Characterization of novel semi-synthetic taxanes capable of modulating P-glycoprotein multidrug resistance
Vredenburg, Michael Ryan
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Resistance to a variety of classes of chemotherapeutic agents is termed multi-drug resistance (MDR), and is a result of membrane drug efflux mediated by ATP-binding cassette (ABC) transporters. Cell membrane efflux pumps limit the intracellular accumulation of multiple classes of cancer chemotherapeutic agents, via membrane binding and efflux of the drug. The ATP-dependent cell membrane spanning protein, P-glycoprotein (Pgp) has been the most studied cellular efflux pump. Pgp renders tumor cells resistant to numerous important, often used, chemotherapeutic agents including taxanes. Since paclitaxel and docetaxel are widely used cancer chemotherapeutic agents, my research focused on discovering avenues to overcome Pgp mediated resistance to taxanes, in Pgp expressing breast and colon tumors. The end goal of my thesis work was to evaluate (1) taxane analogues that could overcome Pgp mediated resistance, (2) taxane derived molecules that lack inherent toxicity that could overcome Pgp mediated resistance and increase the intracellular concentrations of other cytotoxic antitumor agents susceptible to Pgp mediated efflux and (3) taxanes that demonstrate low host toxicity that could be dosed in a metronomic fashion to target both the tumor and the nourishing tumor vasculature. Our hypothesis was that through minor alterations in taxane structure and via structure activity relationship studies, excellent candidates for the clinic could be obtained that would not possess Taxol ® 's susceptibility to Pgp. The aims of my thesis work were to (1) assess and understand the in-vitro and in-vivo activity of the semi-synthetic, taxane IDN-5109 (Orataxel) against Pgp expressing, human colon and breast tumors, (2) characterize the mechanism by which IDN-5109 overcomes Pgp mediated multi-drug resistance and conduct structure activity relationship studies, (3) to evaluate tRA96023, a non-toxic, semi-synthetic taxane analogue that lacks a tubulin binding side chain, as an adjunct therapy to (as a drug resistance reversal agent) in the treatment of multi-drug resistant breast and colon tumors, (4) study the well tolerated, semi-synthetic taxane IDN-5390 as an anti-angiogenic taxane that is dosed in-vivo in a daily fashion (metronomic dosing), as opposed to classic chemotherapeutic regimens that use higher doses and significant toxicity recovery periods, against Pgp expressing, multi-drug resistant human colon and breast tumors.