picibanil and Lymphoma

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Division; Combined Modality Therapy; Female; Humans; Lymphoma; Male; Picibanil

Topics: Animals; Antibodies, Monoclonal; BCG Vaccine; Brain Neoplasms; Cell Fusion; Glioma; Humans; Hybridomas; Immunotherapy; Interferon Inducers; Interferons; Leukemia; Levamisole; Lymphoma; Mice; Mice, Inbred BALB C; Picibanil

We isolated the lipoteichoic-acid-related molecule (OK-PSA) from OK-432, a streptococcal preparation, by affinity chromatography on CNBr-activated Sepharose-4B-bound monoclonal antibody TS-2, which neutralizes the interferon (IFN)-gamma-inducing activity of OK-432. We have previously reported that OK-PSA is a potent inducer of Th1-type cytokines in human peripheral blood mononuclear cells in vitro. In this study, we conducted an animal experiment to examine whether OK-PSA exhibits an anti-tumor effect in vivo by acting as a Th1 inducer in syngeneic Meth-A tumor-bearing BALB/c mice, in which the Th2 response is genetically dominant. It was found that OK-PSA induced Th1-type cytokines [IFN-gamma, tumor necrosis factor-alpha, interleukin (IL)-2, IL-12 and IL-18] in BALB/c mice bearing Meth-A tumor and caused a marked anti-tumor effect. Although it was suggested by an in vitro study. using spleen cells derived from the animals, that IL-18 plays the greatest role in the induction of the Th1-dominant state and tumor cell killing induced by OK-PSA, the in vivo experiments demonstrated that both IL-12 and IL-18 are essential in the anti-tumor effect exhibited by OK-PSA. These findings strongly suggest that OK-PSA is a major effector molecule of OK-432 and may be a useful immunotherapeutic agent, as a potent Th1 inducer, for cancer patients with a Th2-dominant state.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Apoptosis; Chromatography, Affinity; Drug Screening Assays, Antitumor; Fas Ligand Protein; fas Receptor; Female; Fibrosarcoma; Interleukin-12; Interleukin-18; Killer Cells, Natural; Lipopolysaccharides; Lymphokines; Lymphoma; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Moloney murine leukemia virus; Neoplasm Transplantation; Penicillin G; Perforin; Picibanil; Pore Forming Cytotoxic Proteins; Spleen; Streptococcus pyogenes; Teichoic Acids; Th1 Cells; Th2 Cells; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

To investigate the histological effect of intranodal injection of the streptococcal preparation OK-432, we performed intranodal injection in 4 patients with cervical lymph node (CLN) metastases of malignant head and neck tumors (squamous cell carcinoma (SCC) of the oropharynx, SCC of the parotid gland, malignant lymphoma, and rhabdomyosarcoma of the nasal cavity). An initial dose of 5 klinische Einheit (KE) and a maintenance dose of 10 KE of OK-432 were administered into each metastatic or residually involved CLN twice a week. The total dose of OK-432 ranged from 105 KE to 395 KE and the number of administrations ranged from 11 to 40. Post treatment histological examination of excised tissue specimens revealed no tumor cells; there was only fibrosis and inflammatory cell infiltration. These findings suggest that intranodal injection of OK-432 can be utilized for treatment of relatively small CLN metastases of malignant head and neck tumors.

Topics: Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Humans; Lymphoma; Male; Middle Aged; Neoplasm Metastasis; Picibanil; Retrospective Studies; Rhabdomyosarcoma

