Kazusamycin B

The isolation and characterization of the title antibiotics, which are produced by the same Streptomyces sp., is described. The potent antitumor agent, PD 124,895, is an analog of hydroxyelactocin (PD 114,721). PD 124,966 is a new member of the depsipeptide family of antibiotics.

Kazusamycins A and B and leptomycin B have a structure characteristic of an unsaturated, branched-chain fatty acid with a terminal delta-lactone ring, and show antibacterial activity on some kinds of fungi. Kazusamycin A (KZM-A) showed cytotoxic activity on mammalian cells at very low concentrations (ng/ml) in vitro. The antibiotic inhibited not only the growth of transplantable murine tumors and their metastases to the lung but also human mammary tumors inoculated into nude mice. KZM-A became immediately distributed to the main organs of mice, and a certain quantity of the antibiotic was inactivated by binding to high-molecular-weight substances such as albumin. A large quantity of KZM-A was carried to the liver and excreted into the bile, but was then reabsorbed by the small intestine. The growth of tumor metastases (L5178Y cells) in the liver was suppressed by KZM-A. The antibiotic induced severe diarrhea by causing necrosis and/or lysis of the mucous membrane of the small intestine. In contrast to this, the degree of myelotoxicity was relatively slight. The active site of the fatty acid of KZM-A appeared to consist of conjugated double bonds, carboxylic acid and hydroxyl moieties.

The effect of a potent antitumor antibiotic, kazusamycin B, on the cell cycle of L1210 cells was examined. Kazusamycin B arrested synchronized L1210 cells at G1 phase. Retardation of metaphase initiation was also observed. Flow cytometric analysis of kazusamycin B-treated asynchronized cells also confirmed G1 arresting effect of kazusamycin B. In addition, an unidentified cell population with lower fluorescence intensity than G1 population was observed when the cells were exposed to the drug longer than 12 hours. Morphology of kazusamycin B-treated L1210 cells revealed that the intranuclear structure changed within 4 hours, and that abnormal condensation of nuclei coincided with the appearance of unidentified population. Kazusamycin B inhibited RNA synthesis moderately but specifically at 2 hours. However, this inhibition might be a secondary effect of the antibiotic-induced structural abnormality of the nuclei.