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. We have previously shown that DNA-dependent RNA polymerase II in chicken myeloblastosis leukemic cells is different both quantitatively and qualitatively from that in normal chicken bone marrow cells. We have also isolated a protein factor from the chicken leukemic cells, whch stimulates the initiation of in vitro RNA synthesis by RNA polymerase II. We propose to further purify the RNA polymerase and its initiation factor to homogeneity. The purified enzymes from leukemic as well as normal cells will be studied with regard to their properties, functions, subunit structures and reconstruction, and analysis of their product RNA. 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 meloblast cells, avian myeloblastosis viral non-producer cell line, human leukemic and human blyphoma 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. We propose to continue our studies on several currently used and newer experimental antineoplastic agents for thier inhibitory effects on neoplastic gene transcription, as well as the biochemical mechanisms of the inhibition. The agents used in this proposal include cytosine arabinoside, notrosourea compounds, adriamaycin and its derivatives (AD 32, AD 41 and AD 142), 6-mercaptopurine and its methylated derivatives. 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.