picibanil and Peritonitis

Eighty gastric cancer patients with peritoneal dissemination were analyzed to evaluate the effect of intraperitoneal chemo- and/or immunotherapy on abdominal ascites. Among them, 19 were treated with intraperitoneal chemo- and/or immunotherapy, and 21.1% of them showed decreased ascites and better QOL. Patients treated with intraperitoneal administration with OK-432 showed good survival. Among patients with OK-432 administration, those receiving postoperative chemotherapy showed better survival than those given immunochemotherapy. Conversely, among patients with chemotherapy, those given postoperative immunochemotherapy showed better survival than those on chemotherapy. Patients with HLA-type I and III, and those with preoperative normal immune status showed good response when they received intraperitoneal therapy.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Cisplatin; Female; Humans; Immunity, Cellular; Immunotherapy; Infusions, Parenteral; Male; Middle Aged; Mitomycin; Peritonitis; Picibanil; Stomach Neoplasms; Survival Rate

Intraperitoneal and pleural immunotherapy has been used as an effective therapy for malignancy. Recently we treated two patients with peritonitis and pleuritis due to cancer by intraperitoneal and pleural administration of IFN-gamma, OK-432 and antitumor agents. One patient with gastric cancer (stage IIIb) was treated with intraperitoneal administration of IFN-gamma and OK-432 in combination with intraarterial infusion of MMC, ADM, 5-FU and CDDP. Two months later, ascites and pleural fluid diminished. Another patient with ovarian carcinoma (stage IV), was administered IFN-gamma, OK-432 and CDDP into ascites with general medication of CDDP and Epi-ADM. Two months later, her ascites and tumor size decreased. This patient was treated with palaplatin every two months for the ten months and hysterosalpingecctomy and tumorectomy of Douglas pouch were performed at the sixteenth month. The histopathological examination of resection from this patient showed complete necrotic tissue of tumor. Endogenous cytokine therapy with intraperitoneal and pleural administration of IFN-gamma for priming and OK-432 for eliciting in combination with antitumor agents may be effective treatment for malignant peritonitis and pleuritis.

Topics: Adenocarcinoma, Mucinous; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Epirubicin; Female; Humans; Infusions, Intravenous; Infusions, Parenteral; Interferon-gamma; Male; Middle Aged; Ovarian Neoplasms; Peritonitis; Picibanil; Pleural Effusion; Pleurisy; Stomach Neoplasms

Although 58 patients with peritonitis carcinomatosa underwent multidisciplinary therapy over the last 5 years in our department, about half of them died within 3 months after treatment. In addition, the prognosis was poor for gastric and colon cancer patients, who had macroscopic peritoneal dissemination. Therefore intraoperative intraperitoneal administration of either BRM or anticancer drugs was performed for the microscopic peritoneal dissemination of the cancer, and the immunological response in the peritoneal cavity was examined. In terms of subpopulation of peritoneal exudate cells, neutrophil leucocytes were predominant and thereafter lymphocytes increased. As for the cytokines in the exudate from peritoneal cavity, the concentration of interleukin-6 peaked within 24 hours after administration, followed by a gradual decrease, while the concentration of interferon-gamma was detectable at more than 24 hours after operation, followed by a gradual increase. Tumor necrosis factor-alpha was also detectable in the exudate. Its concentration decreased when both OK-432 and MMC were administered, but it increased when CDDP was administered. The above results indicated that preventive intraoperative intraperitoneal administration of BRM and anticancer drugs should bring about individual immunokinetic modulation in tumor bearing host and both cytokines and immunocytes could play an important role in locoregional tumor immunity.

