The water-insoluble camptothecin analogues: promising drugs for the effective treatment of haematological malignancies.
After failing to exhibit benefits in clinical studies with cancer patients in the early 1970s, camptothecin (CPT) and its water-insoluble analogues are re-emerging as promising drugs with multiple actions in the treatment of human haematological malignancies. CPT analogues interfere with the mechanism of action of the nuclear enzyme topoisomerase I, while the cells progress through the S-phase of the cell cycle and this results in cell death by apoptosis. Modulations of topoisomerase I phosphorylation may indirectly modulate the cytotoxic activity of CPT analogues. In vitro, CPT analogues have exhibited increased or unaltered killing activity against leukaemia cells resistant to epipodophyllotoxins, anthracyclines, anthracenediones, and Vinca alkaloids, while development of resistance to CPT analogues renders leukaemia and lymphoma cells more sensitive to topoisomerase II-directed drugs, inducers of cell differentiation, and immunotoxins. Oral administration of the CPT analogues has circumvented the inconvenience of solubility of these drugs. Metabolic conversion of the CPT analogue 9-nitro-CPT to equally or more potent 9-amino-CPT practically makes unnecessary treatment of the patient with 9-amino-CPT, which, in addition, is costlier to prepare than 9-nitro-CPT. Considering the therapeutic, economic and handling viewpoints, the overall conclusion is that the water-insoluble CPT analogues are very promising antileukaemia/antilymphoma agents that warrant further preclinical and clinical studies.
Pantazis
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Stehlin Foundation for Cancer Research, St. Joseph Hospital, Houston, Texas, USA.
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001711:Biotransformation; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D007942:Leukemia, Experimental / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D012995:Solubility; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin