| Overexpression of ATP-binding cassette (ABC) transport proteins, including P-glycoprotein (Pgp), multidrug resistance protein (MRP-1), and breast cancer resistance protein (BCRP), is a common mechanism of multidrug resistance (MDR) in cancer. Based on the importance of ABC protein-mediates MDR in cancer, we examined several means to overcome MDR through the development of noncytotoxic paclitaxel analogs that modulate MDR function or through the synthesis and selection of anthracycline analogs that are not affected by these membrane pumps.; The taxanes paclitaxel and docetaxel are strong substrates for Pgp, but are weak substrates for MRP-1 and are not effluxed by BCRP. Taxane-based drug resistance reversal agents (tRAs) are semi-synthetic, noncytotoxic modulators that retain the ability to bind to Pgp, but lack cytotoxicity by virtue of removal of the C-13 side chain responsible for tubulin binding. We investigated a series of tRAs for broad-spectrum modulating ability, identified lead compounds, tRAs 98006 and 99020, for clinical development, compared their activities to those of “established” modulators and examined their mechanism of MDR modulation and structure-activity relationships.; Similarly, members of the anthracycline family are substrates for efflux by Pgp, MRP-1 and BCRP. Anthracycline efflux by BCRP depends on the amino acid at position 482: wild-type protein with arginine does not efflux doxorubicin or daunorubicin, whereas mutant BCRP with threonine or guanine does. Two analogs of doxorubicin, WP744 and WP769, were studied for their ability to bypass each MDR pump in leukemia/myeloma and breast cancer model systems. Both agents had significantly reduced resistance profiles in comparison to the anthracyclines in current clinical use. They both demonstrated tumor cell growth inhibition in the low nanomolar range in both parental and MDR-overexpressing cell lines—a desirable property for a potential clinical agent. Combination of either of these new anthracyclines with the lead broad-spectrum tRA, tRA 98006, further decreased multidrug resistance conferred by the MDR pumps.; In conclusion, both the noncytotoxic modulating tRAs and the cytotoxic anthracycline analogs, WP744 and WP769, are promising agents for clinical application. Therapeutic modulation or bypassing of MDR efflux pumps may lead to improvements in antitumor therapy, enabling physicians to overcome resistance, which is the greatest obstacle to successful cancer chemotherapy. |
