Modulation of camptothecin analogs in the treatment of cancer: a review.
The topoisomerase I inhibitors reviewed in this paper are all semisynthetic analogs of camptothecin (CPT). Modulation of this intranuclear enzyme translates clinically in to antitumor activity against a broad spectrum of tumors and is therefore the subject of numerous investigations. We present preclinical and clinical data on CPT analogs that are already being used in clinical practice [i.e. topotecan and irinotecan (CPT-11)] or are currently in clinical development (e.g. 9-aminocamptothecin, 9-nitrocamptotecin, lurtotecan, DX 8951f and BN 80915), as well as drugs that are still only developed in a preclinical setting (silatecans, polymer-bound derivates). A variety of different strategies is being used to modulate the systemic delivery of this class of agents, frequently in order to increase antitumor activity and/or reduce experienced side effects. Three principal approaches are discussed, including: (i) pharmaceutical modulation of formulation vehicles, structural alterations and the search for more water-soluble prodrugs, (ii) modulation of routes of administration and considerations on infusion duration, and (iii) both pharmacodynamic and pharmacokinetic biomodulation.
Kehrer
D F
DF
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, The Netherlands. kehrer@vvdh.azr.nl
Soepenberg
O
O
Loos
W J
WJ
Verweij
J
J
Sparreboom
A
A
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin