CANCER CHEMOTHERAPY AT TRANSCRIPTIONAL LEVEL

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The aim of the proposed research is to study the chemotherapy of cancer at the level of gene transcription. To achieve this goal RNA prolymerase and its initiation factor will be purified from chicken myeloblastosis leukemic cells to homogeneity. The purified enzymes from leukemic as well as normal cells will be studies with regard to their properties, functions, subunit structures and reconstitution, and produce RNA analysis. This is expected to provide further evidence for a leukemic-specific RNA polymerase. The purified RNA polymerase initiation factor will be studied to determine its properties, physiological functions and the mechanism by which it stimulates the initiation of RNA synthesis. Attempts will also be made to determine its activity in other normal and malignant cells (normal chicken myeloblast cells, avian myeloblastosis viral nonproducer cell line, human leukemic and human lymphoma cell lines). These studies will reveal whether the factor is specific for the gene expression of cancerous growth or it is universally required for the RNA synthesis of eukaryotic cells. Concurrently several currently used and newer experimental antineoiplastic agents will be studied for their inhibitory effects on neoplastic gene transcription. The agents used in this proposal include adriamycin and 6-mercaptopurine and their derivative (AD 32, AD 41, AD 143, and methylated mercaptopurines). The ultimate goal of the proposed research is to determine if it is possible to arrest neoplastic expression of cancer cells at transcriptional level by selectively inhibiting the activity of malignant RNA polymerase (or its regulatory factor) without affecting the normal enzyme.