A new antitumor antibiotic is produced in fermentation liquors of Streptomyces zelensis sp.n. The antibiotic is biologically active at extremely low concentrations. At 40 pg/ml, it inhibited 90% of the growth of L1210 cells in culture in tube dilution assays. The minimal inhibitory concentrations against Gram-positive bacteria is between 1-10 ng/ml, while these values for Gram-negative bacteria and fungi are mostly under 1 jig/ml. A microbiological assay with Bacillus subtilis can detect concentrations of I-2 ng/ml. A new antitumor antibiotic, CC-1065, was discovered in our laboratories''. It was isolated from fermentation liquors of a new species of Streptomyces which was designated Streptomyces zelensis DIETZ and Li sp. n. (UCH-5923). This communication describes the production of the drug, the taxonomic study of the producing microorganism, the in vitro activity, and the microbiological assay. The methods of isolation and evaluation against experimental animal tumors will be described in separate communications.
CC-1065 (NSC 298223) is a potent new antitumor antibiotic with a unique structure produced by Streptomyces zelensis. Improved production, isolation, and assay methods are described along with physico-chemical properties and antitumor activity. Screening for soil cultures producing agents displaying both cytotoxic activity against L1210 cells in culture and in vivo activity against P388 leukemia in mice afforded a culture, Streptomyces zelensis, producing a new, potent antitumor antibiotic, CC-1065. Its production, in vitro biological activity, microbiological assays, and taxonomy have already been described1) ; a preliminary communication announced the structure2) shown in Fig. 1. Details of the structure determination have recently been described3). A molecular model of CC-1065 displayed a remarkable curvature, shape,
Chartreusin was produced in the fermentation liquors of Streptomyces chartreusis at peak concentrations of 200 to 300 ,ug/ml. The titers could be increased by 200 to 300% or more by incorporating r.-fucose, a part of the chartreusin molecule, into the fermentation media. A microbiological assay with Sarcina lutea could detect concentrations of the drug of 0.5 to 1.0 ,ug/ml. Chartreusin (Fig. 1) is an antimicrobial antibiotic that was first described by Leach et al. in 1953 (3). Recently, chartreusin was shown to inhibit experimental tumors in animals (4). Such results generated renewed interest in this drug. Much of the fermentation technology has changed during the 23 years since the drug was first discovered. Accordingly, a considerable amount of work was done recently both on the fernentation and in the development of a suitable microbiological assay. The pertinent results are reported herein.
Improved fermentation and isolation procedures for antitumor antimetabolites U-42,126 and U-43,795 increased drug yields 30-fold. The sensitivity limit of a newly developed assay is 0.03 μg of U-42,126 and 2.0 μg of U-43,795 per ml. The in vitro antimicrobial effect of both drugs was antagonized by histidine.
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