Mécanismes de résistance aux agents cytostatiques

Most of the time, the mechanisms of drug resistance in tumoral cells are multifactorial. The most studied mechanism is the MDR (multi-drug resistance) phenotype, because it is related to major cytostatic drugs like anthracyclins, vinca-alkaloïds and epipodophyllotoxins. MDR is due to the presence of transporter proteins (ABC proteins) that are able to expel drugs of natural origin (xenobiotics). The presence of P-gp, the most studied protein of this family, is of value for predicting drug resistance in acute myeloid leukemia. This explains the use of “modulators” of P-gp like quinine, cyclosporine or PSC833 in this disease. A benefit for the patient is observed only in case of functional P-gp present on the leukemic cells. The role of the other ABC pumps (MRPs, BCRP) is not clearly demonstrated in hematological malignancies. Another important mechanism of resistance is the inhibition of drug-induced apoptosis, due to modification of p53 or proteins of the bcl-2 family. Enzyme modifications are also important in resistance to nucleotide analogs like cytosine arabinoside, largely used in acute leukemia. The use of doses ten-fold higher than the standard dosing allows overcoming resistance to this drug.