FUTURE PERSPECTIVES FOR THE DEVELOPMENT OF P-GLYCOPROTEIN MODULATORS

Resistance to chemotherapeutic agents constitutes one of the major obs tacles to the successful treatment of cancer. While several mechanisms underlying drug resistance have been elucidated, the most widely stud ied mechanism involves the efflux of antineoplastic drugs from cancer cells by P-glycoprotein, the 170 kD glycoprotein product of the MDR-I gene. The observation that several compounds are able to inhibit P-gly coprotein in vitro created optimism that the problem of multidrug resi stance in cancer could be quickly resolved by moving these compounds i nto the clinic. However, despite a large number of clinical trials wit h several different putative Pgp modulators, the value of Pgp modulati on in clinical oncologic practice remains unresolved. While these init ial trials have not answered the question of whether Pgp is an importa nt mechanism of resistance in human cancers, or whether modulation of Pgp is likely to positively impact on the treatment of cancer, they ha ve provided insights regarding the problems inherent in conducting tri als of this nature. These clinical insights, along with knowledge gain ed from continued basic research on drug resistance mediated by Pgp an d related transporters, will form a strong foundation for future resea rch into the role of Pgp and Pgp modulation in the treatment of cancer . The ubiquitous nature of transporters and the high prevalence of tra nsporter substrates among antineoplastic drugs, compel the development of modulators that can be used to prevent or reverse drug resistance.