In vitro-in vivo studies on the susceptibility of the solid Yoshida sarcoma to drugs and hyperthermia (42 degrees).

Abstract

Summary Over 2000 allogeneic solid Yoshida tumors of rats were studied to examine the predictive value of in vitro testing for tumor sensitivity to drugs and hyperthermia. In vitro , the alkylating agent methylenedimethanesulfonate (MDMS) caused a concentration-dependent inhibition of respiration, anaerobic glycolysis, and radioactive thymidine, uridine, and leucine uptake into cultures of the tumor over 24 hr. Hyperthermia (42°) had a progressive inhibitory effect on these parameters over 1 to 4 hr. MDMS potentiated the effect of 42° temperature on the tumor in vitro . Tumor regression correlated with as little as 25 to 30% inhibition of respiration by the drug in vitro; inhibition of respiration also provided a reliable and rapid index of in vivo response to hyperthermia. In vivo , exposure to 42° for 1 hr led to disappearance of 1.5-ml foot tumors within 12 to 14 days, and MDMS (2.5 mg/kg) caused significantly more rapid tumor regression within 8 to 10 days. MDMS potentiated the effect of heat on tumor regression. Biochemical and histological data showed that in the animal the two therapies had different modes of action not predicted by the in vitro system. Following MDMS, there was tumor cell pyknosis, fibroblast infiltration, and a rapid decrease in tumor volume, accompanied by progressive decrease in respiration, glycolysis, and isotope uptake in the regressing tumor. Hyperthermia resulted in less rapid cell death, slower removal of dying cells, and more gradual replacement of tumor architecture by connective tissue. This was associated with a more protracted decrease in isotope uptake and an inhibition of respiration; glycolysis was depressed only temporarily. Other cytotoxic drugs (except alkylating agents) were ineffective, both in vitro and in vivo . The results indicate that in vitro testing can be of predictive value for assessing the response of a tumor in the host to drug or heat therapy.