Topoisomerase I inhibitors: clinical studies on oral administration and/or combinations with cisplatin

textabstractThe topoisomerases were discovered in 1971, but it was not until the 1980s that the significance of these enzymes as potential therapeutic targets was appreciated. Topoisomerase I plays a crucial role in the normal replication of DNA. In its physiological state in the chromosome, the DNA helix is supercoiled. Replication requires transient relaxation and unwinding of the parent DNA. In order to achieve this, transient cleavage of the DNA is required mediated by the formation of a cleavable-complex consisting of a covalent intermediate between topoisomerase I and DNA, allowing passage of the intact strand. The enzyme-bridged breaks are resealed afterwards. Topoisomerase I inhibitors stabilize the cleavable complex. thereby inhibiting the religation step. This results in collision of the replication fork and, finally, in double strand breaks and cell death. In the early 1970s, the parent compound camptothecin, an extract from the Camptotheca acuminata, an oriental tree, entered clinical studies. Although some antitumor activity was observed, severe and unpredictable toxicities prevented further clinical development. It was not until the discovery of the mechanism of action of camptothecin, that numerous semi-synthetic camptothecin analogues were developed with a more predictable toxicity profile and better water-solubility and entered clinical trials. The first two of these, irinotecan and topotecan, were recently registered for different indications. Preclinical studies with different topoisomerase I inhibitors showed more antitumor efficacy with prolonged low dose exposure to the drugs, and in animal models, low dose exposure resulted in less toxicity. These. preclinical findings were the stimulus for early clinical studies with low dose continuous infusion of topoisomerase I inhibitors in patients with advanced solid tumors. However, the use of prolonged continuous infusion schedules is associated with the complications of the use of central venous catheters and the cost of administration is high. Aside from economic considerations, patients with advanced malignancies, when asked, preferred oral administration of cytotoxic drugs over the intravenous formulation, provided that no significant reductions in efficacy or duration of response would result from this mode of treatment. The reasons for patients' preferences included convenience, current concern or previous difficulties with intravenous access lines, or preference to control the chemotherapy administration environment. An oral formulation would also provide a more convenient method for prolonged drug administration. Considering their mode of action, topoisomerase I inhibitors may also interfere in processes involved in DNA repair.This renders them attractive for further investigations in combination with other cytostatic agents, especially DNA-damaging agents. Preclinical studies have revealed synergism between topoisomerase I inhibitors and platinum-derivatives, topoisomerase II inhibitors and taxanes in a number of different human cancer cell lines and xenografts. This thesis includes clinical and pharmacological studies on the oral administration of the novel topoisomerase I inhibitor 9-amino-20(S)-camptothecin and studies on the combination of cisplatin with the topoisomerase I inhibitors irinotecan and oral topotecan