Inhibition of growth of human tumor cells in nude mice by a metalloproteinase inhibitor.

The effects of a new metalloproteinase inhibitor, BE16627B [L-N-(N-hydroxy-2-isobutylsuccinynamoyl)-seryl-L-valine, MW: 375.2] isolated from microbial cultures, on human tumor cell growth in nude mice were investigated. BE16627B inhibited metalloproteinases in enzyme assays, as well as gelatinolysis and collagenolysis in cell cultures. BE16627B at 100 micrograms/ml showed no apparent cytotoxicity to human tumor cells in culture and its LD50 in mice was more than 1,000 mg/kg (i.p.). The effects of BE16627B on the in vivo growth of 2 human tumor cell lines were examined: HT1080 fibrosarcoma, which overproduces metalloproteinases, and HCT116 colon carcinoma, which barely secretes metalloproteinases. When BE16627B was administered to mice at 2 mg/mouse/day by an osmotic pump implanted s.c. for 3 weeks from 1 week after i.v. inoculation of HT1080 cells, the number and size of nodules of HT1080 cells on the lung surface were reduced to 24.3 and 46.4%, respectively, of those of controls, and the increase in lung weight due to tumor-cell growth was inhibited 85.5% without body-weight loss. Moreover, BE16627B inhibited 71.2% of the growth of HT1080 cells inoculated s.c. into mice under the same conditions, but did not significantly inhibit the s.c. growth of HCT116 human colon-carcinoma cells. Thus, BE16627B inhibited metalloproteinase-dependent human tumor-cell growth as well as lung colonization without showing cytotoxicity in nude mice.

Inhibition of metalloproteinase activity of rheumatoid arthritis synovial cells by a new inhibitor [BE16627B; L-N-(N-hydroxy-2-isobutylsuccinamoyl)-seryl-L-valine].

The effect of a new metalloproteinase (MP) inhibitor [BE16627B; L-N-(N-hydroxy-2-isobutylsuccinamoyl)-seryl-L-valine, MW: 375.2] isolated from Streptomyces sp. was evaluated by using primary cultures of synovial cells from rheumatoid arthritis patients. BE16627B selectively inhibited MPs such as human stromelysin and 92 kD gelatinase. After the cells were cultured with BE16627B for 5 days, BE16627B inhibited MP activity in the primary culture supernatants from synovial cells in a dose-dependent fashion without showing apparent cytotoxicity or affecting the production and secretion of MPs. Its IC50 for active collagenolysis before activation by trypsin was 25 microM.

Antitumor effect of forphenicinol, a low molecular weight immunomodifier, on murine transplantable tumors and microbial infections.

The antitumor activities of forphenicinol against murine transplantable tumors were examined. Ehrlich carcinoma was suppressed by treatment with 0.08 approximately 0.31 mg/kg/day of forphenicinol given for 10 days starting 5 days after tumor inoculation. IMC carcinoma was also suppressed by treatment with 0.5 approximately 5 mg/kg/day given for 5 days starting 8 days after the inoculation. The antitumor activity was dependent on the number of tumor cells inoculated, schedule of administration and dose. However, even in case of fast growing tumors such as L1210 and inoculation with a large number of tumor cells, forphenicinol markedly enhanced the antitumor effect of 6-mercaptopurine, aclacinomycin and cyclophosphamide. Forphenicinol showed a protective effect on Pseudomonas infection in mice.

Antitumor effect of bactobolin and its influence on mouse immune system and hematopoietic cells.

Bactobolin prolonged survival period of mice bearing leukemia L-1210 in various dose schedules. The administration of bactobolin before or at time of immunization with sheep red blood cells (SRBC) did not affect antibody formation and delayed-type hypersensitivity (DTH) to SRBC. The administration after immunization suppressed antibody formation markedly but not DTH response. Bactobolin showed stronger suppressive action on antibody formation in vitro than mitomycin C. Bactobolin did not reduce establishment of tumor immunity which was mediated by T cells and macrophages. Comparing to other antitumor antibiotics which were effective against L-1210, bactobolin did not affect phagocytosis of mouse peritoneal macrophages. It has an extremely low toxicity to mouse spleen cells treated by concanavalin A (Con A) and lipopolysaccharide (LPS). It did not affect colony formation of mouse bone marrow cells in the presence of LPS-induced colony stimulating factor. The administration of bactobolin did not reduce the number of leucocytes in peripheral blood. From these results, the usefulness of bactobolin in the treatment of cancer was discussed.

Effect of bestatin on mouse immune system and experimental murine tumors.

Effect of bestatin on the establishment of delayed-type hypersensitivity (DTH) to sheep red blood cells (SRBC) and oxazolone was examined in normal and immunity-impaired mice. Administration of a low dose of bestatin (0.1 approximately 100 microgram/mouse) augmented DTH to SRBC and restored their impaired DTH to oxazolone. The effect of bestatin in the mouse was age-dependent. Bestatin retarded the growth of slow growing solid tumors of Gardner lymphosarcoma and IMC carcinoma and the effect was influenced by the time of the administration and the number of cells inoculated. Bestatin enhanced the antitumor action of the antitumor antibiotics, bleomycin and adriamycin. Bestatin also retarded the induction of skin cancer by 20-methylcholanthrene.