asialo-gm1-ganglioside and Salivary-Gland-Neoplasms

An interferon-gamma (IFN-gamma)-inducing molecule (OK-PSA) has been purified from OK-432 by an affinity chromatographic technique performed on cyanogen bromide-activated Sepharose 4B-bound TS-2 monoclonal antibody, which neutralizes IFN-gamma-inducing activity of OK-432. OK-PSA has striking anti-tumor activity in vivo and in vitro. In the current study, the liposomes were used to improve the delivery of the agent (OK-PSA) to effector cells and to increase the therapeutic effect. Significantly less OK-PSA encapsulated into liposomes (Lipo-OK-PSA) than OK-PSA alone (1/100 or less of OK-PSA alone) was required to induce IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), TNF-beta, interleukin-1 beta (IL-1 beta), natural killer, and lymphokine-activated killer activities by human peripheral blood mononuclear cells and mouse spleen cells. Furthermore, higher levels of these activities were detected in peripheral blood mononuclear cells and mouse spleen cells treated with Lipo-OK-PSA than in those treated with OK-PSA. All of these activities induced by Lipo-OK-PSA were almost completely neutralized by anti-asialo-GM1 antibody and complement (p < 0.001). In in vivo experiments, Lipo-OK-PSA elicited striking anti-tumor activity on syngeneic Meth-A tumor-bearing and colon 26-bearing BALB/c mice and on salivary gland tumor-bearing nude mice far better than did OK-PSA. Furthermore, high levels of natural killer and lymphokine-activated killer activities and a significant increase in the number of cells positive for asialo-GM1, IFN-gamma, TNF-alpha, or IL-1 beta were detected in the spleen cells derived from the animals given Lipo-OK-PSA compared with those given saline. These findings clearly indicate that OK-PSA plays an important role in the anti-tumor efficiency of OK-432, and that, for the most part, liposome encapsulation of this molecule markedly accelerates its effect mediated by asialo-GM1-positive cells (mainly natural killer cells).

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cells, Cultured; Cytokines; Cytotoxicity, Immunologic; Drug Carriers; G(M1) Ganglioside; Humans; Interferon-gamma; Interleukin-1; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Leukocytes, Mononuclear; Liposomes; Lymphotoxin-alpha; Mice; Mice, Inbred BALB C; Picibanil; Salivary Gland Neoplasms; Sarcoma, Experimental; Spleen; Streptococcus pyogenes; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

It has been reported that certain chemotherapeutic agents exhibit effects that enhance the antitumor host responses in the patients with malignant diseases. In the present study, we investigated whether cis-diamminedichloroplatinum (cisplatin) and 5-fluorouracil (5-FU) may induce cytokines and effector cells with antitumor efficacy in vivo and in vitro. The cultivation of human peripheral blood mononuclear cells (PBMC) in the presence of cisplatin (0-1.0 microg/ml) or 5-FU (0-5.0 microg/ml) resulted in the significant augmentation of natural killer (NK) and lymphokine-activated killer (LAK) cell activities as well as generation of interferon (IFN) gamma, tumor necrosis factor (TNF) alpha, beta interleukin(IL)-1beta, IL-6 and IL-12 in vitro. In addition, all of these activities were almost completely neutralized by addition of anti-asialoGM1 antibody and complement (P < 0.05). In an in vivo model, the administration of anti-asialoGM1 antibody significantly shortened the survival time extended by the treatment with cisplatin or 5-FU (P < 0.05), both on nude mice bearing salivary gland tumors and on syngeneic MethA-tumor-bearing BALB/c mice. Furthermore, high levels of NK and LAK activities and significant increases of the numbers of cells positive for asialoGM1, IFNgamma, TNFalpha, or IL-1beta were detected in the spleen cells derived from animals given cisplatin or 5-FU as compared with those given saline (P < 0.001-0.05). These findings clearly indicate that cisplatin and 5-FU are potent inducers of several types of cytokines and effector cells carrying antitumor activity mediated by asialoGM1-positive cells (mainly NK cells) for the most part, and that these abilities are closely associated with the in vivo antitumor effect of these agents.

Topics: Adenocarcinoma; Animals; Antibodies; Antimetabolites, Antineoplastic; Antineoplastic Agents; Cisplatin; Cytokines; Female; Fluorouracil; G(M1) Ganglioside; Humans; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Leukocytes, Mononuclear; Mice; Mice, Inbred BALB C; Mice, Nude; Salivary Gland Neoplasms; Spleen; Tumor Cells, Cultured

An IgG2a mouse monoclonal antibody (MoAb) to the human salivary gland adenocarcinoma cell line HSG, 5B/10, has been generated in our laboratory. In the current study, the antitumor effects mediated by MoAb 5B/10 in human salivary gland adenocarcinoma (HSG)-bearing nude mice or the antibody-dependent cell-mediated cytotoxicity (ADCC) against HSG cells using human peripheral blood mononuclear cells (PBMC) as effector cells were examined. In addition, effects of the streptococcal preparation OK-432 on the growth of HSG tumors or on the MoAb 5B/10-mediated cellular cytotoxicity were studied. MoAb 5B/10 mediated an ADCC reaction against HSG cells that were insensitive to NK cells but not to the reaction of antibody and complement-mediated cytotoxicity. The coexistence of MoAb 5B/10 and OK-432 caused marked augmentation of cytotoxic effects. Treatment of OK-432-stimulated PBMC with antiasialo Gm1 antiserum plus complement but not with silica particles resulted in a significant decrease of cytotoxic effects as compared with relevant controls. the nude mice inoculated intraperitoneally with HSG cells and treated with MoAb 5B/10, OK-432, or (especially) a combination of the two had significantly prolonged survival times as compared with untreated controls. Moreover, spleen cells from the tumor-bearing mice treated with OK-432 alone or a combination of MoAb 5B/10 and OK-432 were found to carry high levels of effector cell activity in the MoAb 5B/10-mediated cytotoxicity assay using HSG cells as targets.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Biological Products; Cells, Cultured; Chromium Radioisotopes; Combined Modality Therapy; Female; G(M1) Ganglioside; Glycosphingolipids; Humans; Leukocytes, Mononuclear; Mice; Mice, Nude; Neoplasm Transplantation; Picibanil; Salivary Gland Neoplasms; Silicon Dioxide; Spleen