Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development.
Topoisomerase I inhibitors constitute a new class of anti-cancer agents. Recently, topotecan and irinotecan were registered for clinical use in ovarian cancer and colorectal cancer respectively. Cytotoxicity of topoisomerase I inhibitors is S-phase specific, and in vitro and in vivo studies have suggested that, for efficacy, prolonged exposure might be more important than short-term exposure to high concentration. Clinical development of those topoisomerase I inhibitors that have reached this stage is also focused on schedules aiming to achieve prolonged exposure. In this review, we summarize all published preclinical studies on this topic for topoisomerase I inhibitors in clinical development, namely 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin, topotecan, irinotecan and GI147211. In addition, preliminary data on clinical studies concerning this topic are also reviewed. The data suggest that prolonged exposure may indeed be relevant for anti-tumour activity. However, the optimal schedule is yet to be determined. Finally, clinical data are yet too immature to draw definitive conclusions.
Gerrits
C J
CJ
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, The Netherlands.
de Jonge
M J
MJ
Schellens
J H
JH
Stoter
G
G
Verweij
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy; D059004:Topoisomerase I Inhibitors; D019772:Topotecan
D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; C091719:lurtotecan; D000077146:Irinotecan; D019772:Topotecan; D002166:Camptothecin