ABSTRACT
The actinomycins were isolated from two locally-grown Streptomyces cultures S-67-3 and S-62-30. Acute and short-term toxicity studies on S-67-3 using mice, rats, rabbits and monkeys showed much less toxicity than S-62-30. The LD50 of S-62-30 in mice was 1.78 mg/kg by subcutaneous route. In rats, the LD50 by intraperitoneal route were 0.095 mg/kg and 0.1 mg/kg for S-62-30 and S-67-3, respectively. Toxicities of the two fractions, however differ significantly below and above the LD50. While a dose of 1 ug/kg of the S-62-30 fraction proved very toxic to monkeys. S-67-3 showed hardly any toxicity at the same dose level. A dose of 5 ug/kg of S-62-30 was lethal to the two monkeys tested. S-67-3 showed barely any marked acute toxicity on the rabbits up to 1.0 mg /kgPreliminary studies in vitro showed significant activity against ascitic tumors, TB bacillus and Gram-positive bacteria. In vivo studies on three types of experimental tumors showed inhibition of Ehrlich Ascites Carcinomas (EAT) in Swiss albino and Leukemia L-1210 in DBA/2 and BDF, mice but not Sarcoma (S-180) in either C57 or the local strain of white mice. The Sarcoma regressed in both control and experimental groups with necrosis and alopecia at the site inoculation. Such apparent "immunity" was not observed with EAT or L-1210. Marked inhibition of L-1210 was observed with S-67-3 when grown in DBA/2 or BDF, mice, at a dose of level of 20 ug/kg and higher. Dose-response curves on S-67-3 reveal a higher antitumor activity and a lower toxicity as compared with S-62-30 which is rather unusual for cytotoxic agents. Implications in therapy are discussedSignificant alteration in tumor membrane phospholipoprotein was observed at the higher dose levels (20 ug/kg and 40 ug/kg) as assessed by thin-layer-chromatography. Such effects are extrapolated to have produced changes in membrane permeabilityThe role of cyclic-adenyl cyclase system in membranes in relation to "contact inhibition" is also discussed with projections into wound healing, embryogenesis, differentiation, aging and cancerSo far, pharcogenetic studies on mice, rats, rabbits and monkeys now in progress (except on monkeys which was temporarily suspended) have not shown significant results for meaningful evaluation. Studies on the possible immunosuppressive activity are now underway.(Summary)