Summary We evaluated the MDR1 expression levels in 77 osteosarcomas and investigated whether MDR1 mRNA expression in osteosarcomas varies with location within the tumour, following chemotherapy, or after metastasis. We modified the semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) assay to determine accurately the levels of MDR1 mRNA expression in clinical specimens. We show that specimens collected from multiple locations in six tumours revealed very little variation in MDR1 expression suggesting that the levels of MDR1 in these tumours do not vary greatly with location within the tumour mass. In a comparison of pre and post-chemotherapy specimens it was found that MDR1 levels did not change appreciably following chemotherapy in 16 of 20 cases. In addition, in eight of ten specimens obtained before and after metastasis, the amount of MDR1 mRNA was found to remain relatively constant despite metastatic spread. Thus, many osteosarcomas exhibited intrinsic expression of MDRI mRNA before multidrug regimens which invariably included doxorubicin and, in most cases, MDR1 expression was not induced following chemotherapeutic treatment. Our results suggest that some osteosarcoma patients may have primary tumours which are resistant to doxorubicin. These individuals may benefit from different chemotherapeutic regimens, e.g. the addition of MDR reversal agents.
Summary:The development of several types of human tumors is related to amplification of genes that are involved in cell growth. The protein products of these genes give the cells a selective growth advantage. The q13-15 region of chromosome 12 is frequently altered in human sarcomas, and the SAS gene has been identified in an amplification unit mapping to this region. Gene amplification of SAS was analyzed to determine the frequency of genetic alteration of this gene in osteosarcoma. Using Southern blot analysis as well as quantitative polymerase chain reaction, SAS was found to be amplified in 10 (36%) of 28 osteosarcomas. Gene amplification was evaluated in subtypes of osteosarcoma. All seven surface osteosarcomas displayed amplified SAS. In contrast, SAS was amplified in only two (13%) of 15 intramedullary osteosarcomas. The finding that all surface osteosarcomas demonstrated SAS gene amplification suggests that this gene may play a role in the pathogenesis of osteosarcoma subtypes and that surface osteosarcoma may be genetically different from high-grade intramedullary osteosarcoma.-
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