The purpose of this proposal is to further explore the significance of multidrug resistance (MDR) -in human cancers. Increasing evidence indicates that expression of the mdr1 gene contributes to clinical resistance to chemotherapy. Therapeutic trials with verapamil or cyclosporine as modulators of MDR are encouraging particularly for hematolymphoid malignancies, but also reveal major limitations and questions. An important issue is the extent to which MDR modulation will affect the disposition of MDR-related cytotoxins. Data on drug interactions in these trials have led to the hypothesis that the multidrug transporter, P-glycoprotein (P-gp), has a central role in the excretion of MDR-related anticancer agents as well as many other drugs. The implications of P-gp inhibition on toxicity to normal tissues also need to be further defined, with regard to actions of the modulator alone and the combined modulator and cytotoxin. We propose two overall Specific Aims:
Specific Aim 1 : To conduct clinical trials of MDR modulation. These include Phase I trials of the cyclosporin PSC 833 with single agents (etoposide, paclitaxel, doxorubicin); and combination therapies for acute myeloid leukemia (AML) and non-Hodgkin's lymphoma. Primary Phase ll targets are AML, lymphomas, ovarian, and breast cancers. If these demonstrate reversal of resistance, trials will also be performed in colorectal and renal carcinomas. Similar studies with new MDR modulators will involve dexniguldipine, the acridonecarboxamide GF120918, and a verapamil analogue, pending -completion of animal toxicology and other preclinical data. We will evaluate their in vitro efficacy against 4 classes of MDR-related cytotoxins, potency in relation to achievable blood levels, and bioavailability in plasma. Pharmacokinetic studies will introduce compartmental methods to further define drug interactions and validation Of optimal sampling strategies with Bayesian estimations.
Specific Aim 2 : To study mdr1 and related drug resistance gene expression in human cancers. These studies will be an integral part of the Phase I and II trials. Reverse transcriptase polymerase chain reaction (rtPCR), immunohistochemistry, and flow cytometry will be used to assess the expression and function of the mdr1 gene. This methodology will be extended to investigate other potential mechanisms of resistance for MDR- related agents (mrp, topoII, bcl-2, p53) in patients' tumors. Studies in lymphoma and ovarian tissue banks with clinical databases will explore the prognostic roles of these mechanisms in multivariate analyses. A novel methodology of 99Tc-Sestamibi imaging will be used to evaluate P-gp function without and with a modulator in patients' tumors in vivo.
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