Streptomyces antibioticus synthesizes five actinomycins that differ in the "proline site" of the molecule. When cultured in the presence of azetidine-2-carboxylic acid (AzC), antibiotic synthesis was stimulated 40 to 50%, synthesis ofactinomycin IV was inhibited, and one or both prolines were replaced by AzC. AzC incorporation could not be reversed by concomitant supplementation with proline or sarcosine, and only pipecolic acid affected a minor reversal of AzC incorporation. AzC-containing actinomycins were isolated and designated azet-I and azet-II; a third unresolved component or mixture was called azet-III. The molar ratio of AzC to proline was: azet-I, 1:1; azet-II, 2:0. Azet-IHI was equivocal. These azetidine actinomycins (azetomycins) were found to be potently inhibitory, to the growth of selected gram-positive but not as potent to the growth of gramnegative organisms. The relative inhibitory affect against growth and ribonucleic acid synthesis in Bacillus subtilis was: actinomycin IV > azet-I > azet-Il > >> azet-III. Protein synthesis was affected similarly; however, kinetic studies with B. subtilis revealed that ribonucleic acid synthesis was inhibited rapidly followed by an inhibition of protein synthesis. At concentrations less than 1 ,ug/ml, deoxyribonucleic acid synthesis was stimulated by these actinomycins.
2,3-Dihydroxypropanal is a minor component of normal carbohydrate metabolism; apparently both isomers of the racemic compound (D, L-glyceraldehyde) are metabolized in liver. In mice, single doses of 0.4 g/kg dihydroxypropanal reduced both sarcoma and carcinoma growth by more than 90%. Single doses also increases longevity of mice with L-1210 and P-388 leukemias by +48–60%. The responses of these two murine cancers in vivo appear similar to drug responses of human cancers. Mice of both sexes demonstrated no significant inhibition of blood-forming elements in femoral marrow following 1.5 g/kg doses of dihydroxypropanal, a circumstance rarely observed with drugs which inhibit cancer. Single large doses of dihydroxypropanal failed to effect either significant fluctuations in quantities of circulating erythrocytes, eosinophils or lymphocytes (although they induced a slight transient elevation in circulating neutrophils) or in quantitites of marrow erythroblasts, erythrocytes, lymphocytes, neutrophils or myeloid precursor cells. Intraperitoneal doses of 1.5 g/kg dihydroxypropanal produced gut irritation, but elicited no signs of gross or microscopic pathology in cardiac, renal, adrenal, testicular, hepatic, pneumal or splenic tissues. In mice, dihydroxypropanal may preferentially inhibit cancer growth without concomitantly damaging many normal tissues usually sensitive to drugs which inhibit cancer growth.
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