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Three olivoretins, A, B and C (isolated from Streptoverticillium olivoreticuli), which are O-methylated teleocidin B isomers, were found to be biologically inactive. A fourth olivoretin, D, which has a free hydroxyl group and is identical to one of the four teleocidin B isomers, teleocidin B-4 (teleocidin B of Hirata) was biologically active. These findings indicate that the free primary hydroxyl group of teleocidin B isomers is necessary for activity. The effect on biological activity of the structural difference between des-O-methylolivoretin B (teleocidin B-1) and des-O-methylolivoretin C was also studied.

A new gelatin particle agglutination test was developed for assay of natural antibodies to adult T-cell leukemia virus (ATLV/HTLV-I). Partially purified viral antigen from culture fluid of a virus-producer cell line was coated on artificial gelatin particle carriers. A high correlation was observed between the titers of antibodies determined by the agglutination test and by indirect immunofluorescence assay. The agglutination test is simple, sensitive and specific, and should be useful for mass screening of human sera for viral antibodies.

By means of high pressure liquid chromatography, the role of flavin-containing monooxygenase (FMO) and cytochrome P-450 (cyt. P-450) in the metabolism of N-methyl-4-aminoazobenzene (MAB) by rat liver microsomes in vitro was studied with the help of antibodies and a chemical inhibitor. Antibody against cyt. P-488 from 3-methylcholanthrene-treated rats (MC-P-448) decreased the formation of N-hydroxy-N-methyl-4-aminoazobenzene (N-OH-MAB) by about 30% in microsomes from MC-treated rats (MC-microsomes), but showed no inhibitory effect on the formation of N-OH-MAB in microsomes from untreated rats (untreated microsomes) or in microsomes from phenobarbital-treated rats (PB-microsomes). Antibody against cyt. P-450 from PB-treated rats did not inhibit N-hydroxylation of MAB by any of the microsomes tested. A competitive inhibitor of FMO, methimazole, inhibited the N-hydroxylation of MAB by 65% in the case of MC-microsomes, and the residual activity was inhibited completely by anti-NADPH-cytochrome P-450 reductase (anti-fPT) antibody. These results indicate that in MC-microsomes, the N-hydroxylation of MAB is catalyzed by both FMO and MC-P-448, but in untreated and PB-microsomes the reaction is catalyzed exclusively by FMO.

When human alveolar macrophages (AM) obtained by lavage of the lungs of healthy donors were incubated in medium with or without lipopolysaccharide (LPS) they released a factor(s) with tumor cell killing activity. This tumor cytolytic and/or cytotoxic factor(s) (TCF) was assayed by measuring its effect in inhibiting target cell growth. TCF activity was not observed in the supernatant from cultures of LPS-treated hematopoietic malignant cell lines (monocytic leukemia, B-cell leukemia and T-cell leukemia cell lines). Human TCF was significantly cytotoxic to 13 of 15 solid-tumor cell lines tested and to 7 of 9 hematopoietic malignant cell lines, but not to two different normal, nontumorigenic cell lines. TCF-rich supernatants contained low levels of interferon (IFN) activity that were not significantly cytotoxic to A-375 melanoma cells. Human TCF and IFN-alpha or IFN-beta had additive cytotoxic effects. These data suggest that human TCF released by activated human AM may be of potential use in the treatment of malignant disseminated diseases.

Synthetic analogues (indolactams) related to the tumor promoter teleocidin were synthesized chemically. Of four indolactam-Vs lacking the monoterpenoid moiety of native teleocidin, (-)-indolactam-V bound to the 12-O-tetradecanoylphorbol-13-acetate receptor in cell membranes and induced both adhesion of HL-60 cells and ornithine decarboxylase activity in mouse skin, although its effects were weaker than those of teleocidin. (+)-Indolactam-V and two isomers of epi-indolactam-V showed no induction of ornithine decarboxylase. These results indicate that the S,S configuration of native teleocidin at the isopropyl residue and the hydroxymethyl group is necessary for activity.

The nature of the carcinogen present in bracken fern has not yet been elucidated. Very recently, we succeeded in isolating ptaquiloside, a novel norsesquiterpene glucoside of the illudane type, from bracken. Ptaquiloside was shown to be a carcinogenic principle of bracken fern. It induces mammary cancer and multiple ileal tumors in high incidences when given orally to female Sprague-Dawley rats.

A new water-soluble nitrosourea derivative, methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU), was tested for antitumor activity against murine tumors (L1210 and P388 leukemias, B16 melanoma, and Lewis lung carcinoma) and BC-47 rat bladder carcinoma, and the results were compared with those for four other nitrosourea derivatives; chlorozotocin, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (GANU), 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1- nitrosourea hydrochloride (ACNU), and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (methyl-CCNU). MCNU was shown not only to have a broad antitumor spectrum against all the tumors tested, but also to be effective over a wide range of dosages. The antitumor activity of MCNU was superior to those of GANU and chlorozotocin and similar to those of ACNU and methyl-CCNU. Furthermore, MCNU and other nitrosoureas were evaluated for toxicity in BDF1 female mice with respect to body weight changes. Weight loss in mice given MCNU at a dose lethal to 10% of the mice was relatively mild and the treated mice regained body weight most rapidly to the pretreatment level among all groups receiving the above drugs at equitoxic doses. These results may suggest that MCNU is a new nitrosourea derivative worthwhile to perform clinical trials.

DNAs were isolated from about 30 species of animals and digested with EcoRI. DNA fragments of about 20-30 kilobase pairs from pig and wild boar cells hybridized with a probe for the pol gene of human T-cell leukemia virus type I.

The promoting effects of 5 bile acids on liver carcinogenesis were investigated in male Fischer rats initially treated with diethylnitrosamine (DEN). Two weeks after a single dose of DEN (200 mg/kg, intraperitoneally), rats were given bile acids for 8 weeks. At 3 weeks following DEN administration, all rats were subjected to partial hepatectomy. Among the bile acids tested, cholic acid (CA) and deoxycholic acid (DCA) exerted promoting activity as evidenced by significantly increased values of gamma-glutamyl transpeptidase-positive (gamma-GT+) foci as compared with the corresponding controls given DEN alone. In contrast, the other 3 bile acids tested, chenodeoxycholic acid (CDCA), lithocholic acid (LCA) and ursodeoxycholic acid (UDCA), did not significantly increase the level of gamma-GT+ foci over that induced by DEN alone. It is noteworthy that only bile acids of the same metabolic pathway, CA as a primary bile acid and DCA as a secondary bile acid, showed promoting effects whereas CDCA and its metabolic derivatives, LCA and UDCA, were inactive. The results indicate that CA and DCA might act as endogenous promoters of hepatocarcinogenesis in pathological conditions with increased levels of serum bile acids.

A small population of normal thymic lymphocytes, like the majority of thymic leukemia cells, formed cellular complexes with thymic epithelium-like stromal cells in pseudoemperipolesis. The properties of the complex-forming cells in preleukemic AKR thymus were analyzed after separation of the cells into subpopulations on the basis of cell size and surface antigen expression by using a fluorescence-activated cell sorter. Complex-forming ability was associated with large cells and the following phenotypes: high Thy-1.1, low brain associated theta antigen, high H-2Kk, high Lyt-1, high gp70 and Ia negativity. These properties coincide in general with those of blast cells in the subcapsular zone of the thymus, which have been shown to consist mostly of complex-forming cells. The possible significance of complex formation of normal and leukemic thymocytes with thymic stromal cells is discussed.