Topoisomerase Inhibitors

Topoisomerase-I and topoisomerase-II inhibitors were the next chemotherapy class to be investigated for treatment of relapsed and newly diagnosed neu-roblastoma. Etoposide, a topoisomerase-II inhibitor, as detailed above, has been incorporated into relapse and primary treatment regimens for the past two decades, and is quite effective incorporated into regimens for newly diagnosed neuroblastoma (see Chap. 11). Unfortunately, a significant proportion of cell lines obtained from patients after relapse have demonstrated resistance to this agent, even when cell lines from the same patient obtained at diagnosis were sensitive. Furthermore, cross-resistance with other topoisomerase inhibitors, the camptothecins topotecan and irinotecan, was demonstrated in these cell lines (Keshelava et al. 2000b). Nonetheless, up to 10-15% of children with relapsed neuroblastoma could achieve disease stabilization or partial remission with chronic administration of oral etoposide (Davidson et al. 1997; Kushner et al. 1999; Ng et al. 2000; Schiavetti et al. 2001). Camptothecin is a naturally occurring cytotoxic alkaloid that targets topoi-somerase I, a nuclear enzyme that reduces the tor-sional stress of supercoiled DNA during the replication, recombination, transcription, and repair of DNA. Topotecan and irinotecan are synthetic analogues developed for parenteral administration of the active lactone form of the compound (Garcia-Carbonero and Supko 2002).

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