POINT MUTATIONS IN THE MDR1 PROMOTER OF HUMAN OSTEOSARCOMAS ARE ASSOCIATED WITH IN-VITRO RESPONSIVENESS TO MULTIDRUG-RESISTANCE RELEVANT DRUGS

Among human sarcomas, osteosarcomas usually display high intrinsic mdr 1 expression while malignant fibrous histiocytomas (MFH) do not. A com parative polymerase chain reaction (PCR)-based sequence analysis of th e mdr1 promoter revealed point mutations in seven out of nine osteosar comas at nucleotides + 103 (2 cases T-->C) and +137 (5 cases G-->T). N o changes were seen in eight MFHs. When COS cells transfected with CAT constructs containing the T-->C chloramphenicol acetyltransferase mut ant mdr1 promoters were treated with vincristine or doxorubicin, expre ssion of the CAT gene was enhanced to a higher extent than with constr ucts containing wild-type or G-->T-mutant mdr1 promoters. We suggest t hat there is a correlation between the type of mdr1 promoter mutation and responsiveness to MDR relevant drugs.