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The antitumor activity of spicamycin analogue SPM VIII against human stomach, breast, lung, colon and esophageal cancers was compared to that of mitomycin C (MMC) in the human tumor-nude mice xenograft model. Comparative studies of SPM VIII given i.v. at 6 mg/kg/day daily for 5 days and MMC given i.v. at 6.7 mg/kg on day 1 revealed that the antitumor spectrum of SPM VIII showed a different pattern from that of MMC and that SPM VIII caused tumor mass reductions in more tumors than did MMC in colon cancers (4/12 versus 1/11). In addition to this study, a comparative study of SPM VIII given i.v. at 12 mg/kg/day 8 times at 3- or 4-day intervals and 5'-deoxy-5-fluorouridine (5'-DFUR) given po at 185 mg/kg/day 5 days per week for 4 weeks showed that SPM VIII had the highest effect on SC-9 human stomach cancer and COL-1 human colon cancer among the 3 compounds, resulting in a significant reduction of tumor mass. Although other pharmacological studies are in progress, these results suggest that SPM VIII might be a novel antitumor compound effective for human cancers including cancer of the digestive organs.

KRN5500, (6-[4-Deoxy-4-(2E,4E)-tetradecadienoylglycyl]amino-L-glycero - beta-L-mannoheptopyranosyl]amino-9H-purine), was semi-synthesized in an attempt to increase the therapeutic effects of spicamycin analogues. The present study evaluated the antitumor activity of KRN5500 against murine tumors and human tumor xenografts. KRN5500 prolonged the survival of P388 leukemia- and B16 melanoma-bearing mice but was marginally effective on colon adenocarcinoma 26. The antitumor activity of KRN5500 (4 mg/kg/day x 5, IV) against xenografts of 10 human stomach, 14 colon and 2 esophageal cancers was evaluated with two parameters: the tumor growth inhibition rate (TGIR) and the tumor mass reduction by comparison with mitomycin C (MMC, 6.7 mg/kg/day x 1,IV). KRN5500 showed a marked efficacy in the human tumor xenograft model. The overall response rate of 26 cancers to KRN5500, evaluated by TGIR, was approximately equal to their response rate to MMC (72% vs. 73%). However, more tumors were reduced by KRN5500 than by MMC (52% vs. 39%). It is notable that the response rates of 14 colon cancers to KRN5500 were significantly higher than those to MMC, both in TGIR (69% vs. 58%) and in tumor mass reduction (46% vs. 23%). Among the tumors sensitive to KRN5500, COL-1 showed a marked response (TGIR 93%) and a significant reduction in tumor mass (0.22-fold the starting volume). In the mode of action, KRN5500 was found to show an inhibitory effect on protein synthesis in P388 cells (IC50 1.5 microM). However, KRN5500 was ineffective even at 170 microM in inhibition of protein synthesis in rabbit reticulocyte lysates.(ABSTRACT TRUNCATED AT 250 WORDS)

Free radical scavenging activities of various carbazole compounds, carazostatin, carbazomycin B and their chemically modified derivatives were studied in vitro and ex vivo. Among these compounds, carazostatin, which was isolated as a free radical scavenger from the culture of Streptomyces chromofuscus, showed the most potent inhibitory activity against lipid peroxidation of rat brain homogenate in vitro. Carbazomycin B, a known antimicrobial antibiotic, also exhibited strong activity in this system. Although O-modified derivatives of carazostatin and carbazomycin B retained considerable activity, N,O-dimethyl derivatives did not suppress the peroxidation. On the other hand, the results from the ex vivo evaluation of these carbazoles in the lipid peroxidation system of mouse blood plasma showed that the original compounds as well as their O-modified derivatives had a strong inhibitory activity upon oral administration to mice. These findings suggest that these natural carbazoles and their effective derivatives can protect tissues from the peroxidative damage due to generation of free radicals.

Thiazohalostatin has been isolated from the culture broth of Actinomadura sp. by a screening program designed to find novel cytoprotective substances. It was purified by use of column chromatography on silica gel, reversed phase HPLC and then isolated as colorless powder. Thiazohalostatin prevented cell death caused by calcium overload and exhibited an inhibitory activity against lipid peroxidation.

Phenazoviridin is a newly discovered free radical scavenger from microorganisms. It was isolated from the culture of Streptomyces sp. HR04. The structure of phenazoviridin was determined as 6-(3-methyl-2-butenyl)phenazine-1-carboxylic acid 6-deoxy-alpha-L-talopyranose ester on the basis of its spectroscopic and physico-chemical properties. The novel substance showed strong inhibitory activity against lipid peroxidation in rat brain homogenate and exhibited antihypoxic activity in mice.

Spicamycin, a nucleoside antibiotic containing fatty acids with a variety of chain lengths (C12-C18), showed potent antitumor activity against human gastric cancer SC-9 and human breast cancer MX-1 in a xenograft model. We have made several semi-synthetic spicamycin analogues (SPMs) which differed in the chain length of the fatty acid moiety, and examined their structure-antitumor activity relationship. The cytotoxic activities of SPMs depended on the chain length of the fatty acid moiety, with dodecanoyl, tetradecanoyl, hexadecanoyl and icosanoyl analogues (SPM VIII, SPM X, SPM XII and SPM XVI) exhibiting the most potent cytotoxic activity against P388 murine leukemia cells. SPM VIII showed the most activity against SC-9 in the human tumor xenograft model with the highest therapeutic index among SPMs. The antitumor activity of SPM VIII was superior to that of mitomycin C.

Rumbrin has been isolated from a fungus, Auxarthron umbrinum, by a screening program designed to find microorganism-produced cytoprotective substances. It was purified by use of column chromatography on silica gel, reversed phase HPLC and then isolated as fine red needles. Rumbrin prevented cell death caused by calcium overload and exhibited a potent inhibitory activity against lipid peroxidation.

Pyrrolostatin, a new lipid peroxidation inhibitor, was isolated from the culture of Streptomyces chrestomyceticus EC40. The structure was determined to be 4-geranylpyrrole-2-carboxylic acid on the basis of its spectroscopic and physico-chemical properties. Pyrrolostatin inhibited lipid peroxidation in rat brain homogenate.

An acid alpha-glucosidase (EC 3.2.1.20) was purified to homogeneity from the culture medium of Tetrahymena thermophila CU 399. Its general molecular, catalytic and immunological properties were compared to those of the T. pyriformis W enzyme. The enzyme from T. thermophila was a 105-kD monomer and the N-terminus (25 amino acid residues) displayed some homology with that of T. pyriformis enzyme. The purified enzyme was most active at 56 degrees C and showed resistance to thermal inactivation. The acid alpha-glucosidase appears to have alpha-1,6-glucosidase as well as alpha-1,4-glucosidase activity. The Km values determined with p-nitrophenyl-alpha-glucopyranoside, maltose, isomaltose and glycogen were 0.7 mM, 2.5 mM, 28.5 mM and 18.5 mg/ml, respectively. The enzyme was antigenically distinct from T. pyriformis acid alpha-glucosidase.