Topics: Cisplatin; Humans; Immunotherapy; Infusions, Parenteral; Mitomycin; Pancreatic Neoplasms; Peritonitis; Picibanil; Stomach Neoplasms

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Ascitic Fluid; Cisplatin; Female; Humans; Infusions, Parenteral; Lymphocyte Subsets; Male; Middle Aged; Peritonitis; Picibanil; Postoperative Period; Prognosis; Stomach Neoplasms

The effect of intraperitoneal administration of OK-432 followed by intraperitoneal instillation of recombinant interleukin-2(rIL-2) was examined in tumor bearing animals and in four recurrent gynecological cancer patients with peritonitis carcinomatosa which had been resistant to chemotherapeutic drugs. Seven days after intraperitoneal inoculation of tumor cells (10(6) cells/body of MH134 hepatoma into C3H/He mice and 10(5) cells/body of Meth-A fibrosarcoma into BALB/C mice, respectively), OK-432 was administered intraperitoneally. Two days later, a 14 day course of daily intraperitoneal instillation of rIL-2 followed. The survival time for animals treated with OK-432 combined with rIL-2 was significantly prolonged. Three of the 8 C3H/He mice and one of the 8 BALB/C mice in this group survived more than 150 days without forming ascites. However, the group treated by rIL-2 alone did not survive for more than 40 days. The group treated by OK-432 alone as well as the untreated group did not survive for more than 20 days. Ascitic fluid disappeared clinically in two of four cases and decreased in the rest. Ascitic cancer cells disappeared in one case and decreased in three cases. The serum CA125 level declined significantly in all cases. The surface markers of ascitic lymphocytes were analyzed by flow cytometry on day 8. The CD4+ subset accounted for 70-90% whereas the CD8+ subset accounted for only 7-17%. In three cases in which two color analysis was performed, the CD4+, CD29+ helper inducer T cell was dominant. We could conclude that LAK cells were not the main effector cells.

Topics: Adult; Animals; Female; Humans; Injections, Intraperitoneal; Interleukin-2; Lymphocyte Activation; Lymphocyte Subsets; Mice; Middle Aged; Ovarian Neoplasms; Peritonitis; Picibanil; Recombinant Proteins

We studied the effect of intraperitoneal injection of OK-432 on the growth of original tumor mass in patients with malignant ascites and a possible mechanism of reduction of tumor volume. Sixteen patients with valuable original tumor mass and a large amount of ascites caused by gastro-intestinal cancer were studied. Tumor cells were separated from ascitic fluids and cultured in vitro before the study. Lymphocytes were collected from the fluids at varying intervals after intraperitoneal injection of OK-432 and cultured 24 hours in vitro. Effect of the culture supernatant on ascites-derived autologous tumor cell growth was examined in vitro using microplate assay. The results were as follows. 1) Reduction of tumor mass more than four weeks was found in 4 of 16 cases. 2) Before OK-432 injection, the culture supernatant from ascites-derived lymphocytes did not inhibit autotumor cell growth in vitro. But, the supernatant from lymphocytes which were collected from the ascites after OK-432 injection markedly inhibited tumor growth in all of 4 tumor mass reduction cases. In 12 non-reduction cases the supernatant slightly inhibited tumor growth only in 2 cases. 3) A similar growth inhibitory factor was detected in the mixed culture-supernatant of peripheral blood lymphocytes and OK-432 in vitro. 4) Preliminary studies indicated that the tumor growth inhibitory factor might be different from tumor necrosis factor and interferons. These results indicate that ascites-derived lymphocytes-producing factor may play an important role in reduction of tumor mass volume in patients with cancerous ascites.

Topics: Adenocarcinoma; Adult; Aged; Biological Products; Chronic Disease; Female; Gastrointestinal Neoplasms; Humans; Injections, Intraperitoneal; Male; Middle Aged; Peritonitis; Picibanil

