Toxicity of diethylaminoreserpine to a transplantable tumor: the significance of the presence of hypoxic cells.

The survival of clonogenic cells from two transplantable mouse tumors has been measured following i.p. injection of diethylaminoreserpine (DL-152) to the tumor-bearing mouse. Reduction of surviving fraction was seen for both tumors following injection of the drug, minimal numbers of surviving cells being seen from 24 to 48 hr after injection. Greater cell kill was observed for the KHT fibrosarcoma (surviving fraction = 3 x 10(-2) at 48 hr) than for the EMT6 mammary carcinoma (surviving fraction = 2 x 10(-1) at 48 hr). Reduction in surviving fraction of the KHT tumor was already observed at 1 hr after injection of the drug, and survival at that time was reduced if tumor cells were acutely hypoxic prior to excision of the tumor. Results also indicated that chronically hypoxic radioresistant cells were more sensitive to the drug than were aerated cells. Significant reduction in surviving fraction was seen for doses of DL-152 as low as 5 mg/kg. Using KHT tumors growing as lung nodules, it was shown that toxicity of DL-152 was not apparent until 11 to 14 days after initiation of the tumor and that subsequent sensitivity of cells to DL-152 increased with increasing age of the lung tumor. Hypoxic cells were detectable in 10-day-old lung tumors, a time at which the tumors were still resistant to the toxic effects of DL-152. In vitro experiments using KHT cells in suspension showed that a high concentration of DL-152 was toxic to both hypoxic and aerated cells but that hypoxic cells were more sensitive to lower concentrations than were aerated cells.