picibanil and Colonic-Neoplasms

Topics: Animals; Colonic Neoplasms; Disease Models, Animal; Humans; Immunologic Surveillance; Immunotherapy; Interleukin-2; Killer Cells, Natural; Liver; Liver Neoplasms; Picibanil

The chemical structure and characteristics, the antitumour activity, the antibacterial, antiviral, antifungal, antiparasitic activities, immunological properties and mode of action of immunomodulators of microbial origin, especially antitumour polysaccharide lentinan, have been discussed immunopharmacologically in comparison with pachymaran, schizophyllan, DiLuzio's yeast glucan, Coriolus preparation PS-K, Streptococcal preparation OK-432, Nocardia rubra cell wall skeleton N-CWS together with BCG and Corynebacterium parvum. Lentinan exerts its inhibitory action not only on allogeneic tumours but also on syngeneic and autologous tumours, and prevents chemical and viral carcinogenesis. The phase III randomized control study of lentinan in cancer patients with gastric and colo-rectal cancer showed the clinical efficacy of lentinan in prolonging the life span and improving host immune responses. Experimental and clinical application demonstrated the advantage of N-CWS over BCG-CWS, and a recent study on OK-432 showed similar results to those obtained with C. parvum. In future work on microbial immunomodulators, it will be essential to find a parameter of the host-tumour relationship which will indicate the protocol for application of immunomodulators, and to find a new-type of selective immunostimulant. For this purpose, exhaustive studies on lymphokines, monokines and lymphocyte tropic hormones are indispensable.

Topics: Adjuvants, Immunologic; Animals; Bacteria; BCG Vaccine; Blood Proteins; Carbohydrate Conformation; Chemical Phenomena; Chemistry; Colonic Neoplasms; Fungi; Glucans; Humans; Immunotherapy; Infections; Lentinan; Lymphocytes; Macrophage Activation; Neoplasms, Experimental; Picibanil; Polysaccharides; Proteoglycans; Rectal Neoplasms; Sizofiran; Stomach Neoplasms; Structure-Activity Relationship

Topics: Antineoplastic Agents; Colonic Neoplasms; Drug Therapy, Combination; Humans; Immunotherapy; Lymphocyte Activation; Mitomycins; Picibanil; Rectal Neoplasms

We investigated the efficacy and safety of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil (carmofur, HCFU) and uracil/tegafur (UFT).. Patients with stage II, III, or IV (Dukes' B, C) colorectal cancer were enrolled and randomly assigned to one of three groups: an immunochemotherapy group (mitomycin C [MMC] + 5-fluorouracil [5-FU] + HCFU + OK-432), a chemotherapy group (MMC + 5-FU + HCFU), and a control group (surgery alone) for those with colon cancer (study 1); and an immunochemotherapy group (MMC + 5-FU + UFT + OK-432), a chemotherapy group (MMC + 5-FU + UFT), and a control group (surgery alone) for those with rectal cancer (study 2).. A total of 760 patients with colon cancer and 669 patients with rectal cancer were entered into this randomized clinical trial (RCT). The incidence of side-effects was in the order of: immunochemotherapy group >> chemotherapy group >> control group in both the cohort of patients with colon cancer and the cohort with rectal cancer. In particular, the frequency of leucopenia and skin disorders was significantly higher than control groups. There were no severe adverse events such as death related to the adjuvant therapy. In both the colon cancer and rectal cancer cohorts, no significant difference in the 5-year survival rate and disease-free survival rate was noted among the three groups.. The results of an RCT demonstrated that the combination of MMC + 5-FU + HCFU + OK-432 for colon cancer and that of MMC + 5-FU + UFT + OK-432 for rectal cancer could not prolong the survival of patients with surgically resected colorectal cancer, but that both combinations were well tolerated as adjuvant therapy. We investigated the efficacy and safety of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil (carmofur, HCFU) and uracil/tegafur (UFT).

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Drug Combinations; Female; Fluorouracil; Humans; Injections, Subcutaneous; Male; Middle Aged; Mitomycin; Neoplasm Staging; Picibanil; Pyrimidines; Radiotherapy, Adjuvant; Rectal Neoplasms; Survival Analysis; Tegafur; Treatment Outcome; Uracil

In Japan, long-term oral therapy with tegafur in combination with immunopotentiators is commonly used as adjuvant therapy after curative resection of gastric or colorectal can for gastric and colorectal cancer. When the outcome was analyzed in terms of the relative performance (R.P.) and the individual dose intensity (I.D.I.) of OK-432, gastric cancer patients with a R.P. of 0.5 or higher tended to have a better survival curve. There were no marked differences in lymphocytes subsets, except that the Leu 7 level at 3 months after gastric cancer resection was significantly higher (p < 0.05) in group B than in group A. Thus, no inhibition of the anticancer effect of UFT was noted during long term combination therapy with UFT and an immunopotentiator as postoperative adjuvant therapy for patients who underwent curative resection of gastric or colorectal cancer. The results suggest that UFT combined with long-term OK-432 maintenance therapy may contribute to improve survival rates in gastric cancer patients.

Topics: Adjuvants, Immunologic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Combinations; Humans; Middle Aged; Picibanil; Rectal Neoplasms; Stomach Neoplasms; Survival Rate; Tegafur; Uracil

We have previously reported that the antitumor effect of OK-432, a streptococcal preparation, is markedly augmented when injected intratumorally together with fibrinogen (OK-432/fbg) [1]. In order to elucidate the effects of this immunotherapy on regional lymph nodes (RLN), we carried out both morphological and functional analyses of the RLN from colonic cancer patients treated with OK-432/fbg. Computer-aided morphometry revealed that the maximal cross-sectional areas and the broadest diameters of the RLN were significantly greater (p < 0.01) in patients who had undergone local immunotherapy than in patients who had not. The component structures of RLN, such as sinus, follicle and paracortex, were all enlarged in the OK-432/fbg-treated patients, and necrosis of metastatic tumors was observed. RLN lymphocytes recovered from OK-432/fbg treated patients showed elevated reactivity to phytohemagglutinin (PHA) and the stimulation index was clearly higher than that of control patients. Flow cytometric analysis revealed a predominance of T-cells, especially CD4 subsets, and higher positivity for both CD25 and HLA-DR. Furthermore, RLN lymphocytes killed more effectively K562 and Daudi cells in the patients who had had immunotherapy. These results suggest that the effect of local immunotherapy with OK-432/fbg is not restricted to the site of injection but extends to the lymph nodes, and contributes to tumor regression through the augmentation of cellular immunity.

Topics: Aged; Colonic Neoplasms; Combined Modality Therapy; Female; Fibrinogen; Flow Cytometry; Humans; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Lymph Nodes; Lymphocyte Activation; Lymphocytes; Male; Middle Aged; Phenotype; Picibanil

One hundred and eighty nine patients who had undergone curative resection of colorectal cancer were treated with a prospective randomized controlled adjuvant chemo-immunotherapy consisting of Tegafur, Adriamycin (ADM), Mitomycin C (MMC) and OK432. One hundred and thirty five patients with Dukes' B and Dukes' C carcinoma were valid for evaluation. Effects of the therapy were estimated by cumulative survival rate. There was no significant survival difference in colonic carcinoma and Dukes' B rectal carcinoma between the treated and control groups. But there was an advantage in two and three years survival for the chemo-immunotherapy in Dukes' C rectal carcinoma (p less than 0.1). Examining the survival rate of Dukes' C rectal carcinoma for each combination of therapeutic agents, the patients treated with Tegafur and ADM had the most favorable survival rate, the patients treated with Tegafur alone had the next favorable one, the patients treated with Tegafur and MMC had the lowest one. The administration of MMC during operation was less effective than the post operative administration in Dukes' C rectal carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Combined Modality Therapy; Doxorubicin; Female; Humans; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Prospective Studies; Rectal Neoplasms; Tegafur

Topics: Aged; Antineoplastic Agents; Catheter Ablation; Colonic Neoplasms; Combined Modality Therapy; Female; Humans; Injections, Intralesional; Liver Neoplasms; Lung Neoplasms; Picibanil; Radio Waves; Remission, Spontaneous; Reoperation; Tomography, X-Ray Computed

Conventional therapy for colorectal carcinoma using 5-fluorouracil (5-FU) has shown limited antitumor action. The purpose of our study was to investigate synergistic antitumor effects of the streptococcal preparation of OK-432 and 5-FU, and to elucidate the mechanisms of interaction between the 2 agents in mice. Biochemical modulation of OK-432 and 5-FU were determined in vivo against colon-26 carcinoma. The concentration of 5-FU and its metabolites, and the activity of thymidylate synthase and thymidine kinase, respectively, were measured using cytosolic extracts of the tumors. Combination treatment with OK-432 produced a significant increase in intratumor 5-FU and 5-FU in RNA (F-RNA) concentrations, increased the thymidylate synthetase inhibition rate, and decreased thymidine kinase activity, as compared with the results observed in the control mice. These additive antitumor effects are obtained by use of the 2 agents; the mechanism of action is considered to be the suppression of both the de novo and the salvage pathway for DNA synthesis, along with the suppression of RNA synthesis.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorodeoxyuridylate; Fluorouracil; Male; Mice; Picibanil; RNA; Thymidine Kinase; Thymidylate Synthase

In order to study the clinical usefulness of biological response modifiers (BRMs) in eliminating malignant solid tumors, we have investigated the effect of various combination therapies on the murine Colon26 solid tumor model. When the tumor-bearing mice were treated with chemotherapeutics, G-CSF and OK-432 (streptococcal preparation), the tumors completely disappeared from all of the treated mice. When these survivors were rechallenged with Colon26 tumor cells on Day 120, all of them survived without showing any sign of recurrence or metastases. The results indicate that mice with malignant solid tumors, which can not be cured using chemotherapeutics alone, may be completely healed with a combination immuno-chemotherapy. During the course of this combination therapy, study, it was found that there was a clear positive correlation between immunosuppressive acidic protein (IAP) levels and tumor sizes. Suppressor macrophages (sM phi) which produce IAP were found to be decreased in bone marrow and spleen of treated mice. This suggests that the combination therapy may make the mice recover from a suppressed immune state caused by sM phi. In conclusion, the combination therapy with chemotherapeutics and BRMs could cure the solid tumor-bearing mice very effectively through not only synergistic direct tumor cell destruction but also indirect immunomodulation of the host.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Colonic Neoplasms; Cyclophosphamide; Cytotoxicity, Immunologic; Epirubicin; Female; Granulocyte Colony-Stimulating Factor; Immunologic Factors; Macrophages; Mice; Mice, Inbred BALB C; Mitomycin; Neoplasm Proteins; Picibanil; Recombinant Proteins; Tumor Cells, Cultured

The effect of intratumoral administration of BRMs in Meth-A solid tumor has been analyzed in BALB/c mice. The effect of BRMs on in vitro invasion by murine RL male-1 leukemia cells was studied using Biocoat Matrigel Invasion Chamber (Becton Dickinson Labware). We determined the ability of tumor cells to penetrate matrigel-coated filters in the presence or absence of BRM. PSK or OK-432 inhibited tumor cell invasion of matrigel-coated filters in a dose-dependent manner. PSK, OK-432 and Cepharanthin inhibited invasion of murine Colon 26 carcinoma cells and human A 375. S2 melanoma cells. On the other hand, polysaccharide preparations without protein, Lentinan or Sonifilan inhibited neither tumor growth nor tumor cell invasion.

Topics: Animals; Colonic Neoplasms; Humans; Immunologic Factors; Injections, Intralesional; Leukemia, Experimental; Male; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Picibanil; Proteoglycans; Sarcoma, Experimental; Tumor Cells, Cultured

We have previously demonstrated that administration of killed streptococcal preparation (OK432), a biological modifier, increased the number of asialo GM1-positive cells in the liver, enhanced NK activity of hepatic mononuclear cells, and reduced the number of hepatic metastases of colon 38 adenocarcinoma that were inoculated into the superior mesenteric vein of C57BL/6 strain mice. In the present study, to clarify the role of the spleen in immune surveillance of the liver, the effect of splenectomy on hepatic metastasis of colon carcinoma and on hepatic NK activity has been examined. The number of hepatic metastasis increased in the splenectomized mice, compared with that in sham-operated mice. Administration of OK432 increased the number of asialo GM1-positive cells in the liver and enhanced NK activity of hepatic mononuclear cells in both groups, but NK activity of hepatic mononuclear cells in the splenectomized mice was less than that of the sham-operated mice. An enhanced NK activity of these cells was abolished by treatment with anti-asialo-GM1 antibody plus complement in vitro. Interleukin-2 mRNA expression was increased in the spleen 2 hr after OK432 administration and persisted until 8 hr, but was scarcely noted in the liver. On the other hand, NK activity of hepatic mononuclear cells in the asialo GM1-positive cell-depleted (previous administration of antiserum against asialo GM1) mice was enhanced after OK432 administration in the sham operated and splenectomized mice, but an enhanced NK activity in these mice was only partially or not at all abolished by treatment with anti-asialo GM1 antibody plus complement in vitro, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Colonic Neoplasms; G(M1) Ganglioside; Interleukin-2; Killer Cells, Natural; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Picibanil; RNA, Messenger; Spleen; Splenectomy

A simple and highly reproducible mouse colonic cancer model with mesenteric lymph node (MLN) metastasis was established by injecting COLON-26 tumor cells into lymphatic nodules in the tip of vermiform appendix of BALB/C mice. In this model, antitumor effect of orally administered OK-432 was examined. OK-432 was given orally at three different periods: before injection of COLON-26 cells (Protocol-A), early after injection of COLON-26 cells (Protocol-B), and late after injection of COLON-26 cells (Protocol-C). As a result, MLN metastasis was significantly suppressed and survival rate was significantly improved in every protocol as compared to mice without OK-432 administration. Then, in vivo anti-tumor activities of MLN cells and splenic lymphocytes were evaluated by Winn assay. Tumor neutralizing activity against syngenic COLON-26 cells was induced in the MLN cells after OK-432 administration and the effector cells were found in CD4-positive T lymphocytes because MLN cells treated with anti-L3/T4 and anti-LFA plus complement lost their anti-tumor efficacy. In conclusion, oral administration of OK-432 appears to be an effective immunotherapy against colonic cancer especially in the prevention and the treatment for MLN metastasis.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents; Colonic Neoplasms; Immunotherapy; Lymphatic Metastasis; Male; Mesentery; Mice; Mice, Inbred BALB C; Nitrosomethylurethane; Picibanil

An experimental model for hepatic metastasis with a transplantation route of free-pedicled subcutaneous-embedded spleen was established in BALB/c mice. Colon-26 tumor cells to produce hepatic metastasis were inoculated into the spleen and the influence of surgical stress by means of a 20-min exposure of the abdominal cavity on the incidence of hepatic metastasis was examined. Hepatic metastasis was more promoted by the surgical stress in order when it was given on the same day, the 7th day and the 3rd day of the inoculation. Administration, without surgical stress, of ASGM 1, a specific inhibitor of the natural killer activity, also facilitated the hepatic disease. Administration of OK-432 prior to the surgical stress or ASGM 1 was at least partly effective for prevention of the hepatic metastasis and prolonged the survival of the inoculated mice. Preoperative immunotherapy utilizing OK-432 might be a possible means to prevent hepatic metastasis triggered in colorectal surgery for cancer.

Topics: Animals; Antibodies; Antineoplastic Agents; Colonic Neoplasms; Cytotoxicity, Immunologic; Disease Models, Animal; G(M1) Ganglioside; Killer Cells, Natural; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplastic Cells, Circulating; Picibanil; Stress, Physiological; Surgical Procedures, Operative

Inhibitory effects of OK-432 administered orally on DMH-induced colon tumors in rats were examined. As for the immunological parameter, NK activity was measured. ODC activity and nuclear DNA ploidy pattern of the tumor involved areas were evaluated and the histological examination was done in the process of the occurrence of tumors. Rats were divided into four groups as follows; control group, OK-432 group, DMH group and DMH+OH-432 group. As for the appearance of DMH induced colon tumors, the average numbers of tumors per rat in the DMH+OK-432 group were inhibited significantly compared with those in the DMH group, and the rate of cancer in situ in the DMH+OK-432 group significantly increased compared with that in the DMH group. NK activity of lymphocytes in the spleen and lymph nodes in the colon was increased after the oral administration of OK-432, but it was decreased following the peak activity, and it was lower level than that of the control group. An appropriate oral administration of OK-432 may be effective against chemically induced carcinoma of the colon.

