Ordered biochemical program of gene expression in cancer cells.

Our introduction of the molecular correlation concept and the key enzyme concept and the use of biologically meaningful tumor models and control systems resulted in the discovery of an ordered pattern of enzymic and metabolic imbalance and the elucidation of the linkage with transformation and progression. We showed that the biochemical and enzymic pattern of alterations was the result of a reprogramming of gene expression that was both quantitative and qualitative and was characteristic to neoplasia, since no similar pattern of imbalance was observed in any of the control normal, regenerating, or differentiating tissues. Important aspects of gene logic were identified. These include demonstration of operation of reciprocal control of activities of opposing key enzymes and antagonistic pathways of synthesis and catabolism in pyrimidine, purine, ornithine, and carbohydrate metabolism and recently in signal transduction. The extent of increase in the activities of key enzymes of pyrimidine and purine biosynthesis related to the absolute activity of the enzymes in resting liver. The qualitative alterations in gene expression included the isozyme shift of key regulatory enzymes. We identified a segment of gene expression that is essential for neoplasia. We pointed out the selective advantages that reprogramming of gene expression confers to cancer cells. Understanding these alterations in the enzymology and biochemistry of cancer cells made it possible to identify potentially sensitive targets for anticancer chemotherapy. In recent clinical studies we targeted the increased IMP dehydrogenase activity in leukemic blast cells by an inhibitor drug, tiazofurin, and achieved 77% responses, including complete remissions.