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 mdr1 expression while malignant fibrous histiocytomas (MFH) do not. A comparative polymerase chain reaction (PCR)-based sequence analysis of the mdr1 promoter revealed point mutations in seven out of nine osteosarcomas at nucleotides +103 (2 cases T-->C) and +137 (5 cases G-->T). No changes were seen in eight MFHs. When COS cells transfected with CAT constructs containing the T-->C chloramphenicol acetyltransferase mutant mdr1 promoters were treated with vincristine or doxorubicin, expression of the CAT gene was enhanced to a higher extent than with constructs containing wild-type or G-->T-mutant mdr1 promoters. We suggest that there is a correlation between the type of mdr1 promoter mutation and responsiveness to MDR relevant drugs.
Laboratory of Drug Discovery Research and Development, National Cancer Institute, Frederick Cancer Research and Development Center, MD 21702-1201.
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Stein
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Walther
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Wunderlich
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D001483:Base Sequence; D015152:Blotting, Northern; D001859:Bone Neoplasms / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D018219:Histiocytoma, Benign Fibrous / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D012516:Osteosarcoma / Q000235:genetics*; D017354:Point Mutation / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014750:Vincristine; D004317:Doxorubicin