drugs; safe use demands a working knowledge of their mechanisms, kinetics, interactions and adverse effects (G&G 14e Ch.69, p.1337).
• The biological basis of toxicity: most cytotoxics act on rapidly proliferating cells, and normal tissues that proliferate fast — bone marrow, hair follicles, GI/oral epithelium, gonads, reticuloendothelial system — are damaged in parallel with the tumour (G&G 14e Ch.69, p.1337; KDT 8e Ch.64, pp.916–8).
  • Cell-cycle context: DNA-damaging agents act maximally in S phase; vinca alkaloids and taxanes block the M-phase spindle; cell-cycle-nonspecific agents (alkylators, nitrosoureas, antibiotics, cisplatin) hit dividing and resting cells alike (G&G 14e Ch.69, p.1338, Fig 69–2).
• Because malignant cells are host cells with deranged growth regulation (not foreign organisms), drug selectivity is intrinsically limited — so a battery of selectivity-enhancing / toxicity-ameliorating measures is needed to make chemotherapy survivable (KDT 8e Ch.64, p.933).
• The cautionary principle that frames all supportive care: it is imperative to recognise toxicities early, alter dose or discontinue the offending drug, and provide vigorous supportive care — cardiac, pulmonary, neurological and renal toxicities may be irreversible if recognised late (G&G 14e Ch.69, p.1342).
• Two converging trends have made toxicity more manageable and dose-intensification feasible: better antiemetics and granulocyte colony-stimulating factor to restore marrow function (G&G 14e Ch.69, pp.1339–40, cross-refs Ch.45 & Ch.54).

General toxicities that the ameliorative agents are deployed against (KDT 8e Ch.64, pp.916–8):

• Bone marrow — granulocytopenia, thrombocytopenia, aplastic anaemia; the most serious and usually dose-limiting toxicity → countered by myeloid growth factors / transfusion.
• Oral cavity & GIT — stomatitis/mucositis, diarrhoea, haemorrhage from reduced mucosal renewal (prominent with fluorouracil, methotrexate, daunorubicin, doxorubicin, bleomycin, actinomycin D).
• Nausea & vomiting — by direct CTZ stimulation + emetic mediators from upper GIT → countered by antiemetics.
• Hyperuricaemia — secondary to massive purine release from tumour lysis → countered by allopurinol/urate-lowering.
• Specific organ injuries — anthracycline cardiomyopathy, cisplatin nephro/oto/neurotoxicity, oxaliplatin/taxane neuropathy, cyclophosphamide/ifosfamide haemorrhagic cystitis — each with a targeted protectant.