zinostatin and Stomach-Neoplasms

Neocarzinostatin (NCS) is an antibiotic from streptomyces carzinostaticus which inhibits DNA synthesis. Clinical trials in Japan began in 1971. NCS is active against S-180, Ehrlich tumor, L1210, Yoshida sarcoma, and a range of ascitic hepatomas. In rabbit NCS is distributed at high concentrations in the kidney, skin, stomach, pancreas, lung, and muscles. The high distribution in the pancreas and the stomach suggested possible effectiveness in human tumors at these sites. In clinical studies NCS has been shown to be active against acute leukemia. As a single agent 9 out of 51 obtained a CR with 9 more achieving a PR. Anorexia, nausea, and vomiting were the most frequent side effects. NCS has been tried in combination with Ara-C, daunorubicin and prednisolone and CR was ssen in 11 out of 14. In stomach cancer responses of some kind were observed in 12 out of 141 cases, while in the case of pancreatic tumors there were 10 out of 68.

Topics: Antibiotics, Antineoplastic; Drug Therapy, Combination; Japan; Kinetics; Leukemia; Neoplasms; Pancreatic Neoplasms; Stomach Neoplasms; Urinary Bladder Neoplasms; Zinostatin

The significance and effectiveness of adjuvant intraoperative chemotherapy using subserosal or submucosal administration of Neocarzinostatin (NCS) and CH 40 for gastric cancer and colorectal cancer were studied. Tissue NCS concentration of proximal lymph nodes were higher than for distant lymph nodes, while the immunocompetency of distant lymph nodes (lower NCS concentration) showed slightly higher activity than that of proximal lymph nodes. From these results, it is suggested that loco-regional administration of NCS might be effective for chemical lymph node cleaning of the cancer.

Topics: Carbon; Chemotherapy, Adjuvant; Colonic Neoplasms; Gastric Mucosa; Humans; Injections, Intralesional; Lymph Nodes; Lymphocyte Activation; Rectal Neoplasms; Stomach Neoplasms; Zinostatin

An early phase II multicentered study of YM 881 (zinostatin stimalamer) was conducted in 36 patients to investigate response and the safety of the drug in malignant tumors. The response could be evaluated in 18 patients, one with brain tumor, 2 with lung cancer, one with breast cancer, one with liver cancer, one with pancreatic cancer, 6 with gastric cancer, and 6 with colon cancer. PR was found in the patient with brain tumor. Major subjective unwanted effects were gastrointestinal symptoms. Objective evidence of hematological changes (thrombocytopenia, decreased hematocrit, and lymphocytopenia) was also obtained.

Topics: Adult; Aged; Anorexia; Brain Neoplasms; Drug Evaluation; Female; Humans; Injections, Intravenous; Lung Neoplasms; Male; Maleic Anhydrides; Middle Aged; Neoplasms; Polystyrenes; Stomach Neoplasms; Thrombocytopenia; Vomiting; Zinostatin

The monoclonal antibody A7 (Mab A7) against human colonic cancer also reacts with human gastric cancer at a high rate. We produced a conjugate of neocarzinostatin (NCS) with Mab A7 (A7-NCS). The in vitro anticancer effect of A7-NCS on the antigen-positive human gastric cancer cell line MKN45 was stronger than that of free NCS. Nude mice models of peritoneal dissemination were established by the intra-peritoneal inoculation of MKN45. These models were divided into three groups. The anticancer effect observed in the group that received the intra peritoneal injection of A7-NCS was superior to that observed in the group that received the intra-venous injection and the group that received no treatment. In conclusion, the intra-peritoneal injection of A7-NCS was a useful treatment method for the peritoneal dissemination of gastric cancer.

Topics: Adenocarcinoma; Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antigens, Neoplasm; Cell Line, Tumor; Humans; Infusions, Parenteral; Injections, Intravenous; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Seeding; Peritoneal Neoplasms; Stomach Neoplasms; Zinostatin

To clarify the effect of SMANCS on malignant pleural carcinomatosis, seven patients with malignant pleural effusion were treated with SMANCS administered via an intracavitary route. Five patients showed improvement after one or two injections of SMANCS into the thoracic cavity, although 2 patients needed further therapy with the immunopotentiating agent picibanil (OK-432). No serious adverse effects were observed. This simple therapeutic tactic with SMANCS may be effective in cases of malignant pleural carcinomatosis.

Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Colonic Neoplasms; Female; Humans; Lung Neoplasms; Male; Maleic Anhydrides; Middle Aged; Pleural Effusion, Malignant; Polystyrenes; Stomach Neoplasms; Zinostatin

A7-NCS, which is a conjugate of the monoclonal antibody A7 against a human colonic cancer and the anticancer agent neocarzinostatin (NCS), reacts with human gastric cancers at a high rate. The anticancer effect of A7-NCS is stronger than that of free NCS. Nude mice models of peritoneal dissemination were established simply by intra-peritoneal inoculation of the antigen-positive human gastric cancer cell line MKN45. Using these models, the anticancer effect of A7-NCS against the peritoneal dissemination of gastric cancer was examined. The murine peritoneal dissemination models were divided into three groups. The anticancer effect of the group injected intra-peritoneally with A7-NCS 2 days after cancer inoculation was compared with that injected 18 days after inoculation. The anticancer effect in the 18-day group was inferior to that in the 2-day group, but was superior to that in the non-treated group. To get a better result in the 18-day group, which is in the advanced stage of peritoneal dissemination, repeated injection and the dose of A7-NCS should be examined.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Humans; Immunotoxins; Mice; Mice, Nude; Peritoneal Neoplasms; Stomach Neoplasms; Zinostatin

The murine monoclonal antibody A7 (MAb A7) is reactive against most human gastric cancer cell lines. Using a nude mouse peritoneal dissemination model of human gastric cancer, we investigated targeted chemotherapy using a conjugate of neocarzinostatin (NCS) with MAb A7 (A7-NCS). After demonstrating cytotoxicity of the complex against the human gastric cancer cell line MKN45 in vitro, we intraperitoneally injected A7-NCS, NCS or saline into nude mice bearing peritoneally disseminated human gastric cancer. A7-NCS inhibited peritoneal dissemination significantly more effectively than NCS. MAb A7 may prove to be an effective carrier for antineoplastic drugs in patients with peritoneal dissemination of gastric cancer.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Humans; Immunotoxins; Male; Mice; Mice, Nude; Neoplasm Transplantation; Peritoneal Neoplasms; Stomach Neoplasms; Tumor Cells, Cultured; Zinostatin

Topics: Humans; Injections; Lymph Nodes; Lymphatic Metastasis; Serous Membrane; Stomach; Stomach Neoplasms; Tissue Distribution; Zinostatin

Zinostatin stimalamer (YM881) is an antitumor agent, chemically synthesized by coupling one molecule of neocarzinostatin (NCS), with 2 molecules of styrene maleic acid half-butylester copolymer. YM881 showed strong cytotoxicity to human (KB, ST4 and others) and mouse (P388, L1210) tumor cell lines and also drug-resistant tumor cell lines. The antitumor effects were observed in murine MM46, colon 26 and other tumor models. The antitumor activity was as effective as NCS or better than NCS at the effective dose ranges.

Topics: Animals; Antineoplastic Agents; Colonic Neoplasms; Drug Screening Assays, Antitumor; Fibrosarcoma; Humans; Leukemia L1210; Leukemia P388; Maleic Anhydrides; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred DBA; Polystyrenes; Stomach Neoplasms; Zinostatin

As a postoperative adjuvant chemotherapy for gastric cancer, we have administered a combination of NCS (Neocarzinostatin) and 5-FU (NF treatment method) and in this paper we have compiled the results obtained in patients who were treated for 5 years in an attempt to compare the 5-year survival rate with that of patients administered a combination of MMC and 5-FU (MF treatment group) and a control group administered no anticancer agents. As the selection of either NF or MF treatment was conducted on an annual basis, this study can be considered an historical controlled study. The results obtained are summarized as follows. On comparing the survival rate of the NF treatment group and the control group, the 5-year survival rate for all patients who underwent curative resection and all patients with histological stage III cancers and the curative resection PS (+) group, as well as the survival period of the non-resected patients, showed a statistically significant difference, indicating that the survival rate was higher in the NF group. On comparing the NF group and the MF group, although no statistically significant difference was observed between then based on a stratified analysis of all resected cases, histological stage differences and n.ps factors, etc., certain values tended to indicate a higher survival rate for the NF group. Moreover, the survival rate of the non-resected patients was more favorable in the NF group. These results confirm that NCS is useful for the treatment of stomach cancer and compares favorably with MMC. The appearance of side-effects was significantly lower in the NF group in comparison with the MF group and the number of patients who had to discontinue therapy was extremely low.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Fluorouracil; Humans; Male; Middle Aged; Mitomycin; Mitomycins; Postoperative Period; Stomach Neoplasms; Zinostatin

Monocyte-derived macrophages (M phi) from cancer patients injected with low doses of Neocarzinostatin (NCS, 500 units/day, three times a week) 12 times produced significantly more superoxide (O2-) than controls. Lymphocyte functions, such as PHA response, surface marker and serum IAP, before and after NCS injections were the same. M phi from normal persons cultured with NCS (0.4 microgram/ml) for three days produced more O2- than controls, but those cultured with rINF gamma did not. These results suggest that the increased O2- production of M phi from patients taking low doses of NCS may be due to the direct action of NCS on the M phi.

