[Cancers of the kidney: multiple drug resistance]

The treatment of kidney cancers raise difficult problems. Usual treatments combining surgery, radiation therapy, chemotherapy and hormonotherapy are poorly effective. The immunotherapy gave only an objective response rate of 25% in metastatic renal cell carcinomas. Among cellular resistance mechanisms of renal carcinoma, the multi-drug resistance (MDR) phenotype and the glutathione redox cycle have been studied. The MDR is related to overexpression of a 170 kDa membrane glycoprotein, the so-called P glycoprotein (Pgp). This protein is a pump able to extrude from cytoplasm drugs with various structures and mechanisms. The Pgp is encoded by the MDR1 gene expression is very low in most of the normal tissues, except in colon, liver and kidney. In these tissues, the Pgp would ensure a detoxifying function related to cellular toxic compounds, elimination or transfer of molecules synthesized by the cells. According to the intrinsic resistance of renal carcinoma, MDR1 gene expression has been determined. Approximately, 80% of fresh kidney cancer before chemotherapy express resistance phenotype. Reversal compounds specifically inhibiting Pgp were found, such as verapamil, cyclosporin or quinidine. Unfortunately, the two first compounds give cardiac toxicity and immunosuppression, respectively. So far, clinical trials have not been demonstrating, but no biological resistance measures were determined, in parallel. According to the multifactorial resistance the association of reversals to chemotherapy should be introduced in clinical trials, in correlating clinical response to biological mechanisms of resistance.