Arlette Gamier-Suillerot Pages 69 - 82 ( 14 )
Up to now , the only h ope to cure systemic cancers such as leukemia and lymphoma and unifocal tumours that have spread by metastasis resides in systemic treatment s such as chemotherapies and Immunotherapies. Unfortunately, the appearance of cell populations resistant to multidrug-based chemotherapy constitutes the major problem to achieve cures in the patients. Multidrug resistance (MDR) confers upon cells ability to withstand exposure to lethal doses of many structurally unrelated antmeoplast1c agents. MDR IS assocm ted w1th decreased drug accumulation resulting from enhanced drug efflux. This is correlated with the presence of a membrane protein, P-glycoprotein, which pump s drugs out of cells thus reducing their cytotoxicity. The search for new compounds able to overcom e MDR is of prime importanc e in the clinic . One of the strategies to reverse MDR is based on the design an synthesis of non-cross-resistant analogs of MDR drugs. The activity of a drug depend s upon its intracellular concentration which Itself depend son the kmet1csof influx and efflux of the drug across the cell membrane . Analysis of the literature and our own data show that m the drug design of new antitumor drugs able to overcome MDR , it seems more efficient to consider the modulation of the parameter s that will lead to an increase of the kinetics of uptake than those which could lead to a lowering of the kinetics of the P-gly coprotein-mediated efflux.