Mechanisms of cellular resistance to camptothecins.
The camptothecins are among the most promising antitumor agents endowed with a unique mechanism of action, because they act through inhibition of DNA topoisomerase I, an enzyme involved in regulating critical cellular functions including DNA replication, transcription and recombination. On the basis of the pharmacological interest of camptothecins in cancer chemotherapy, medicinal chemistry has played a crucial role in the development of novel analogs, and recently some compounds have emerged as promising agents for clinical evaluation. A major limitation to the clinical efficacy of camptothecin-containing therapies is represented by drug resistance. As with other cytotoxic drugs, clinical resistance to camptothecins may be a multifactorial phenomenon likely involving pharmacological and tumor-related factors. An additional problem in understanding clinically relevant resistance mechanisms is the observation that preclinical cell/tumor models may be not adequately predictive of clinical resistance. Here, we review the mechanisms of cell sensitivity/resistance to camptothecins and current approaches to overcome specific mechanisms, either by chemical modifications or by combination with modulating agents. In particular, the realization that most camptothecins are substrates for ATP binding cassette transporters has stimulated efforts in molecular design of novel non-cross-resistant analogs. Finally, a better understanding of the mechanism of cell response at a cellular level could help in defining new strategies to overcome resistance as well as chemical features required for efficacy.
Beretta
G L
GL
Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy. paola.perego@istitutotumori.mi.it
Perego
P
P
Zunino
F
F
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000493:pharmacokinetics; D002166:Camptothecin / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*
D018528:ATP-Binding Cassette Transporters; D002166:Camptothecin