The development of combination therapy involving camptothecins: a review of preclinical and early clinical studies

Camptothecin analogues are a family of anticancer agents with a unique mechanism of action, which is the reversible inhibition of DNA topoisomerase I (1, 2). DNA topoisomerases are essential nuclear enzymes involved in multiple functions such as chromosomal recombination, DNA repair, transcription and chromatin assembly. Topoisomerase I inhibitors exert their cytotoxic action through the stabilization of the topoisomerase I-DNA complex, the so-called cleavable complex. This results in collision of the DNA replication fork, finally leading to irreversible DNA double-strand breaks and cell death (3,4). Topoisomerase I inhibitors are of great clinical interest because of their unique mode of action, their important antitumour activity as single agents in a broad spectrum of tumour types (5-30 and the high expression of the enzyme in various human tumour types (31-34). In addition, topoisomerase I inhibitors may also interfere with the processes involved in DNA repair (35-37). The latter renders them attractive for further investigations of combination therapies, especially involving those with DNA-damaging agents. Preclinical studies have revealed synergism between topoisomerase I inhibitors and drugs such as cisplatin, topoisomerase II inhibitors and paclitaxel in a number of different human cancer cell lines and xenografts. This paper reviews the development of combination therapy with topoisomerase I inhibitors with a focus on the two topoisomerase I inhibitors [irinotecan and