ENZYME PATTERN-DIRECTED CHEMOTHERAPY - SYNERGISTIC INTERACTION OF 3-DEAZAURIDINE WITH D-GALACTOSAMINE

  • 1 January 1976
    • journal article
    • research article
    • Vol. 60  (7) , 835-843
Abstract
An experimental approach in which the specialized enzymatic pattern characteristic of the tissue of origin of a tumor might be exploited to target and enhance drug selectivity was tested. The D-galactosamine induced depletion of UTP (primarily a hepatic event) was employed to enhance growth inhibition caused by 3-deazauridine. As predicted, the drug effect was most pronounced in the slower growing, well differentiated rat hepatoma lines where the activities of certain hepatic metabolic pathways and enzymes, though decreased, were still operative. The interactions of D-galactosamine and cytosine arabinoside with 3-deazauridine were examined in vitro in 4 liver tumor cell lines and 2 nonhepatic lines. The effects of D-galactosamine and 3-deazauridine on the growth of the Morris hepatoma cell lines 3924A, 8999S and 8999R were synergistic. On the Novikoff hepatoma and nonhepatic cell lines they were only additive. The combination of 3-deazauridine with cytosine arabinoside gave approximately additive growth inhibition with all cell types, without selective toxicity toward the hepatocellular lines. Results of growth inhibition studies with the combination of D-galactosamine and cytosine arabinoside and combinations of all 3 agents are also presented. These results are analyzed in the context of the regulation of hepatic pyrimidine nucleotide metabolism and the design of enzyme pattern-directed drug selectivity.