Topics: 1,2-Dimethylhydrazine; Administration, Oral; Animals; Colonic Neoplasms; Cytotoxicity, Immunologic; Dimethylhydrazines; Killer Cells, Natural; Male; Picibanil; Rats; Rats, Sprague-Dawley

The effect of OK432 on hepatic metastasis, induced by inoculating 1 x 10(6) ACL-15 cells from a rat colon adenocarcinoma cell line into the ileocolic vein of male F344 rats, was investigated in this study. Metastases were detected 14 days after inoculation in the control rats, however, pretreatment 3 days prior to the tumor cell inoculation with an anti-asialoGM1 antibody, which eliminates natural killer (NK) cell activity in vitro, increased the number of hepatic metastases, shortened the survival time, and decreased the NK activity of the nonparenchymal liver cells (NPC). In contrast, pretreatment with OK432 2 days prior to tumor inoculation significantly decreased the number of hepatic metastases, prolonged the survival time, and augmented the NK activity of the NPC, although treatment with OK432 3 or 7 days after inoculation did not decrease the number of hepatic metastases. Moreover, NPC from the OK432-pretreated rats had a marked antitumor effect against ACL-15 cells in the Winn's neutralization test. The results of this study indicate that pretreatment with OK432 before tumor cell inoculation inhibits hepatic metastasis in this experimental model, possibly by augmentating liver-associated NK activity.

Topics: Adenocarcinoma; Animals; Colonic Neoplasms; Killer Cells, Natural; Liver; Liver Neoplasms; Male; Neoplasm Transplantation; Neutralization Tests; Picibanil; Rats; Rats, Inbred F344; Spleen; Tumor Cells, Cultured

The patient was an 82-year-old female with a 32-month clinical course after right hemicolectomy for ascending colon cancer. Serum carcino embryonic antigen (S-CEA) increased about 38 ng/ml, and metastatic spleen tumor was recognized by abdominal CT and MRI. To induce endogenous LAK, intra-arterial immunochemotherapy with cyclophosphamide (CPM) and OK-432 was performed. Three days after CPM administration, peripheral white blood cells decreased. Recovery from this CPM side effect was achieved with granulocyte colony-stimulating factor (G-CSF). LAK activity of peripheral blood lymphocytes increased from 3% to 17%. Then intra-arterial immunochemotherapy was continued for 7 months, after which the tumor size increased but the S-CEA level remained under 40 ng/ml.

Topics: Aged; Aged, 80 and over; Carcinoembryonic Antigen; Colonic Neoplasms; Cyclophosphamide; Female; Granulocyte Colony-Stimulating Factor; Humans; Immunotherapy; Infusions, Intra-Arterial; Killer Cells, Lymphokine-Activated; Picibanil; Splenic Neoplasms

A human monoclonal antibody, YJ-37 (IgM) was generated through the fusion of human B lymphoblastoid cell line HO-323 with the regional lymph node lymphocytes from a colonic cancer patient who was treated with a local immunotherapy. This antibody was purified and conjugated with biotin, after which direct immunohistochemical staining was performed. The results revealed that YJ-37 selectively reacted with colonic cancer (7/19), gastric cancer (3/6), endometrial cancer (1/2) and colonic adenoma (7/13), but not with normal epithelia. Membrane immunofluorescence and FACS analysis also showed that YJ-37 bound to tumor cell surfaces. Furthermore, the chemical structure of the antigen defined by YJ-37 was analyzed by means of thin-layer chromatography immunostaining and ELISA. The results indicated that YJ-37 reacted with sialylated lacto-series carbohydrate chains, which have been reported to accumulate in cancer cells.

Topics: Adenoma; Antibodies, Monoclonal; B-Lymphocytes; Carbohydrate Conformation; Carbohydrate Sequence; Cell Fusion; Cell Line; Colonic Neoplasms; Endometrial Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Fibrinogen; Glycolipids; Humans; Immunotherapy; Lymph Nodes; Lymphocytes; Molecular Sequence Data; Picibanil; Stomach Neoplasms

The effects of OK-432 on artificial liver metastasis of tumor-bearing mice were assessed using murine colon adenocarcinoma MCA-38 in C57 BL/6 mice. OK-432 injection into the spleen reduced the liver metastases. In gastro-intestinal cancer patients, the effects of OK-432 injection into the spleen were assessed with functional T cell subsets. The treatment resulted in an increase in the number of cytotoxic T cells, but a decrease in the suppressor T cells. The facts suggested that OK-432 injection into the spleen had an ability to prevent liver metastases.

