Inhibitors of insulin-like growth factor-1 receptor tyrosine kinase are preferentially cytotoxic to nutrient-deprived pancreatic cancer cells.

Chronic deprivation of nutrients is rare in normal tissues, however large areas of tumor are nutrient-starved and hypoxic due to a disorganized vascular system. Some cancers show an inherent ability to tolerate severe growth conditions. Therefore, we screened chemical compounds to identify cytotoxic agents that function preferentially in nutrient-deprived conditions.

Augmentation of cellular immunity by kigamicin D.

Kigamicin D did not show any immunosuppressive activity in mixed lymphocyte culture reaction and mitogen induced lymphocyte blastogenesis in vitro and graft versus host reaction in vivo. Natural killer cell activity in spleen cells was not affected by oral administration of kigamicin D. Instead, delayed-type hypersensitivity response to sheep red blood cells was stimulated at a broad dosage level.

Antitumor effect of kigamicin D on mouse tumor models.

Kigamicin D is a novel anticancer agent that was identified using a new screening strategy that targets the tolerance of cancer cells to nutrient starvation [1, 2]. Oral administration of kigamicin D was previously described to show a strong antitumor effect in human tumor xenograft models of pancreatic tumors [2]. In this paper we describe that kigamicin D shows the same selective cytotoxicity against normal human cells such as lung fibroblast and prostate stromal cells under nutrient starved condition as against cancer cells.

ICM0201, a new inhibitor of osteoclastogenesis from Cunninghamella sp. F-1490. I. Taxonomy, fermentation, isolation and biological activities.

In the course of screening for inhibitors of osteoclastogenesis, a new substance designated as ICM0201 was isolated from a fermentation broth of Cunninghamella sp. F-1490. ICM0201 inhibited the formation of osteoclasts in mouse bone marrow cells with an IC50 value of 0.

Action of cytogenin on lymphoid cells and their cytokine production.

Action of cytogenin on macrophages and T cells was investigated. Phagocytosis of yeast and production of PMA-elicited superoxide anion by macrophages taken from mice given cytogenin po were augmented. Cytogenin enhanced productions of IL-1 alpha by macrophages and IFN gamma and GM-CSF by spleen cells although it did not enhanced production of TNF alpha by macrophages and IL-6 by macrophages and spleen cells.

Cytostatin, a novel inhibitor of cell adhesion to components of extracellular matrix produced by Streptomyces sp. MJ654-NF4. I. Taxonomy, fermentation, isolation and biological activities.

Cytostatin has been identified as a novel inhibitor of cell adhesion to components of extracellular matrix (ECM) in cultured broth of Streptomyces sp. MJ654-NF4. Though cytostatin did not inhibit EL-4 cell adhesion to ECM components such as laminin and fibronectin; it inhibited the adhesion of B16 melanoma cells to laminin and collagen type IV but not to fibronectin.

Effect of conagenin in tumor bearing mice. Antitumor activity, generation of effector cells and cytokine production.

Antitumor effects and function of T cells in tumor bearing mice given conagenin (CNG), a low molecular immunomodulator, were investigated. The administration of CNG, once a week for 4 weeks, was the most effective schedule in inhibiting growth of IMC carcinoma, a syngeneic tumor. In this regimen, cytotoxic T lymphocytes and natural killer activities in spleens of CNG treated mice were maintained at higher levels than those of non-treated mice.

T cell activation by conagenin in mice.

Conagenin (CNG), a low molecular immunomodulator, enhanced incorporation of [3H]thymidine into T cells activated by concanavalin A but did not to non-activated T cells. The culture supernatants of activated T cells treated with CNG enhanced incorporation of [3H]thymidine into cytokine dependent cell lines, CTLL-2 and IC-2 cells. This indicates that CNG exclusively acts on activated T cells and stimulates them to promote DNA synthesis and to produce lymphokines, which may include T cell growth factors and hematopoietic growth factors.

Delaminomycins, novel extracellular matrix receptor antagonist. IV. Structure-activity relationships of delaminomycins and derivatives.

Delaminomycins A, B, C and their derivatives were prepared and investigated biological activities of them. Among these compounds, spiro compounds (A2, B2 and C2) showed stronger inhibitory activity than natural products (A1, B1 and C1) on B16 melanoma cells adhesion assay and Con A-induced proliferation of murine splenic lymphocytes assay. In MLCR and antimicrobial assay, however, A1, B1 and C1 showed more potent inhibitory activity than spiro compounds (A2, B2 and C2).

Delaminomycins, novel nonpeptide extracellular matrix receptor antagonist and a new class of potent immunomodulator. I. Taxonomy, fermentation, isolation and biological activity.

In order to develop a new class of immunomodulator we have searched for a low molecular weight inhibitors of cell adhesion to components of extracellular matrix (ECM), fibronectin (FN), laminin (LM) and collagen type IV (CL), and succeeded to find a group of novel antibiotics, named delaminomycins. Delaminomycins were isolated from the mycelium and cultured broth of Streptomyces albulus MJ202-72F3. It was purified by use of centrifugal partition chromatography (CPC), preparative reverse phase HPLC and Sephadex LH-20 and was obtained as a white powder.

Biological activities of IC201 ((3S,8E)-1,3-dihydroxy-8-decen-5-one), a low molecular weight immunomodulator produced by Streptomyces.

IC201 was found in cultured broth of Streptomyces cirratus as an antitumor antibiotic which was effective in retarding growth of the established solid tumor of Ehrlich carcinoma by treatment starting 8 days after tumor inoculation. It retarded growth of the established solid tumor of IMC carcinoma but had no cytotoxicity at 100 micrograms/ml. IC201 treatment kept NK cell activity of tumor-bearing mice at normal level and stimulated cytostatic activity of peritoneal macrophages.

Induction of antitumor resistance to mouse leukemia L1210 by spergualins.

Spergualin and its analog, 15-deoxyspergualin showed a marked antitumor effect against L1210 by intraperitoneal and oral administrations. After treatment with these substances 40- or 60-day survivors (cured mice of L1210) were resistant to reinoculation of L1210 cells. They were resistant only to L1210.

Production and characterization of monoclonal strain-specific antibodies against prototype strains of Rickettsia tsutsugamushi.

We have developed 18 hybridoma cell lines which secrete murine monoclonal strain-specific antibodies to prototype strains of Rickettsia tsutsugamushi: nine anti-Gilliam, four anti-Karp and five anti-Kato antibodies. All the monoclonal antibodies reacted only with their homologous strains in direct and indirect immunofluorescence (IF), or indirect immunoperoxidase (IP) test. By IF and IP tests with the monoclonal antibodies, 22 strains of R.

Augmented mitotic response of human peripheral lymphocytes in the presence of lymphocytes from nude mice: detection of a small number of functional human lymphocytes in the explanted host.

In the present paper, authors showed a method to detect a small number of functional human peripheral lymphocytes (HPL) in the presence of lymphoid cells of nude mouse (n-ML). HPL was mixed with n-ML to give a total number of 5 X 10(4) cells and cultured in vitro in the presence of PHA for 5 days. HPL responded will to PHA while n-ML did not, as assessed by 3H-TdR incorporation in the presence of the mitogen.

A histopathological study of lymphoid tissue reaction to metastatic nasopharyngeal carcinoma in nude mice.

In attempts to heterotransplant human NPc into nude mice, using seven cultured cell lines, we have succeeded in growing a carcinoma simplex, composed of Epstein-Barr virus-determined nuclear antigen-positive and Epstein-Barr virus genome-positive cancer cells, at the injected site with two of the cell lines. These originated from a spindle-cell carcinoma (Chinese NPC-204) and from a combined-cell carcinoma (Chinese NPC-501), respectively. During the first few passages, wandering macrophages were prevalent and increased in number in response to the presence of the tumours.