THE WATER-INSOLUBLE CAMPTOTHECIN ANALOGS - PROMISING DRUGS FOR THE EFFECTIVE TREATMENT OF HEMATOLOGICAL MALIGNANCIES

After failing to exhibit benefits in clinical studies with cancer pati ents in the early 1970s, camptothecin (CPT) and its water-insoluble an alogues are re-emerging as promising drugs with multiple actions in th e treatment of human haematological malignancies. CPT analogues interf ere with the mechanism of action of the nuclear enzyme topoisomerase I , while the cells progress through the S-phase of the cell cycle and t his 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 unalte red killing activity against leukaemia cells resistant to epipodophyll otoxins, anthracyclines, anthracenediones, and Vinca alkaloids, while development of resistance to CPT analogues renders leukaemia and lymph oma 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 thes e drugs. Metabolic conversion of the CPT analogue 9-nitro-CPT to equal ly or more potent 9-amino-CPT practically makes unnecessary treatment of the patient with g-amino-CPT, which, in addition, is costlier to pr epare than g-nitro-CPT. Considering the therapeutic, economic and hand ling viewpoints, the overall conclusion is that the water-insoluble CP T analogues are very promising antileukaemia/antilymphoma agents that warrant further preclinical and clinical studies.