Taxanes are highly promising agents for the treatment of human cancers. However, the efficacy of taxane therapy using either paclitaxel or docetaxel may be limited due to resistance to these drugs. Clinical resistance to both paclitaxel and docetaxel is often associated with the amplification of P-glycoprotein (Pgp); MRP and LRP appear to be less of a factor in taxane resistance. Several Pgp positive tumor cells demonstrate cross-resistance to paclitaxel by decreasing their intracellular drug levels. Clearly, second generation taxanes that have improved therapeutic activity against multi-drug resistant (MDR1 gene mediated) tumors would be advantageous. To circumvent Pgp-associated multi-drug resistance to paclitaxel, we are proposing two major strategies. First, the development of cytotoxic analogs of paclitaxel that are not substrates for Pgp. Second, the development of non- cytotoxic taxane-based reversal agents (tRAs) which modulated Pgp- mediated efflux of active agents. In the first strategy, we will evaluate new taxanes synthesized by Dr. Ojimi, SUNY Stony Brook, with potentially higher cytotoxic activity against Pgp-resistant human cancer cell lines as compared with either paclitaxel or docetaxel. To this end, we have evaluated several hundred taxanes and have selected lead compounds (i.e., IDN5109, IDN5111, and fluoro-taxanes 97003/4) for further pre-clinical drug development. These agents have demonstrated up to 30-fold higher anti-tumor activity than either paclitaxel or docetaxel against mdr1 Pgp containing human tumor cell lines (e.g., MDA435/LCC6/MDR1 breast ca., UO31 renal ca. and HCT15 colon ca.). Recent results, from our laboratory and others, have indicated that IDN5109 AND idn511, in comparison to paclitaxel, display equivalent efficacy against drug-sensitive, human tumor xenografts in mice and significantly improved activity against multi-drug resistant tumors. In the second strategy, we are evaluating tRAs and developing their combinations with paclitaxel, new-taxanes and/or doxorubicin for the treatment of Pgp- resistant tumors. We have recently discovered several tRAs (e.g., 96023) which in combination with paclitaxel or IDN5109, resulted in an additional 20 to 30-fold increase synergy) against multi-drug resistant (Pgp positive) tumor cell lines. We will now devote significant effort to defining and optimizing the preclinical anti-tumor spectrum for these new agents and significant effort to defining and optimizing the pre- clinical anti-tumor spectrum for these new agents and treatment. New in vivo studies have demonstrated significant therapeutic efficacy in nude athymic mice for a combination of IDN5109 with 96023 against the MDA435/LCC6/MDR1 breast tumor xenograft, a highly drug resistant tumor. Pharmacokinetic approaches will be used to investigate the cellular uptake and retention of new taxanes, as well as the modulation of Pgp- mediated efflux of drugs by tRA, both in vivo and in vitro. Using tRNA 96023 as a selecting agent, clothes containing mutated mdr sequences have recently been generated which will be used in the mapping of the taxane-binding site within Pgp. This and other data accumulated with these new semi-synthetic taxanes will be used to generate three- dimensional structural activity relationships (Q-SAR), elucidating the molecular interactions of these taxanes and aiding our design of more selective compounds. It is anticipated that this research will lead to the discovery and development of new taxanes and reversal agents with significant anti-tumor activity against multi-drug-resistant tumors have mdr1 Pgp expression.
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