REPORT ON MULTIDRUG-RESISTANCE IN ONCOLOG Y AND HEMATOLOGY

Background: Drug resistance, which often occurs also during chemothera py, is yet a great obstacle to the success of the human malignancies t reatments. Among many possible mechanisms of drug resistance (biologic al, biochemical, kinetic or pharmacological), both typical and atypica l 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 dep end on the expression of an 170 KD protein, the P-170 or P-glycoprotei n, that acts as an energy-dependent pump removing possible toxic agent s, including antiblastic drugs, from the cell. High levels of the mdr1 expression have been found in normal adrenal gland, kidney, colon, je junum and liver, whereas low levels were detected in skin, muscle, bra in, nervous system and bone marrow, where CD34+ stem cells are P-170 p ositive. Moreover, heat shock proteins or oncogene transfection, cell differentiation or proliferation could modulate the P-glycoprotein exp ression: low protein levels were described in resting B lymphocytes an d monoblast cells, whereas plasmacells and monocytes express higher P- 170 levels. On the contrary, more differentiated myeloid cells show a low MDR1 expression. Methods: Since normal kidney and haematopoietic c ells physiologically express P-170 protein, 20 renal cell carcinomas a t the surgery and many hematological patients were evaluated in this s tudy, including acute leukemias, chronic myeloid, chronic lymphocytic leukemias and multiple myeloma. Moreover we evaluated the MDR expressi on in 23 non small cell lung cancers. The MDR1 gene expression was sho wed by RT-PCR assays, whereas the P-170 protein was detected by immuno logical and cytofluorometric reactions employing the C-219 and JSB1 mo noclonal antibodies. Results and Conclusions: 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 chemothera py, with an higher positivity in monoblastic types; on the contrary, a ll lymphoblastic leukemias resulted P-170 negative and only 2 of 13 pa tients resulted drug resistant. A very high MDR expression was showed in chronic disorders: in the lymphocytic ones, only samples CD5/CD19 n egative (3 of 42) resulted P-170 negative, confirming the basal MDR ph enotype expression. In these cases, nevertheless, the protein expressi on was not related to the treatment response. Also in the multiple mye loma patients, no relations between clinic parameters and P-170 expres sion were found; however a significant relationship between treatment response and P170 expression was found. In kidney and lung cancer samp les examined, a low percentage of positive samples was detected withou t any relationship to the evaluated clinical parameters.