Interference with energy production as a means of causing injury to a human pancreatic carcinoma

The ATP content of a human pancreatic carcinoma, cultured as a xenograft in athymic nude (nu/nu) mice, dropped by 70% within 1 h of treating the hosts with hydralazine (10 mg/kg s.c.), while the energy charge fell from 0.79 to 0.53. By 24 h, the pattern of adenine nucleotides, as shown by the energy charge, had reverted to normal; meanwhile, the ATP level recovered somewhat, showing an eventual loss of 41%. A second administration (also 10 mg/kg s.c.) 23 h after the first produced no further effect on energy metabolism 1 h later, indicating that a state of drug refractoriness had been established. Losses of adenine nucleotides from the carcinoma 24 h after the initial treatment with hydralazine amounted to 37%, from which it was estimated that 35-40% necrosis could be expected from the procedure.