A number of antibiotics have been derived from the organisms belonging to S. hygroscopicus series. A new antifungal agent, copiamycin, was recently isolated in the authors’ laboratory from the mycelium of Streptomyces No. 1898, which, according to the detailed mycological studies, was also found to be a variant of S. hygroscopicus. The name S. hygroscopicus var. chrystallogenes was given to the organism and taxonomic description will be made elsewhere. The present paper deals with the production, isolation, chemical and physical properties and the biological activities of copiamycin.
In 1957, carzinostatin was found in our laboratory in the culture filtrate of Streptomyces carzinostaticus and its isolation and characteristics were reported by Shoji in 19611). The antibiotic consisted of two components, A of high molecular weight and B of low molecular weight, and the coexistence of the two components was essential for inhibition of the growth of Ehrlich ascites tumor in mice. Biological studies so far reported1~5) were therefore done with the mixture designated as carzinostatin complex. Owing to technical difficulties, purification of both of the components was discontinued. However, the antibiotic was too effective to be abandoned, and we resumed the study. We concentrated our effort first on the selection of more potent descendants of the producing strain. During the course of such study, one of the potent producers, Streptomyces carzinostaticus var. F-41, was found to produce an antibiotic which exerts its biological effects as a single entity. The antibiotic was an acidic polypeptide and had more pronounced inhibitory effect on ascites form of sarcoma 180 and on ascitic leukemia SN-36 in mice than that of carzinostatin complex. The antibiotic was designated as neocarzinostatin.
The present paper describes details of isolation, physicochemical properties, and antitumor activities of neocarzinostatin.
An antibiotic, blasticidin S (BcS), found in 1958 by Takeuchi et al1). from Streptomyces griseochromogenes Fukunaga and isolated in a pure crystalline state has been widely used in Japan to protect against blast disease of paddy rice plant. Misato et al2). have found that the antibiotic completely inhibits protein synthesis in mycelia of the rice blast fungus, Pilicularia oryzae, although it shows no effect on incorporation of phosphate into nucleic acid. Recently, Huang et al3). have reported that BcS inhibits the amino acid transfer from sRNA to ribosomal protein in the cell-free system of P. oryzae. A number of papers have been published on the antibiotics that give rise to similar effects, e.g. chloramphenicol (CP)4, 5) puromycin (PRM)6) and cycloheximide7).
A previous paper8) has shown that when the growth of yeast cells is partially inhibited by the addition of BcS, a strikingly large quantity of ribonucleic acid (RNA) accumulates in the yeast cells. The RNA accumulated there was quite stable and retained in the cells even after the yeast cells were transferred to a new buffer solution. In a sedimentation experiment, most of the RNA synthesized in the presence of BcS was found to exist in the microsomal fraction9).
Dagley et al10). have found in the sedimentation analysis of bacterial cell extract that CP causes a remarkable accumulation of 14S and 18S ribonucleoprotein (RNP), the former showing a CP-specific RNP and not found in normal cells. Nomura et al11. have reported that 15S RNP found in CP-treated cells of Escherichia coli is converted either to 24S or 31S RNP when magnesium ion concentration is increased. These CP-particles were electrophoretically separated from normal ribosomes. PRM has also been known to produce RNP particles of 30S or those of less than the former in the cell extract of Pseudomonas fluorescence12).
The present paper deals with some investigations of the RNP derived from BcS-treated yeast cells, indicating that BcS also causes formation of abnormal RNP particles in the cells.
A program in which actinomycete fermentation broths are screened for cytotoxic activity yielded a substance active in tissue cell cultures. Subsequent studies showed that the agent, which has been named ossamycin, also inhibited some fungi and protozoa.