A new antitumor antibiotic, 3"-demethylchartreusin was isolated from the culture broth of Streptomyceschartreusis, as a minor component of crude chartreusin. It is structurally related to chartreusin, containing same aglycone of chartreusin, but different sugar moieties. 3"-Demethylchartreusin exhibits somepotent inhibitory activities against murine tumors.Chartreusin (1) is a Streptomyces-produczd antibiotic that was originally reported in 1953.1} It has significant antitumor effects against murine L1210, P388 leukemias, and B16 melanoma. Whenthis drug was given iv, it was rapidly eliminated through the bile and therefore showed no activity by this route.2) Related derivative of chartreusin, elsamicins which were isolated by Konishi et al.,3) have higher solubility and slower elimination than chartreusin. These results indicate the possibility to discover other soluble derivatives. So we started our investigation to search for more potent derivatives from culture broths of Streptomyces chartreusis. In this paper, we describe the identification, purification and biological activity of a compoundrelated to chartreusin from Streptomyces chartreusis. FermentationSpores from a slant culture of the producing organism {Streptomyces chartreusis IFO 1275) were inoculated into a 50-ml test tube. The culture medium(15 ml) consisted of lactose 4%, soybean powder 2%, corn steep liquor 2%, and CaCO35%, the pH being adjusted to 7.0 before sterilization.The test tube was then incubated at 28°C while being shaken at 200rpm for 3 days. Then 15ml of cultured broth was transferred into a 2-liter flask containing 500ml of a culture mediumhaving the same composition Fig. 1. Structure of chartreusin and 3"-demethylchartreusin.
Fludarabine phosphate (2-F-ara-AMP) is an adenine nucleoside analogue that shows significant activity against chronic lymphocytic leukemia and indolent lymphoma. We assessed the cytotoxic interaction produced by the combination of the active metabolite of fludarabine phosphate, fludarabine (9--D-arabinofuranosyl-2-fluoroadenine, 2-F-ara-A), and some commonly used antileukemic agents against human hairy cell leukemia cell line JOK-1, human chronic lymphocytic leukemia cell line SKW-3, and adult T cell leukemia cell lines ED-40810 (−) and SALT-3. The leukemia cells were exposed simultaneously to 2-F-ara-A and to the other agents for 4 days. Cell growth inhibition was determined using MTT reduction assay.
Gel-filtered human platelets exerted lytic activity on autologous red blood cells (RBC) when they were coincubated at 37 degrees C with platelet-activating agents, such as thrombin, collagen, ADP, LPS or PMA in the absence of plasma. Lysis of activated platelets themselves did not occur during the incubation period examined. Morphological observations showed that RBC exposed to thrombin-activated platelets were fragmented and/or transformed into spherocytes. This haemolytic reaction by thrombin-activated platelets did not occur at 4 degrees C, or in the presence of agents which inhibited glycolysis or elevated intracellular levels of cAMP, indicating that energy-dependent and cAMP-regulated platelet metabolism was required for this reaction. When platelets and RBC were incubated in the same vessel, but were prevented from coming into direct cell to cell contact by means of a membrane barrier, their cytotoxicity was reduced but not eliminated completely. No cytotoxic activity against RBC was detected in platelet-free supernatants obtained by centrifugation after activation of platelets with thrombin. On the contrary, activated and washed platelets retained the activity. These observations suggested that the cytotoxic activity was carried by some diffusible and easily inactivated factors, which were continuously produced and liberated from activated platelets. Cyclo-oxygenase inhibitors inhibited the haemolytic activity of thrombin-activated platelets, suggesting a role for some products of platelet-cyclo-oxygenase pathway in platelet-mediated haemolysis. These results provide the first evidence for a direct role of activated platelets in mediation of RBC-damage in the absence of any plasma factors.
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