Topics: Adenocarcinoma; Animals; Colonic Neoplasms; Injections; Leukocyte Count; Liver Neoplasms; Lymphocyte Subsets; Male; Mice; Mice, Inbred C57BL; Picibanil; Receptors, Interleukin-2; Spleen; T-Lymphocytes, Regulatory

Nineteen patients with metastatic liver tumor (9 of gastric cancer, 5 of colon cancer, 2 of pancreatic cancer, one each of mammary cancer, cholecystic cancer, carcinoid of biliary tract) and one patient with primary liver cancer were treated by endogenously induced LAK therapy consisting of transhepatic arterial infusion with ADM or MMC for induction therapy and OK-432 and rIL-2 (TGP-3) for immunotherapy. The following results were obtained. 1) Clinical response for liver tumor showed no CR but 8 cases of PR, for an overall response rate of 42.1%. 2) Reduced tumor marker value was noted in 76.5% cases, and 50% survival term became 349 days after the therapy. 3) Many CD4 and CD8 positive mononuclear cells had infiltrated around liver tumor after therapy by immuno-histochemical staining of surface marker. 4) NK activity of peripheral blood lymphocytes was markedly reduced soon after the therapy and continued for about 4-7 days, while in cases of combined subcutaneous administration with OK-432, NK activity showed only a slight decrease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Doxorubicin; Drug Administration Schedule; Humans; Interleukin-2; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Liver Neoplasms; Mitomycin; Picibanil; Stomach Neoplasms; Survival Rate

Human hybridomas were generated through the fusion of the human B-lymphoblastoid cell line HO-323 with the regional lymph node lymphocytes of colonic cancer patients who had received a local immunotherapy. A total of 353 hybridomas were obtained from 4 patients and 116 of these were found to secrete greater than or equal to 100 ng/ml human immunoglobulin. The efficiency was remarkably high as compared with that from patients without the local immunotherapy. Further immunohistological examination showed that 5 hybridomas secreted IgM which selectively reacted with colonic cancers. The results indicate that local immunotherapy could be an adjunctive tool for the generation of highly potent human hybridomas through augmenting the host's immunity.

Topics: Antibodies, Monoclonal; B-Lymphocytes; Colonic Neoplasms; Fibrinogen; Humans; Hybridomas; Immunoglobulin M; Lymph Nodes; Picibanil

This study investigates the role of hepatic asialo GM1-positive cells in inhibiting hepatic metastasis of colon carcinoma (colon adenocarcinoma 38) in mice after administration of a biological response modifier, streptococcal derivative (OK432). Administration of OK432 increased the number of asialo GM1-positive cells in the liver, enhanced natural killer activity of hepatic mononuclear cells and reduced the number of hepatic metastases of colon carcinoma inoculated into the superior mesenteric vein. Administration of antiserum against asialo GM1 reduced the number of hepatic asialo GM1-positive cells, abolished natural killer activity of hepatic mononuclear cells and increased the number of hepatic metastases. In addition, administration of antiserum against asialo GM1 even after OK432 treatment also decreased the number of asialo GM1-positive cells, reduced natural killer activity of hepatic mononuclear cells and increased the number of hepatic metastases of colon carcinoma. However, administration of gadolinium chloride, which suppresses phagocytic function of Kupffer cells, did not influence the natural killer activity of hepatic mononuclear cells or the number of hepatic metastases. In vivo tumor-neutralization assay revealed that tumor growth was inhibited by the hepatic mononuclear asialo GM1-positive cells, but not by T lymphocytes or Kupffer cells after OK432 administration. These results suggest that an increased number of hepatic asialo GM1-positive cells after administration of OK432 plays an important role in protecting against metastasis of colon carcinoma in the liver.

Topics: Animals; Carcinoma; Colonic Neoplasms; G(M1) Ganglioside; Immunologic Factors; Killer Cells, Natural; Kupffer Cells; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Picibanil

When peripheral blood mononuclear cells (PBMC) were incubated with a streptococcal preparation, OK-432, for 24 h, PBMC acquired cytolytic activity against cultured and fresh human tumor cells. Such PBMC were called OK-432-activated mononuclear cells (OK-MC). OK-MC produce several kinds of cytokines such as interferon alpha (IFN alpha), IFN gamma, and tumor growth inhibitory factor (TGIF) both in vitro and in vivo. OK-MC-produced cytokines also inhibited the growth of cultured and fresh human tumor cells. The growth inhibition was examined by human tumor clonogenic assay using a double-layer agar technique. The results indicate that two pathways of anti-tumor activity are induced in OK-MC, i.e., cell-mediated and cytokine-mediated.

Topics: Adenocarcinoma; Burkitt Lymphoma; Colonic Neoplasms; Cytokines; Cytotoxicity, Immunologic; Growth Inhibitors; Immunologic Factors; Leukocytes, Mononuclear; Picibanil; Stomach Neoplasms; Tumor Cells, Cultured; Tumor Stem Cell Assay

Forty-three patients with advanced cancer were evaluated for the changes of absolute counts of peripheral blood lymphocytes and lymphocyte subsets during chemotherapy or chemoimmunotherapy. In 27 patients who did not respond to the therapy, whole lymphocytes, T cells, helper/inducer T cells and NK cells decreased significantly in number. In contrast, they showed little decrease in 16 cases responded to the therapy. In situ immunohistochemical analysis of the tumor infiltrating lymphocytes was performed on the carcinoma tissues obtained from 25 gastric cancer patients. T cell infiltration, in which helper/inducer T cells were predominant over suppressor/cytotoxic T cells, and NK cell infiltration were found in most of the tissues comprised various carcinoma types of histology. Furthermore, an analysis of a gastric cancer patient treated with systemic administration of 3 BRMs and intratumoral injection of OK-432 indicated that infiltration of cytotoxic T cells and NK cells augmented by cytokines such as IFN-gamma produced from activated helper/inducer T cells and NK cells. Therefore, it is suggested that movements of helper/inducer T cells and NK cells relate to the response to chemotherapy and participate in prognosis of advanced cancer patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Colonic Neoplasms; Esophageal Neoplasms; Female; Humans; Immunologic Factors; Injections, Intralesional; Interferon-gamma; Killer Cells, Natural; Leukocyte Count; Lymphocytes; Male; Middle Aged; Neoplasms; Picibanil; Remission Induction; Stomach Neoplasms; T-Lymphocytes, Helper-Inducer

