The long-term objective of this research is to elucidate the mechanisms of chemical carcinogenesis in the human uroepithelium with the hope that this knowledge can be used to develop improved strategies to prevent, diagnose, or treat human bladder cancers. The immediate goal of the proposed studies is to analyze the role of alternations in ras cellular proto-oncogenes in transformation in vitro of human uroepithelial cells (HUC), and to relate these findings to multi-stage bladder cancers in vivo. The rationale for studying ras genes in haman bladder cancers is based on the following. (1) Activated ras cellular proto-oncogenes have been idenfified in human bladder cancers. (2) ras proto- oncogenes are activiated by point mutations in rodent cells transformed in vivo and in vitro by some chemical carcinogens including NMU and MCA, which cause bladder cancer in rodents.
The specific aims are: (1) to determine if transformants of HUC generated in vitro by treatment of HUC with bladder carcinogens (e.g., NMU, MCA, and arylamine compounds) have alterations in ras genes which can be detected by molecular genetic analysis; (2) to determine if transfection in vitro of HUC or superficial transitional carcinoma cells by the mutated c-Ha-ras-1 gene from the EJ/T24 human bladder cancer line alone, or together with an oncogene that immortalizes cells (e.g., c-myc), results in neoplastic transformation; and (3) to determine the nature and frequency of alterations in ras genes in metastases of human bladder cancers. The significance of these studies is that they directly address critical questions concerning the etiological role of alterations in ras genes in human bladder carcinogenesis using suitable carcinogens and a relevant human epithelial cell culture system.
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