Topics: Antibiotics, Antineoplastic; Colonic Neoplasms; Humans; In Vitro Techniques; Interferon Type I; Lymphocyte Activation; Lymphocytes; Macrophages; Monocytes; Neoplasm Proteins; Stomach Neoplasms; Superoxides; Zinostatin

The authors presented the results of perfusion chemotherapy in the CSF pathway with neocarzinostatin (NCS) for the treatment of meningeal carcinomatosis. In three cases of stomach cancer and one case of malignant lymphoma, cranial polyneuropathy, progressive hydrocephalus and positive cytology of the CSF were found during treatment of malignant tumors. NCS therapy was performed by means of perfusion from the spinal subarachnoid space to the ventricle utilizing Ommaya's reservoir, or simply by repeated lumbar punctures. In all of four cases the number of malignant cells in the CSF was significantly diminished, and temporary neurological improvement was observed until the patient's death due to advanced primary lesions. These results indicated that in cases of meningeal carcinomatosis, NCS perfusion therapy using the CSF pathway was a much more favorable method than treatment with other chemotherapeutic agents with less noticeable side effects.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Cerebral Ventricles; Female; Humans; Lymphoma; Male; Meningitis; Middle Aged; Perfusion; Stomach Neoplasms; Subarachnoid Space; Zinostatin

This study was designed to evaluate the most effective administration method of NCS for advanced carcinoma of the stomach, mainly nonresectable and/or recurrent cases which were collected by our cooperative study group. Nine hundred seventy six cases were available for clinical evaluation. Rate of the efficacy of NCS alone and combined with 5-FU was higher (P less than 0.1) in the cases administrated intravenously by drip infusion than in those by one shot injection method, and adverse effects were fewer in the former than in the latter cases. The rate of efficacy of NCS was higher in cases treated with 4,000 mu/day alone intermittently 2-3 times for a week than in those with 2,000 mu/day alone every day. The rate of clinical effect was higher in the cases treated with 4,000 mu of NCS combined with 50 mg of 5-FU intermittently than in those with 2,000 mu of NCS combined with 250 mg of 5-FU every day, especially 20.6% of the former cases given more than 50,000 mu of NCS were interpreted as clinically effective by Karnofsky's criteria of I-A over.

Topics: Antibiotics, Antineoplastic; Drug Administration Schedule; Drug Therapy, Combination; Fluorouracil; Humans; Infusions, Parenteral; Injections, Intravenous; Neoplasm Recurrence, Local; Stomach Neoplasms; Zinostatin

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Papillary; Adult; Aged; Antibiotics, Antineoplastic; Drug Therapy, Combination; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasm Staging; Stomach Neoplasms; Zinostatin

AmB/NCS combination therapy against cancer was evaluated. Six gastric cancer patients were treated in this manner, and 7 gastric cancer patients treated with NCS alone to serve as the control. AmB sirup was administered orally for 4 days before surgical operation. NCS was given intraveously at the onset of gastric surgery. Lesion tissues and healthy tissues were collected from each patient and the NCS titers were measured by bioassay. It was shown in the majority of the gastric cancer cases that the NCS levels in the lesion tissues were substantially higher than in the surrounding normal tissues, whereas in the gastric cancer patients who received NCS alone, no significant differences were found between the tissues.

Topics: Adult; Aged; Amphotericin B; Antibiotics, Antineoplastic; Biological Assay; Drug Synergism; Female; Humans; Male; Middle Aged; Stomach Neoplasms; Zinostatin

Topics: Adult; Aged; Antibiotics, Antineoplastic; Drug Therapy, Combination; Female; Fluorouracil; Humans; Lymphatic Metastasis; Male; Middle Aged; Preoperative Care; Stomach; Stomach Neoplasms; Zinostatin

AmB/NCS combination therapy against cancer was evaluated. Seven gastric cancer and 2 gastric polyp cases were treated in this manner and in addition 2 gastric cancer patients were treated with NCS alone, to serve as the control. AmB dissolved in glucose solution was administered intravenously as was NCS, which was given at the onset of gastric surgery. Lesion tissues and healthy tissues were collected from each patient and the NCS titers measured by bioassay. It was shown in the majority of the gastric cancer cases that the NCS levels in the lesion tissues were substantially higher than in the surrounding normal tissues, whereas in the gastric polyp and the gastric cancer patients who received NCS alone, no significant differences were found between the tissues.

Topics: Adult; Aged; Amphotericin B; Antibiotics, Antineoplastic; Female; Gastric Mucosa; Humans; Male; Middle Aged; Polyps; Stomach Neoplasms; Zinostatin