The present study was designed to determine whether antitumor activity of macrophages induced with OK-432 and cyclophosphamide was mainly dependent on their ability to produce a soluble factor, that is, L-arginine-dependent nitric oxide as measured by nitrite concentration. Nitrite production by peritoneal macrophages from NIH Swiss mice pretreated with OK-432 (125 KE/kg) i.p. twice at 1-week intervals and with cyclophosphamide (200 mg/kg) i.p. 2 days before the second OK-432 treatment, increased with time for 24 h, and proportionally depended on macrophage numbers. Nitrite production was inhibited by actinomycin D and puromycin but not by mitomycin C. NG-Monomethyl-L-arginine, a specific competitive inhibitor of L-arginine-dependent nitric oxide synthesis, also inhibited production. There was a close correlation between nitrite production and antitumor activity in macrophages from mice pretreated with either OK-432 and cyclophosphamide, OK-432, or thioglycolate broth. OK-432 increased both nitrite production and antitumor activities when added to the macrophage from mice pretreated with OK-432 but not with thioglycolate broth. Both activities of macrophages from mice pretreated with OK-432 and cyclophosphamide were enhanced with increasing concentrations of L-arginine (0.125-1 mM) in the culture medium. D-Arginine, however, did not substitute for L-arginine. Neither activity was affected by contact between the macrophage and the EL4 cell. The macrophage showed antitumor activity through a membrane filter though the activity was greatly reduced. This antitumor activity of macrophages through a membrane was also inhibited by NG-Monomethyl-L-arginine, and increased by OK-432. However, conditioned media, obtained by culturing macrophages induced with OK-432 and cyclophosphamide, inhibited growth of EL4 cells. This activity was carried out by dialysable and non-dialysable factors. One of the dialysable factors was nitrite, an oxidized product of nitric oxide. The antitumor activity of non-dialysable factors was heat-stable and production of factors was increased by NG-Monomethyl-L-arginine and OK-432. Also, non-dialysable factors increased both antitumor and nitrite production activities of OK-432-elicited macrophages, when incubated with factors. Such activity of factors was also heat-stable. The production of factors increased with incubation time of macrophages, and was not inhibited by NG-Monomethyl-L-arginine. These results indicate that in vitro antitum

Topics: Animals; Arginine; Cell Adhesion; Cell Division; Culture Media; Cyclophosphamide; Immunity, Cellular; In Vitro Techniques; Lymphoma; Macrophage Activation; Macrophages; Mice; Nitric Oxide; Nitrites; Picibanil; Tumor Cells, Cultured

The secretory function of the natural killer (NK) cells has been considered to be essential for cytolytic activity against their target cells. In this study, the distribution and spatial relationship of various cell organelles which participate in the secretory process, i.e., Golgi apparatus, vesicles, granules and microtubules, were examined ultrastructurally in non-treated and OK-432-activated rat NK cells bound to the tumor cells, with special reference to the rod-cored vesicles which are the most characteristic structure of the NK cells. Rod-cored vesicles and their closely related structures, "empty" vesicles, were derived from the end portion of the Golgi trans cisternae and became accumulated in the central area which was surrounded by the Golgi apparatus, nucleus and contact surface. Some of the vesicles appeared to be further transported to the contact area along the microtubules extending from the centrioles toward the bound targets. The access of the vesicles to the contact surface occurred at that portion where subplasmalemmal actin lattice was thin. The distribution of the dense granules and multivesicular bodies was similar to that of the vesicles, but the area of their occurrence was a little wider. At the outer aspect of the Golgi apparatus was situated the endoplasmic reticulum from which transitional vesicles came to the inner or cis cisternae of the apparatus. The present observations indicate that the cell organelles of the conjugated NK cells are purposefully arranged in the cytoplasm in such order that the generated rod-cored vesicles and "empty" ones are efficiently directed toward the bound tumor cells.

Topics: Animals; Cytoplasmic Granules; Golgi Apparatus; Killer Cells, Natural; Lymphoma; Microscopy, Electron; Microtubules; Mitochondria; Neoplasms; Organelles; Picibanil; Rats; Rats, Inbred Strains; Tumor Cells, Cultured

