picibanil and Salivary-Gland-Neoplasms

Topics: Adenolymphoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Humans; Lymphatic Diseases; Male; Middle Aged; Neck; Neck Dissection; Neoplasms, Multiple Primary; Picibanil; Salivary Gland Neoplasms; Salivary Glands, Minor; Tegafur; Uracil

Toll-like receptor 4 (TLR4) plays a significant role in cancer therapy as receptors of bacteria-derived immunotherapeutic agents such as OK-432, a streptococcal immunotherapeutic agent. In addition, recent reports demonstrated that TLRs, including TLR4, are also expressed in cancer cells as well as in immunocompetent cells. It is a problem in cancer therapy that the immunoadjuvant may activate survival signals such as nuclear factor (NF)-κB or mitogen-activated protein kinases (MAPKs) in cancer cells via TLRs. In the current study, we investigated responsiveness of human head and neck cancer cell lines against TLR4 ligands, OK-PSA, an active component of OK-432, and a lipopolysaccharide (LPS). Stimulation with LPS or OK-PSA resulted in the activation of NF-κB in these cell lines expressing TLR4 and MD-2 that is a significant coreceptor for TLR4 signaling. Interestingly, OK-PSA induced cell-growth inhibition, while LPS enhanced the proliferation of the cancer cells. OK-PSA induced NF-κB activation more slowly than that induced by LPS. In addition, phosphorylation of p38 MAPK by OK-PSA was only slight compared with that by LPS. OK-PSA also induced apoptosis of the cancer cells mediated by the activation of caspase 1, 3 and 8 in a p53-independent manner. These findings strongly suggest that active components of OK-432 may elicit anti-cancer effects via enhancing host immunity as well as via directly inducing the growth inhibition and apoptosis of head and neck cancer cells through TLR4 signal.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Caspases; Humans; Lipopolysaccharides; Lymphocyte Antigen 96; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Picibanil; Salivary Gland Neoplasms; Toll-Like Receptor 4

The measurement of the intra-tumoral level of thymidylate synthetase (TS), and dihydropyrimidine dehydrogenase (DPD), may be useful in predicting tumor sensitivity to 5-fluorouracil (5-FU). In this study, we examined the mRNA levels of DPD and TS in 28 oral squamous cell carcinomas (SCC), and 22 salivary gland tumors by semi-quantitative reverse transcription polymerase chain reaction. Then we examined the correlation of the responsiveness of the patients with oral SCC to 5-FU with the intra-tumoral levels of DPD and TS mRNA. All specimens were obtained at the biopsy before treatment, and then the patients were treated by oral administration of a 5-FU compound (UFT), the irradiation of cobalt-60 (upto 60 Gy) and injection of an immuno-potentiator (OK-432). Intra-tumoral levels of DPD mRNA in the patients who showed CR (complete response) and PR (partial response) were significantly lower than those in the patients who showed NC (no change). However, intra-tumoral levels of DPD mRNA did not correlate with the local recurrence of the tumor during the observation period after initial treatment with or without surgical resection of the residual tumors. On the other hand, TS mRNA levels in the tumors did not correlate with any clinico-pathological parameters. These observations suggest that intra-tumoral levels of DPD mRNA may predict the tumor response to 5-FU-based chemo-immuno-radiation therapy in the patients with oral SCC.

Topics: Antimetabolites, Antineoplastic; Biopsy; Carcinoma, Squamous Cell; Cobalt Radioisotopes; Combined Modality Therapy; Dihydrouracil Dehydrogenase (NADP); DNA Primers; Drug Resistance, Neoplasm; Fluorouracil; Humans; Immunotherapy; Oxidoreductases; Picibanil; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Salivary Gland Neoplasms; Thymidylate Synthase; Tumor Cells, Cultured

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

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

An immunoglobulin M mouse monoclonal antibody (MAb) to the streptococcal preparation OK-432, TS-1, was generated. The TS-1 antigen is a carbohydrate epitope. This antigen is stable upon fixation and embedding in paraffin. The tissue and cellular OK-432 localization in human salivary adenocarcinoma-bearing nude mice given OK-432 intratumorally was examined by various methods according to the immunological procedures using the purified TS-1 MAb. The presence of OK-432 antigen recognized by TS-1 MAb was clearly observed in the tumor as well as the spleen and lung 24 or 48 h after OK-432 administration, whereas transfer of OK-432 from the site of injection to the organs, such as liver and kidney, was rarely seen. The presence of OK-432 antigen in some immunocompetent cells, as defined by Mac-1 antigen or asialo GM1 antigen, was observed by the double-antibody labeling technique in the tumor and spleen from tumor-bearing nude mice. Moreover, interaction between OK-432 and macrophages or natural killer (NK) cells in relation to expression of interferon (IFN) in tumor-bearing nude mice given OK-432 was observed. Consequently, significant increases of Ia-positive or Ia-negative macrophages, NK cells as well as IFN-alpha/beta- or IFN-gamma-positive cells in the tumor and/or spleen were found when compared with those without OK-432 administration.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Biological Products; Female; Humans; Killer Cells, Natural; Macrophages; Mice; Mice, Nude; Neoplasm Transplantation; Picibanil; Salivary Gland Neoplasms; Transplantation, Heterologous