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.