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

Twelve patients with malignant ascites caused by gastro-intestinal cancer were treated by intraperitoneal administration of OK-432. Tumor cells from these patients were separated from ascitic fluid and cultured in vitro before OK-432 therapy. OK-432 was given intraperitoneally one to two times a week at doses ranging from 5 to 20 KE suspended in saline. Mononuclear lymphocytes were collected from the fluid at various intervals throughout the therapy. The effect of ascites-derived lymphocytes on ascites-derived autologous tumor cell growth was studied in vitro using microplate assay. Nine (responders) of 12 patients showed complete disappearance or significant reduction of ascitic fluid. Ascites-derived lymphocytes slightly inhibited autologous tumor cell growth only in one case before OK-432 therapy. Lymphocytes collected from ascites after OK-432 injection significantly inhibited auto-tumor cell growth in all of 9 responders. In 3 non-responders, however, auto-tumor cell growth inhibition was found only in one case. Interestingly, lymphocytes from non-responders significantly inhibited the growth of tumor cells taken from responders. Conversely, lymphocytes from responders did not inhibit non-responder-derived tumor cell growth. These findings imply that auto-tumor killing by OK-432-induced lymphocytes may depend more on the condition of the tumor cells than on the condition of the lymphocytes, and that the measurement of auto-tumor killing activity by ascites-derived lymphocytes may be useful as an indicator in OK-432 therapy.

Topics: Abdominal Neoplasms; Ascites; Biological Products; Cytotoxicity, Immunologic; Drug Evaluation; Humans; Intestinal Neoplasms; Methods; Peritonitis; Picibanil; Stomach Neoplasms; T-Lymphocytes, Cytotoxic

Large numbers of neutrophils appear in the peritoneal cavity within a few hours after administration of OK-432 into the peritoneal cavity, and play an important role in the destruction of cancer cells. As OK-432 can activate complement in vitro, it is possible that a chemotactic factor such as C5a is generated and attracts neutrophils into the cavity. We injected OK-432 with fresh human serum preincubated at 37 degrees C for 60 min in order to generate large amounts of complement-derived chemotactic factor. Neutrophils increased in number within a few hours after the injection of OK-432 with preincubated human serum into the peritoneal cavity of a recurrent gastric cancer patient with carcinomatous ascites, and persisted much longer compared with treatment using OK-432 alone. Cancer cells rapidly decreased in number and ascites disappeared two weeks after the treatment with OK-432 and preincubated human serum. It was found that C5a levels measured by RIA initially increased a few hours before neutrophils appeared, and then decreased gradually, after injection of either OK-432 with preincubated human serum or with OK-432 alone. Although complement-derived chemotactic factor might be responsible for attracting neutrophils into the peritoneal cavity, the role of other chemotactic factors should also be investigated.

Topics: Adenocarcinoma; Biological Products; Chemotactic Factors; Complement Activation; Humans; Immunization, Passive; Injections; Neutrophils; Peritoneal Cavity; Peritonitis; Picibanil; Stomach Neoplasms

The effect of intraperitoneal (ip) OK-432 administration and its mechanism were investigated with experimental tumor of rats.. 4 week-old female SD rats (Slc/SD, closed colony). Tumor: An ascitic tumor, produced by intraperitoneal inoculation of strain cells. These have been established from MRMT-1, which originally was induced by 3-methyl cholanthrene administration. Experimental study: On day 4 or 6 of ip inoculation of 1 x 10(6) tumor cells, 50 KE/kg of OK-432 was administered intraperitoneally and cells were daily examined microscopically. Morphological changes around tumor cells were investigated with Papanicolaou-stained preparations. Following results were obtained: A marked increase in neutrophils was noted in ascitis at 24 hours after ip administration of OK-432; macrophages and lymphocytes appearing later than neutrophils. A subsequent decrease in neutrophils was accompanied by gradual increase in tumor cells. When OK-432 was administered intraperitoneally on day 4 of ip inoculation of tumor cells, aggregation of neutrophils around tumor cells was observed on day 6, and rosette formations around tumor cells with 76 to 10 neutrophils were noted on days 7 and 8. Subsequently tumor cells forming centers of rosettes were found to be destroyed and disappeared. On days 10 to 12, regrowth of tumor cells within incomplete rosette formation was found in ascites. The above reactions were not remarkable, when OK-432 was administered intraperitoneally on day 6 of ip inoculation of tumor cells, and were never observed in untreated cases. These results indicated that cytotoxic effects of ip administration of OK-432 were displayed mainly by rosette formation with neutrophilic cells.

Topics: Adjuvants, Immunologic; Animals; Biological Products; Female; Neoplasms, Experimental; Peritoneal Cavity; Peritoneal Neoplasms; Peritonitis; Picibanil; Rats