pd-114-721 and Leukemia-P388

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.

Topics: Animals; Antibiotics, Antineoplastic; Cells, Cultured; Fatty Acids, Unsaturated; Kinetics; Leukemia P388; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental

CI-940, PD 114,721, and PD 118,607 are structurally novel antibiotics, which were isolated from fermentation beers of a previously unknown actinomycete. They are highly lipophilic acids characterized by unsaturated lactone and branched, polyunsaturated aliphatic side-chain moieties. All three agents demonstrated significant cytotoxic activity in vitro against a number of human and mouse tumor lines which encompassed a wide range of tissue types. CI-940 retained full activity in vitro against lines of P388 leukemia that are resistant to Adriamycin, amsacrine, and mitoxantrone. Activity was confirmed for both CI-940 and PD 114,721 against a number of murine experimental tumor systems in vivo, which included the P388 and L1210 leukemias and also B16 melanoma, Ridgway osteogenic and M5076 sarcomas, and mammary adenocarcinoma 16/C. PD 118,607 was also highly active against B16 melanoma. All three agents demonstrated anticancer activity at very low dosages compared with current clinically useful anticancer agents. No significant activity was seen against the MX-1 human mammary xenograft or pancreas 02 tumor models. The primary target for host toxicity of CI-940 and PD 114,721 appeared to be gastrointestinal in nature. Neither CI-940 nor PD 114,721 caused delayed lethality when given either IP or IV. In schedule studies, the toxicities of both CI-940 and PD 114,721 were moderately dependent on the regimen used, with total maximum tolerated dosages for intermittent (q4dx2), daily (qdx5), and divided daily (q4hx3, qdx5) dosing schedules of 1, 0.25, and 0.12 mg/kg, respectively. CI-940 is being developed for clinical trial on the basis of its potent activity against seven different tumor models, its novel structure, and its apparently novel mechanism of action.

Topics: Animals; Antineoplastic Agents; Cell Line; Diarrhea; Drug Evaluation, Preclinical; Fatty Acids, Unsaturated; Injections, Intraperitoneal; Injections, Subcutaneous; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Mice; Neoplasms, Experimental; Structure-Activity Relationship

A new antibiotic kazusamycin, was isolated from the culture broth of Streptomyces sp. No. 81-484, which shows antitumor activity against experimental murine tumors. This antibiotic did not possess antibacterial activity against Gram-positive and Gram-negative bacteria, but showed strong cytotoxic activity against HeLa cells in vitro. The chemical and physico-chemical properties of kazusamycin suggest that the molecular formula of this antibiotic is C33H48O7 (MW 556).

Topics: Animals; Antibiotics, Antineoplastic; Fatty Acids, Unsaturated; Fermentation; HeLa Cells; Leukemia P388; Magnetic Resonance Spectroscopy; Mice; Microbial Sensitivity Tests; Sarcoma 180; Streptomyces