TILs can be isolated and expanded in vitro in the presence of RIL-2. The resulting cells are highly cytotoxic in vitro and in vivo against a variety of tumor targets. Although most of the TILs bear T cell antigens on their cell surface, recent evidence suggests that natural killer (NK) cells may be part of the overall population of infiltrating cells. Based upon this evidence, we have evaluated the effects of Picibanil (OK-432), a well-known inducer of NK cell and T cell cytotoxicity, on TILs. OK-432 was administered intravenously at a dose of 100 micrograms, previously determined to be optimal for NK stimulation, to tumor-bearing animals. Two days later, control and experimental animals had their tumors harvested and processed in order to grow their TILs in vitro in complete medium containing RIL-2 at a final concentration of 1,000 U/ml. The following observations were made: 1) a greater than 300% increase in overall TIL number compared to controls on day 10 of culture returning to normal by day 30; 2) a marked increase in the percent of cells expressing cytotoxic and differentiation antigens in the experimental group compared to controls, such increase seen mostly from day 7 to day 10; 3) a marked increase in the cytotoxic activity of the experimental TILs against an NK-sensitive tumor target, the YAC-1 lymphoma, throughout the period of growth of the TILs (3-4 times controls) and to a lesser extent against an NK-resistant tumor target. These findings may have potential application, in immunotherapeutic trials against human tumors and may help to understand the reasons for the effectiveness of OK-432 in vivo against selected murine tumors.

Topics: Adenocarcinoma; Animals; Antigens, Differentiation, T-Lymphocyte; Biological Products; Cell Division; Cells, Cultured; Female; Fluorescent Antibody Technique; Lymphoma; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Picibanil; Premedication; Sarcoma, Experimental; T-Lymphocytes, Cytotoxic; Up-Regulation

The mean survival age of female AKR/J mice was significantly prolonged, the enlargement of thymus was markedly suppressed, and the proliferation of ecotropic and recombinant murine leukemia viruses was inhibited when 2-month-old female AKR/J mice were injected intraperitoneally with attenuated Streptococcus pyogenes, strain Su (OK-432) twice weekly for 8 weeks. However, these effects of OK-432 in 2-month-old female AKR/J mice were not seen in 5-month-old female AKR/J mice. The difference in the effectiveness of OK-432 in these animals probably depends on the difference in the degree of the proliferation of ecotropic and recombinant murine leukemia viruses in the thymus which consequently lead to thymic lymphoma.

Topics: Animals; Biological Products; Female; Incidence; Leukemia Virus, Murine; Lymphoma; Male; Mice; Mice, Inbred AKR; Organ Size; Picibanil; Spleen; Thymus Gland; Thymus Neoplasms; Uterus

A synergistic therapeutic effect on Meth-A ascites tumor was obtained in BALB/c mice by the simultaneous i.p. injection of OK-432 and interferon alpha A/D (IFN-alpha). BALB/c mice that were cured of their Meth-A tumors showed significant tumor-specific rechallenge resistance. Combined therapeutic effect was significantly weaker in nude mice than in haired mice. The stimulation of host T-cell immunity was indicated to be crucially important for obtaining cured mice. Natural killer activity of peritoneal exudate cells was enhanced and peaked on day 1 with IFN-alpha, on day 3 with OK-432, and was sustained for up to 5 days with combination therapy. Macrophage activity assayed by in vivo resistance to the challenge of Listeria monocytogenes was stronger in order of OK-432 greater than OK-432 + IFN-alpha greater than IFN-alpha. Cytotoxic T-lymphocyte activity induced by immunization with the allogeneic tumor was enhanced most strongly by OK-432 plus IFN-alpha treatment. Each of the agents had tumor inhibitory activity on the growth of Meth-A cells in vitro, and there was a slight additive effect when two agents were used together. These findings suggest that the synergistic therapeutic effect of OK-432 plus IFN-alpha treatment on Meth-A ascites tumor was partly due to the direct antitumor activity of these two agents, but was also due in part to the beneficial antitumor immune responses that were induced. A similar synergism on Meth-A tumor was also observed by OK-432 plus interferon gamma treatment. However, this combination therapy was not effective on MH-134 ascites tumor in C3H mice.

