We tested 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. In the present work, the D-
galactosamine-induced depletion of
uridine 5'-triphosphate (primarily a hepatic event) was employed to enhance the growth inhibition caused by
3-deazauridine. As predicted, the
drug effect was most pronounced in the slower growing, well differentiated
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 four liver tumor cell lines and two nonhepatic lines. The effects of D-
galactosamine and
3-deazauridine on the growth of the
Morris hepatoma cell lines 3924A, 8999S,AND 8999R were strongly synergistic; on the
Novikoff hepatoma and the 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 towards the hepatocellular lines. Results of growth-inhibition studies with the combination of D-
galactosamine and
cytosine arabinoside and with combinations of all three agents are also presented. These results are analyzed in the context of the regulation of hepatic
pyrimidine nucleotide metabolism and our design of
enzyme pattern directed
drug selectivity.