The influence of OK-432 on the activation of UFT, consisting of tegafur and Uracil, was examined in patients with gastric cancer and colonic cancer. In 14 gastric cancer and 15 colonic cancer cases, to which UFT 400 mg/day and OK-432 2KE 2/W were administered orally and intra-muscularly for 2 weeks preoperatively until surgical treatment, intratumor 5-fluorouracil (5-FU) concentration was measured and compared with that of patients who given UFT 400 mg/day orally for 2 weeks (15 gastric cancer and 15 colonic cancer cases). As the results, in the groups of patients given OK-432, the concentration in gastric cancer tissue was 0.093 +/- 0.067 microgram/g and that in colonic cancer was 0.098 +/- 0.058 microgram/g. Both values exceeded 0.05 microgram/g which is considered to be the effective intratumor 5-FU concentration. No difference was observed in these cases given UFT alone. The ratio of intratumor 5-FU concentration vs. that of normal tissue was 2.5 for gastric cancer and 2.7 for colonic cancer and the ratio of tumor vs. serum 5-FU concentrations was 8.5 for gastric cancer and 10.9 for colonic cancer. No difference was also observed in these values in cases given UFT alone. From above results, it seemed that the clinical dose of OK-432 2KE 2/W had no influence on the activation of UFT, so that the combination therapy of UFT and OK-432 was found to be clinically useful.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Products; Biotransformation; Colonic Neoplasms; Fluorouracil; Humans; Lymphatic Metastasis; Picibanil; Stomach Neoplasms; Tegafur; Tissue Distribution; Uracil

The inactivate streptococcal preparation OK432 activates the cytotoxic function of natural killer (NK) cells. Moreover, it induces cytotoxic activity against freshly isolated tumor cells. The present study was aimed at assessing whether OK432-activated effector cells expressed cytotoxicity against tumor cells pleiotropically resistant to cancer chemotherapy agents. OK432-treated lymphoid cells killed the multidrug resistant (MDR) LOVO DX line as efficiently as drug sensitive parental LOVO N carcinoma line. Effector cells involved in killing MDR cells were low density large granular lymphocytes with NK functions. Activation of effector cells has the potential to complement conventional cytoreductive therapy by eliminating residual-tumor cells surviving and resistant to chemotherapy.

Topics: Biological Products; Colonic Neoplasms; Doxorubicin; Drug Resistance; Humans; Lymphocyte Activation; Lymphocytes; Picibanil; T-Lymphocytes, Cytotoxic; Tumor Cells, Cultured

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Products; Breast Neoplasms; Colonic Neoplasms; Humans; Immunity, Cellular; Immunotherapy; Middle Aged; Picibanil; Stomach Neoplasms

The effect of OK-432 on the survival of patients with colorectal cancer who had undergone surgical resection was studied. As postoperative chemotherapeutic agents, mitomycin C and tegafur were administered. The survival time in the OK-432 group was prolonged in comparison with that in the chemotherapy-alone group (control) among patients given curative resection, but not among those not given curative resection. The effect of OK-432 was especially significant in patients with Dukes C-Stage and Dukes C rectal cancer (p less than 0.05). Moreover, OK-432 significantly inhibited the recurrence of cancer at the original lesion in patients with Dukes C cancer who had received curative resection. These results indicate that long-term administration of OK-432 is effective as a postoperative adjuvant for curatively resected colorectal cancer, especially Dukes C cancer.

Topics: Adjuvants, Immunologic; Adult; Aged; Biological Products; Colonic Neoplasms; Female; Humans; Male; Middle Aged; Picibanil; Rectal Neoplasms

The IFN producing activity of RLNL and PBL was studied in cancer patients using K562, PHA-P and OK-432 as inducers. In response to K562, IFN production was significantly greater in the PBL than in the RLNL, and the titer was about equal in the PBL and RLNL when OK-432 was used as an inducer. On the contrary, the amount of IFN produced by PHA-P was significantly higher in the RLNL than in the PBL. There was no definite relationship recognized between tumor progression and IFN productivity in the cases studied.

Topics: Adult; Aged; Cell Line; Colonic Neoplasms; Female; Humans; Interferons; Leukemia, Erythroblastic, Acute; Lymph Nodes; Lymphocytes; Male; Middle Aged; Phytohemagglutinins; Picibanil; Rectal Neoplasms; Stomach Neoplasms

Cancer cells and macrophages produce large amounts of prostaglandin (PG) E2, which suppress cellular immune r action in tumor-bearing individuals. These findings raised a possibility that PG synthetase inhibitor can restore the immune reactivity against tumors. The anti-tumor activity of indomethacin, a potent PG synthetase inhibitor, by oral administration of 0.002% water solution as drinking water from the day 0 or 7 days after tumor transplantation was investigated in BALB/c or CDF1 (BALB/c X DBA/2) mice implanted subcutaneously with colon carcinoma 26 (10(6) cells) as a series of model studies for cancer treatment. The treatment with indomethacin substantially 1) inhibited the tumor growth, 2) prolonged the survival time, 3) caused a regression and disappearance of tumor with some cured mice and 4) reduced the levels of PGE2 and ornithine decarboxylase activity, a first rate limiting enzyme of polyamine synthesis in tumor tissue. Those anti-tumor activities were 5) reduced by a concomitant administration of PGE2 and 6) increased by a combined administration of an immunopotentiating agent, Picibanil (OK-432). The results indicate that indomethacin inhibited the synthesis of PGE2 in the tumor tissue, which suppress the non-specific cellular immune reaction against tumor cells, resulting in the regression and disappearance of tumor. PG synthetase inhibitor may be effective also against human cancer.

