MODULATION AND PREVENTION OF MULTIDRUG-RESISTANCE BY INHIBITORS OF P-GLYCOPROTEIN

Intrinsic and acquired multidrug resistance (MDR) in many human cancer s may be due to expression of the multidrug transporter P-glycoprotein (Pgp), which is encoded by the mdr1 gene. There is substantial eviden ce that Pgp is expressed both as an acquired mechanism (e.g., in leuke mias, lymphomas, myeloma, and breast and ovarian carcinomas) and const itutively (e.g., in colorectal and renal cancers) and that its express ion is of prognostic significance in many types of cancer. Clinical tr ials of MDR modulation are complicated by the presence of multiple-dru g-resistance mechanisms in human cancers, the pharmacokinetic interact ions that result from the inhibition of Pgp in normal tissues, and, un til recently, the lack of potent and specific inhibitors of Pgp. A lar ge number of clinical trials of reversal of MDR have been undertaken w ith drugs that are relatively weak inhibitors and produce limiting tox icities at doses below those necessary to inhibit Pgp significantly. T he advent of newer drugs such as the cyclosporin PSC 833 (PSC) provide s clinicians with more potent and specific inhibitors for MDR modulati on trials. Understanding how modulators of Pgp such as PSC 833 affect the toxicity and pharmacokinetics of cytotoxic agents is fundamental f or the design of therapeutic trials of MDR modulation. Our studies of combinations of high-dose cyclosporin (CsA) or PSC 833 with etoposide, doxorubicin, or paclitaxel have produced data regarding the role of P gp in the clinical pharmacology of these agents. Major pharmacokinetic interactions result from the coadministration of CsA or PSC 833 with MDR-related anticancer agents (e.g., doxorubicin, daunorubicin, etopos ide, paclitaxel, and vinblastine). These include increases in the plas ma area under the curve and half-life and decreases in the clearance o f these cytotoxic drugs, consistent with Pgp modulation at the biliary lumen and renal tubule, blocking excretion of drugs into the bile and urine. The biological and medical implications of our studies include the following. First, Pgp is a major organic cation transporter in ti ssues responsible for the excretion of xenobiotics (both drugs and tox ins) by the biliary tract and proximal tubule of the kidney. Our clini cal data are supported by recent studies in mdr-gene-knockout mice. Se cond, modulation of Pgp in tumors is likely to be accompanied by alter ed Pgp function in normal tissues, with pharmacokinetic interactions m anifesting as inhibition of the disposition of MDR-related cytotoxins (which are transport substrates for Pgp). Third, these pharmacokinetic interactions Of Pgp modulation are predictable if one defines the pha rmacology of the modulating agent and the combination. The interaction s lead to increased toxicities such as myelosuppression unless doses a re modified to compensate for the altered disposition of MDR-related c ytotoxins. Fourth, in serial studies where patients are their own cont rols and clinical resistance is established, remissions are observed w hen CsA or PSC 833 is added to therapy, even when doses of the cytotox in are reduced by as much as 3-fold. This reversal of clinical drug re sistance occurs particularly when the tumor cells express the mdr1 gen e. Thus, tumor regression can be obtained without apparent increases i n normal tissue toxicities. In parallel with these trials, we have rec ently demonstrated in the laboratory that PSC 833 decreases the mutati on rate for resistance to doxorubicin and suppresses activation of mdr 2 and the appearance of MDR mutants. These findings suggest that MDR m odulation may delay the emergence of clinical drug resistance and supp ort the concept of prevention of drug resistance in the earlier stages of disease and the utilization of time to progression as an important endpoint in clinical trials. Pivotal phase III trials to test these c oncepts with PSC 833 as an MDR modulator are under way or planned for patients with acute myeloid leukemias, multiple myeloma, and ovarian c arcinoma.