Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein

Abstract

Intrinsic and acquired multidrug resistance (MDR) in many human cancers may be due to expression of the multidrug transporter P-glycoprotein (Pgp), which is encoded by the mdr1 gene. There is substantial evidence that Pgp is expressed both as an acquired mechanism (e.g., in leukemias, lymphomas, myeloma, and breast and ovarian carcinomas) and constitutively (e.g., in colorectal and renal cancers) and that its expression is of prognostic significance in many types of cancer. Clinical trials of MDR modulation are complicated by the presence of multiple-drug-resistance mechanisms in human cancers, the pharmacokinetic interactions that result from the inhibition of Pgp in normal tissues, and, until recently, the lack of potent and specific inhibitors of Pgp. A large number of clinical trials of reversal of MDR have been undertaken with drugs that are relatively weak inhibitors and produce limiting toxicities at doses below those necessary to inhibit Pgp significantly. The advent of newer drugs such as the cyclosporin PSC 833 (PSC) provides clinicians with more potent and specific inhibitors for MDR modulation trials. Understanding how modulators of Pgp such as PSC 833 affect the toxicity and pharmacokinetics of cytotoxic agents is fundamental for 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 Pgp 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, etoposide, paclitaxel, and vinblastine). These include increases in the plasma area under the curve and half-life and decreases in the clearance of 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 tissues responsible for the excretion of xenobiotics (both drugs and toxins) by the biliary tract and proximal tubule of the kidney. Our clinical data are supported by recent studies in mdr-gene-knockout mice. Second, modulation of Pgp in tumors is likely to be accompanied by altered Pgp function in normal tissues, with pharmacokinetic interactions manifesting 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 pharmacology of the modulating agent and the combination. The interactions lead to increased toxicities such as myelosuppression unless doses are modified to compensate for the altered disposition of MDR-related cytotoxins. Fourth, in serial studies where patients are their own controls and clinical resistance is established, remissions are observed when CsA or PSC 833 is added to therapy, even when doses of...

The involvement of hypoxia‐inducible factor‐1α in the susceptibility to γ‐rays and chemotherapeutic drugs of oral squamous cell carcinoma cells

“…[18][19][20] As is well known, P-gp makes tumor cells highly resistant to a variety of anticancer drugs, and the expression of P-gp is related to the high growth activity of the tumor cells and the poor prognosis of the tumor. 16,17 The fact that P-gp expression is regulated by HIF-1a suggests that HIF-1a expression is involved in chemo-resistance of OSCC cell lines. The present study revealed that the expression levels of P-gp increased in accordance with the HIF-1a expression levels in the 4 OSCC cell lines examined, and the increase of P-gp was intimately associated with the increase of the efflux of CDDP and 5-FU.…”

“…16,17 MDR1 gene expression with subsequent functional P-gp expression is markedly upregulated in a HIF-1-dependent manner in response to hypoxia. 18,19 Hypoxia-elicited MDR1 expression resulting from HIF-1 activation depends at least in part on signaling via activation of JNK.…”

Dexrazoxane significantly impairs the induction of doxorubicin resistance in the human leukaemia line, K562

“…Very few studies have addressed the approach of resistance prevention, most being concerned with resistance reversal. Sikic et al (1997) have shown that the MDR modulator PSC 833 can decrease the mutation rate for resistance to doxorubicin by suppressing the activation of the MDR1 gene and the appearance of MDR mutants. Our findings of reduced MDR1 expression in sublines grown in the presence of both doxorubicin and dexrazoxane support this theory.…”

The Effect of P-Glycoprotein Inhibition and Activation on the Absorption and Serum Levels of Cyclosporine and Tacrolimus in Rats

“…Efflux transporter molecules, particularly P-gp, alter the plasma concentration of the drugs by pumping them back into the intestinal lumen [1]. However, the function of P-gp may be affected by some modulating or inhibiting agents [10]. Verapamil, which increased the intestinal absorption of cyclosporine and tacrolimus in this study, has previously been reported to be a substrate of P-gp when used in low doses and to strongly inhibit P-gp when used high doses [8].…”