Topics: Administration, Oral; Animals; Body Weight; Colonic Neoplasms; Cyclooxygenase Inhibitors; Dinoprostone; Indomethacin; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Picibanil; Prostaglandins E

Carcinomas produce large amounts of prostaglandin (PG) E2, which play an important role in suppression of non-specific cellular immune reaction in tumor-bearing individuals. PG synthesis inhibitor can restore the immune activity against tumors. The anti-tumor activity of indomethacin was investigated in CDF1 mice (BALB/c X DBA/2) implanted intraperitoneally with mouse colon adenocarcinoma 26 (5 X 10(5) or 2 X 10(5) cells) in a model study to prevent peritoneal recurrence after surgery for gastrointestinal cancers. Oral administration of indomethacin (0.002% water solution as drinking water) depressed and inhibited the disseminated tumor growth in the abdominal cavity, and prolonged the survival time, resulting in 30-50% cures of mice. The treatment combined with a small intraperitoneal dose of Picibanil (OK-432) (0.5 mg/kg twice weekly), which activates macrophages in the abdominal cavity, cured 90% of mice. An intraperitoneal dose of 16,16-dimethyl-PGE2 (5 micrograms/mouse, daily) reduced the anti-tumor activity of indomethacin. The results suggest that indomethacin treatment relieved the endogenous(tumor cell- and macrophage-produced) PGE2-mediated immunosuppression. It is postulated that PG-synthesis inhibitor in combination with chemotherapeutic agents, immunotherapeutic agents and low dose radiation, may provide a good therapeutic tool to prevent the development of peritoneal carcinomatosis, particularly in the cases having a small number of residual cancer cells or micrometastases in the abdominal cavity after surgery.

Topics: Adenocarcinoma; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colonic Neoplasms; Dinoprostone; Drug Therapy, Combination; Immune Tolerance; Indomethacin; Mice; Mice, Inbred Strains; Neoplasm Recurrence, Local; Peritoneal Neoplasms; Peritonitis; Picibanil; Prostaglandins E

It is crucial to define the immunological characteristics of peripheral blood mononuclear cells in order to clarify the physiological state of cancer patients. In this study, we examined prostaglandin E2 (PGE2) and interleukin-1 (IL-1) production by plastic-adherent cells stimulated by lipopolysaccharide (LPS). The secretion of PGE2 and IL-1 into media depended on the dose of LPS. Although the addition of silica resulted in suppression of LPS-induced PGE2 production, it caused augmentation of IL-1 production. The effect of BRM therapy on IL-1 production was evaluated in five cancer patients. The results demonstrated that BRM therapy increased the levels of IL-1 at the late assessment point for 3 patients and their quality of life was improved. These findings suggest that production of IL-1 may be used as a monitor for the effectiveness of biotherapy. The association of PGE2 production with host antitumor response was evaluated in IFN-gamma therapy. The results showed that the PGE2 production ratio increased early in the therapy period and declined gradually, whereas the expression of HLA-DR antigen on monocytes and the level of IL-1 increased during the treatment. The exact mechanism by which BRM activates monocytes is unknown. It is possible that a distinct subpopulation of monocytes is responsible for this effect.

Topics: Biological Products; Cell Adhesion; Cells, Cultured; Colonic Neoplasms; Dinoprostone; Humans; Interleukin-1; Lipopolysaccharides; Lung Neoplasms; Macrophages; Monocytes; Neoplasms; Picibanil; Prostaglandins E; Stomach Neoplasms

The postoperative survival rate after radical surgery for large intestinal cancer shown to be differentiated adenocarcinoma is relatively good. However, the effect of surgical adjuvant therapy on this cancer is considered to be the least promising. 5-FU, FT-207, MMC, ADR and VCR are used for chemotherapy and OK-432, PSK, BCG, levamisole and lentinan are also used as forms of immune therapy. There are no significant differences in the statistics used for comparison with controls as to the effects of these adjuvant therapies. A more intensive regional therapy has therefore been adopted for local recurrence of rectal cancer and liver metastasis of colon cancer considering the form of postoperative cancer recurrence. MMC was injected into the superior rectal artery for rectal cancer and into the portal vein during surgery for colon cancer in the 1st program of research of the Kajitani group. However, the efficacy of these procedures was not proved. Although immune therapy with OK-432 has also been subsequently added in the second research program, no efficacy was apparent. Taylor and Birmingham have reported that liver metastasis was remarkably decreased by continuous infusion of 5-FU through the portal vein. There is also a report by GITSG in the USA that a reduction of local recurrence was obtained by combination of 5-FU and Me-CCNU with irradiation treatment after surgery for rectal cancer.

