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RESEARCH PRODUCT

Role of P-Glycoprotein for Resistance of Tumors to Anticancer Drugs: From Bench to Bedside

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Success of cancer chemotherapy is limited by simultaneous resistance towards many anticancer drugs making clinical combination therapy protocols less efficient. P-glycoprotein represents an efflux pump of the ABC transporter family, which recognizes and extrudes anticancer drugs of diverse chemical classes and biochemical functions. The P-glycoprotein-mediated profile of cross-resistance has been termed multidrug resistance (MDR). In our investigations, we focused on MDR of in vivo tumor lines maintained in mice. The development of in vivo resistance towards anthracyclines (doxorubicin, daunorubicin) in L1210 and S180 ascites tumor lines was accompanied with decreased uptake and increased efflux of the fluorescent dye rhodamine 123, overexpression of P-glycoprotein as well as MDR1 mRNA overexpression and MDR1 gene amplification. In addition to acquired multidrug resistance in these syngeneic mouse tumor lines, we investigated inherent drug resistance in human lung xenograft tumors transplanted to nude mice. Drug resistance in these xenografts was also associated with overexpression of P-glycoprotein and MDR1 mRNA, but without MDR1 gene amplification. Furthermore, we explored P-glycoprotein expression in clinical biopsies of diverse tumor entities (leukemia, lung cancer, breast cancer, cervical carcinoma, endometrial carcinoma. nephroblastoma, renal cell carcinoma) and found that high levels of P-glycoprotein expression correlated with pretreatment with chemotherapy, drug resistance, and failure to achieve complete remission. During the past years, a wealth of publications worldwide confirmed a role of the P-glycoprotein for clinical treatment refractoriness and as an unfavorable prognostic factor for survival time of patients.