[Treatment of multidrug resistance in oncology and hematology]

Drug resistance, which often occurs also during chemotherapy, is yet a great obstacle to the success of the human malignancies treatments. Among many possible mechanisms of drug resistance (biological, biochemical, kinetic or pharmacological), both typical and atypical multidrug-resistance (MDR) have been extensively studied. Multidrug resistance is the phenomenon whereby the development of resistance to one drug is accompanied by the simultaneous development of resistance to a variety of structurally unrelated drugs. Typical MDR seems to depend on the expression of an 170 KD protein, the P-170 or P-glycoprotein, that acts as an energy-dependent pump removing possible toxic agents, including antiblastic drugs, from the cell. High levels of the mdr1 expression have been found in normal adrenal gland, kidney, colon, jejunum and liver, whereas low levels were detected in skin, muscle, brain, nervous system and bone marrow, where CD34+ stem cells are P-170 positive. Moreover, heat shock proteins or oncogene transfection, cell differentiation or proliferation could modulate the P-glycoprotein expression: low protein levels were described in resting B lymphocytes and monoblast cells, whereas plasma cells and monocytes express higher P-170 levels. On the contrary, more differentiated myeloid cells show a low MDR1 expression.

Since normal kidney and haematopoietic cells physiologically express P-170 protein, 20 renal cell carcinomas at the surgery and many hematological patients were evaluated in this study, including acute leukemias, chronic myeloid, chronic lymphocytic leukemias and multiple myeloma. Moreover we evaluated the MDR expression in 23 non small cell lung cancers. The MDR1 gene expression was showed by RT-PCR assays, whereas the P-170 protein was detected by immunological and cytofluorometric reactions employing the C-219 and JSB1 monoclonal antibodies.

Of the 32 acute leukemia patients, 15 (47%) resulted P-170 positive; 14 out of the 15 positive, but 12 out of the 17 negative cases were resistant to the chemotherapy, with an higher positivity in monoblastic types; on the contrary, all lymphoblastic leukemias resulted P-170 negative and only 2 of 13 patients resulted drug resistant. A very high MDR expression was showed in chronic disorders: in the lymphocytic ones, only samples CD5/CD19 negative (3 of 42) resulted P-170 negative, confirming the basal MDR phenotype expression. In these cases, nevertheless, the protein expression was not related to the treatment response. Also in the multiple myeloma patients, no relations between clinic parameters and P-170 expression were found; however a significant relationship between treatment response and P170 expression was found. In kidney and lung cancer samples examined, a low percentage of positive samples was detected without any relationship to the evaluated clinical parameters.