Topics: BCG Vaccine; Colonic Neoplasms; Combined Modality Therapy; Doxorubicin; Drug Administration Schedule; Fluorouracil; Humans; Intraoperative Period; Mitomycin; Mitomycins; Picibanil; Postoperative Period; Proteoglycans; Radiotherapy Dosage; Rectal Neoplasms

Topics: Ascitic Fluid; Biological Products; Colonic Neoplasms; Growth Inhibitors; Humans; Picibanil; Stomach Neoplasms

Effects of immunostimulation with OK432, Coenzyme Q10 (Co-Q10), or levamisole on dimethylhydrazine (DMH)-induced colonic carcinogenesis were investigated in 45 Donryu-rats. The manipulation with one of these immunopotentiators did not prevent DMH-induced colonic carcinogenesis in these rats. However, the number of tumors was significantly reduced and the incidence of invasive carcinomas decreased by immunostimulation. The treatment also reduced the number of lesions with epithelial dysplasia within the flat colonic mucosa.

Topics: 1,2-Dimethylhydrazine; Animals; Biological Products; Cell Transformation, Neoplastic; Coenzymes; Colonic Neoplasms; Dimethylhydrazines; Epithelium; Intestinal Mucosa; Levamisole; Picibanil; Rats; Ubiquinone

Using the Su-PS skin test, an attempt was made to evaluate whether or not this reaction could become a useful immune parameter in patients with gastrointestinal cancer. The conclusions were as follows: Late-stage patients with gastric cancer showed a weak response in the Su-PS skin test when examined preoperatively. The skin reaction to Su-PS was shown to become stronger than in the PPD and PHA test when patients received OK-432 treatment. Patients with advanced cancer having longer survival (more than 7 months) showed stronger response in the Su-PS skin test that patients having short survival (less than 6 months). It was suggested that the Su-PS skin test was useful for evaluating the immune response to OK-432 treatment.

Topics: Biological Products; Colonic Neoplasms; Esophageal Neoplasms; Humans; Intradermal Tests; Pancreatic Neoplasms; Phytohemagglutinins; Picibanil; Polysaccharides, Bacterial; Skin Tests; Stomach Neoplasms; Tuberculin Test

Topics: Aged; Biological Products; Colonic Neoplasms; Female; Humans; Injections, Subcutaneous; Macrophage Activation; Male; Middle Aged; Picibanil; Skin; Stomach Neoplasms; T-Lymphocytes

The reaction of skin to 10-micrograms and 20-micrograms quantities of Su-polysaccharide (Su-Ps) were examined in 117 patients with cancer, and the results obtained were as follows. Reaction was a little greater to the 20-micrograms dose than to the 10-micrograms dose, but the two parameters were much correlated with each other. The rates of patients showing positive reactions to each dose were 30.8% for 10-micrograms and 34.2% for 20-micrograms. The reactions were augmented by administration of OK-432. The augmentation of skin reaction by OK-432 was more prominent at 20-micrograms doses than at 10-micrograms doses, therefore appearing to be Su-polysaccharide dose-dependent. The ideal Su-polysaccharide dose for Su-Ps skin reaction thus seemed to be 20-micrograms.

Topics: Breast Neoplasms; Colonic Neoplasms; Female; Humans; Hypersensitivity, Delayed; Intradermal Tests; Male; Neoplasms; Picibanil; Polysaccharides, Bacterial; Skin; Stomach Neoplasms; Streptococcus

In the use of hyperthermia treatment, it is apparent from the work of other investigators that only a proportion of large clinical neoplastic tumors of substantial size and deep location can be heated to adequate temperatures (over 42 degrees c). It is therefore of major significance that we have tested the concept that OK-432 can be used as an immunoheat potentiator. A ThermaTech 2000 was used as the radio-frequency generator at 13.56 MHz, including an ancillary computer in the thermometry unit. Minor response in advanced and metastatic tumors was observed in 3 of 3 evaluable patients using OK-432. With other anticancer drugs, no change was observed in 11 of 16 patients, and progressive disease in 5 of 16. However, OK-432 has severe side effects including chills & fever, therefore improved immunoheat potentiators are desirable.

Topics: Biological Products; Body Temperature; Carcinoma, Renal Cell; Colonic Neoplasms; Female; Humans; Hyperthermia, Induced; Infusions, Parenteral; Kidney Neoplasms; Male; Middle Aged; Picibanil; Rectal Neoplasms

A new clinical trial on immunochemotherapy as an adjuvant therapy of surgery for colorectal cancers was studied. Results were retrospectively evaluated against previous controls treated by chemotherapy alone. As an immunotherapeutic agent, a streptococcal preparation, OK-432 was used. The maintenance dosage of OK-432, was 5 KE once a week and was continued for at least 2 years after surgical resection. As chemotherapeutic agents, mitomycin C for 2 weeks postoperatively and tegafur for 1 year were administered. Delayed skin reactivity to SU-polysaccharide (SU-PS) extracted from Streptococcus pyogenes SU-strain and lymphoproliferative response to phytohemagglutinins (PHA) were significantly enhanced in the OK-432, immunochemotherapy group. Disease-free interval in the immunochemotherapy group (n = 49) was prolonged compared to that in the control group (n = 129), especially in the curative resection cases of Duke's C stage. There was statistical significance between the two groups (p less than 0.05). These results suggested that long-term administration of OK-432 after surgical resection of colorectal cancer was effective on growth inhibition of micrometastasis and could increase the postoperative survival rate.

Topics: Adult; Aged; Biological Products; Colonic Neoplasms; Drug Administration Schedule; Female; Humans; Lymphocyte Activation; Male; Middle Aged; Phytohemagglutinins; Picibanil; Rectal Neoplasms; Skin Tests

Topics: Biliary Tract Neoplasms; Biological Products; Colonic Neoplasms; Humans; Liver Neoplasms; Picibanil; Stomach Neoplasms