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Susan Bates, M.D.
Reversal of Drug Resistance: Clinical and Laboratory Approaches
Achieving a clinical response to chemotherapy has proven to be simple in some diseases, and almost impossible in others. Our laboratory focus has been on understanding multidrug resistance, which can be broadly defined as the simultaneous resistance to a variety of chemically unrelated chemotherapeutic agents. This multidrug resistance is present at the time of diagnosis in some tumor types, such as in renal cell carcinoma, or occurs following one or more courses of chemotherapy in more responsive diseases, such as breast cancer. As a result of this focus on mechanisms which mediate multidrug resistance, we have examined resistance mediated by membrane transporters as well as by intracellular survival mechanisms. Our goal is to identify antineoplastic agents which circumvent resistance, to use alone or in combination with other anticancer agents.
The most widely examined mechanism of this multidrug resistance is that which is due to the overexpression of P-glycoprotein, the membrane transporter that mediates active outward efflux of antineoplastic agents. We have studied the role that this transporter plays in clinical drug resistance and have pursued agents that are able to block the transport and so overcome resistance. Recently, a new multidrug resistance transporter, ABCG2, was cloned in our laboratory from human breast cancer and human colon cancer cells highly resistant to mitoxantrone. These cells express high levels of ABCG2, a half-transporter molecule. ABCG2 confers resistance to several important clinical agents including irinotecan and topotecan, mitoxantrone, and an agent currently in clinical development, flavopiridol. Recently, we identified mutations at amino acid 482 that confer altered substrate specificity. Cells with mutation at this residue have a gain of function mutation, resulting in transport of anthracyclines, while cells with the wild-type sequence have a narrower substrate spectrum. Several inhibitors of ABCG2 have been identified and studies are currently aimed at preclinical development. Identification of this transporter will lead rapidly to studies designed to measure its prevalence in human cancer, determine its clinical significance, and evaluate inhibition of resistance in the clinic.
Our second area of effort is in the development of the depsipeptide FR901228, a novel histone deacetylase inhibitor currently in clinical trials. Our interest in this agent began when we noted depsipeptide to be a substrate for P-glycoprotein-mediated drug efflux. Cells that express high levels of P-glycoprotein are thousands-fold resistant to depsipeptide; one goal is to add a P-glycoprotein inhibitor to depsipeptide for clinical development. In addition, we have pursued the mechanisms responsible for the cell cycle arrest that results from the addition of depsipeptide to sensitive cells. In a phase 2 trial, we have observed that depsipeptide is able to induce durable clinical responses in patients with cutaneous and peripheral T cell lymphoma. We have established non-Pgp-expressing depsipeptide-resistant cell lines in the laboratory with the goal of understanding mechanisms of resistance to depsipeptide.
This page was last updated on 3/12/2013.