Topics: Animals; Biological Products; Cells, Cultured; Combined Modality Therapy; Drug Synergism; Fibrosarcoma; Indomethacin; Interferon Type I; Interferon-gamma; Liver Neoplasms, Experimental; Lymphoma; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Picibanil; T-Lymphocytes

Spleen cells of untreated mice became nonspecifically cytotoxic after cultivation in the presence of a streptococcal preparation, OK-432, for 3 or more days. The cytotoxic cells, named OK-432-induced killer (OIK) cells, injured a variety of target cells including syngeneic EL-4 cells resistant to natural killer (NK) cells, but not NK-susceptible YAC-1 cells. C57BL/6 splenic cells cultured for 5 days in the presence of both OK-432 and interleukin 2 (IL-2) were highly cytotoxic to both EL-4 and YAC-1 cells, and had Thy-1+, Lyt-1,2-, and asialogGM1+ phenotypes, which were identical with those of OIK cells. A test for competitive inhibition with cold target cells and fractionation by centrifugation onto discontinuous density gradients of Percoll showed that cytotoxic cells generated by OK-432 plus IL-2 comprised at least two populations; the cells in the first population were cytotoxic to EL-4 cells but not to YAC-1 cells, and were smaller in size than those in the second population, which were cytotoxic to YAC-1 cells and had NK morphology. Therefore, generation of OIK cells was augmented by IL-2.

Topics: Animals; Biological Products; Cells, Cultured; Cytotoxicity, Immunologic; Dose-Response Relationship, Immunologic; Drug Synergism; Interleukin-2; Killer Cells, Natural; Lymphoma; Male; Mice; Mice, Inbred Strains; Picibanil; Spleen

A case of synchronous multiple primary neoplasms, an intracranial malignant lymphoma and a gastric carcinoma, is presented. A 63-year-old man was admitted to our hospital with complaints of dizziness and a floating sensation on gait. A CT scan after admission, revealed a well-defined, nodular high density area in the left frontal lobe, which was markedly enhanced by the contrast medium. In order to rule out a metastatic brain tumor, examinations were performed as a consequence, and, the gastric carcinoma was found. A partial removal of the brain tumor and a gastrectomy were performed in two stages. Pathologically, the diagnosis of the brain tumor indicated a malignant lymphoma of large cell type, and that of the gastric carcinoma was an adenocarcinoma. The patient received postoperative irradiation and chemotherapy and was discharged in a good condition. He died of pneumonia 21 months after the operation. Necropsy revealed a marked atrophy of the brain without recurrence of the malignant lymphoma and no recurrence of a gastric cancer.

Topics: Adenocarcinoma; Aged; Brain Neoplasms; Combined Modality Therapy; Gastrectomy; Humans; Lymph Node Excision; Lymphoma; Male; Neoplasms, Multiple Primary; Picibanil; Stomach Neoplasms

Topics: Adenocarcinoma; Aged; Biological Products; Cell Cycle; Cytotoxicity, Immunologic; Female; Glycoproteins; Humans; Lung Neoplasms; Lymphoma; Male; Middle Aged; Picibanil; Pleural Effusion; Tumor Necrosis Factor-alpha

Natural killer (NK) activity of mouse splenocytes was significantly augmented when the splenocytes were incubated for 3 to 4 hr with culture supernatants of mouse thymocytes stimulated by OK-432, an antitumor preparation from the Streptococcus pyogenes SU-strain. Antiviral activity was also detected in the culture supernatants, but IL 2 activity was not. When the culture supernatants of thymocytes stimulated by OK-432 were fractionated on a column of Blue Sepharose CL-6B, NK enhancing activity and antiviral activity were observed in partly overlapping fractions that bound to the column. However, the antiviral activity in the Blue Sepharose-bound fraction was neutralized completely by treatment with anti-IFN (alpha, beta) antiserum, whereas significant NK cell enhancing activity was still observed after treatment with anti-IFN (alpha, beta) antiserum. When the Blue Sepharose-bound fraction was subjected to gel filtration, the NK cell enhancing activity was detected in the 25,000 to 35,000 and 40,000 to 67,000 m.w. regions, but antiviral activity was observed in the over 67,000 m.w. region. These results indicate that a new kind of lymphokine, called natural killer cell activating factor (NKAF), distinct from IFN and IL 2, was found. The NKAF was found to have the following properties: its pI value is between pH 5.5 and 6.5, it binds to concanavalin A- and lentil agglutinin-Sepharose, and it is stable with pH 2-24 hr treatment. In addition, NKAF-producing cells were peanut agglutinin (PNA)-thymocytes when thymocytes were fractionated by the agglutination-sedimentation method with the use of PNA.

