Drug-induced interference with energy metabolism in the S180 sarcoma: a new principle in the production of selective tumor injury.

The effects of low doses of L-isoproterenol and hydralazine on energy production in the S180 sarcoma were examined in vivo. Both substances produced dramatic alterations in the tumor adenine nucleotide pattern (TANP) by 1 h, the tumor ATP level falling by 80--84% and the energy charge dropping from 0.81 to 0.27--0.28. The approximate ratios of highest amount tolerated by the animal to lowest effective anti-tumor dose were 500 and 15 respectively. By contrast, the highest tolerated doses of both drugs produced minor and quite dissimilar effects on the adenine nucleotide pattern of mouse liver at 1 h. At 24 h after the initial drug treatment the TANP had largely returned to normal, but total losses of adenine nucleotides of 38--69% were recorded. The effect of hydralazine was both more marked and more reproducible than that of L-isoproterenol. Initial treatments with either drug establishment a refractory state in the tumor by 23--24 h; second administrations 1 hr before death had only modest effects on the TANP. Despite alterations in the macroscopic appearance of the injured tissue, necrosis was not histologically evident 24 h after treatment 24 h, but extensive necrotic areas were readily visible at 5 days.