Topics: Animals; Biological Products; Cell Line; Culture Media; Cytotoxicity, Immunologic; Dose-Response Relationship, Immunologic; Female; G(M1) Ganglioside; Glycosphingolipids; Growth Inhibitors; Immune Sera; Interferons; Isoelectric Focusing; Killer Cells, Natural; Killer Factors, Yeast; Kinetics; Lectins; Lymphocyte Activation; Lymphoma; Mast-Cell Sarcoma; Mercaptoethanol; Mice; Mice, Inbred C3H; Molecular Weight; Peanut Agglutinin; Picibanil; Protein Biosynthesis; Proteins; T-Lymphocytes

Topics: Astrocytoma; Biological Products; Brain Neoplasms; Combined Modality Therapy; Drug Therapy, Combination; Ependymoma; Fluorouracil; Glioma; Humans; Lymphoma; Meningeal Neoplasms; Meningioma; Nimustine; Nitrosourea Compounds; Oligodendroglioma; Picibanil

Topics: Antineoplastic Agents; Drug Therapy, Combination; Humans; Lymphoma; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Picibanil

Topics: Animals; Biological Products; Female; Humans; Indomethacin; Lymphocyte Activation; Lymphoma; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Picibanil

Recently, a streptococcal preparation, OK-432 has been used successfully as an immunopotentiator for immunotherapy in patients with malignant tumors in Japan. In this paper, we report that the administration of OK-432 augments the cytotoxic activity of peripheral blood lymphoid cells against a natural killer (NK) cell-sensitive erythroleukemic cell line, K562, in tumor patients. In patients before or after surgery, sufficient amounts of OK-432 strongly augmented the cytotoxic activity within 3 days after the initial administration of OK-432. Thereafter the levels of cytotoxicity declined rapidly. The administration of a lower dose of OK-432 gave a lower increase in cytotoxicity. Enhanced cytotoxicity occurred with the reintroduction of OK-432 but remained at lower levels of activity. Characterization and fractionation of OK-432-induced effector cells revealed that the augmented cytotoxicity seemed to be carried mainly by NK cells. A low titer of interferon was detected in 3 of 10 patients within 72 hr after the first inoculation of the agent. Furthermore, we discuss the potency of OK-432 for the induction of interferon in detail.

Topics: Adjuvants, Immunologic; Biological Products; Breast Neoplasms; Cell Separation; Cytotoxicity, Immunologic; Humans; Interferons; Lymphoma; Neoplasms; Picibanil; Stomach Neoplasms; Time Factors

Topics: Aged; Biological Products; Female; Humans; Immunotherapy; Lymphoma; Neoplasm Invasiveness; Picibanil; Skin; T-Lymphocytes

Clinical trials of immuno-chemotherapy were conducted on malignant lymphoma patients. Patients during the period from 1972 through 1977 were allocated to two groups retrospectively according to the mode of treatment, i.e., chemotherapy alone (historical control group, 35 patients) and chemotherapy with OK-432 (treated group, 15 patients). Comparisons were made of the two groups, which were homogeneous with regard to induction chemotherapy, maintenance chemotherapy, stage and histologic type of disease. The treated group had a higher remission rate, and a longer remission duration and survival than the control groups, especially in patients with Hodgkin's disease but the difference was not statistically significant owing to the limited number of cases.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Biological Products; Bleomycin; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Immunotherapy; Lymphoma; Male; Middle Aged; Picibanil; Prednisolone; Vincristine

Topics: Antibiotics, Antineoplastic; Humans; Immunoglobulin G; In Vitro Techniques; Leukemia, Lymphoid; Lymphoma; Picibanil; Zinostatin