zinostatin and Pancreatic-Neoplasms

Topics: Antineoplastic Agents; Blood Glucose; Chemoembolization, Therapeutic; Diazoxide; Fasting; Glucagon; Humans; Insulinoma; Magnetic Resonance Imaging; Maleic Anhydrides; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Polystyrenes; Somatostatin; Tomography, X-Ray Computed; Zinostatin

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 purpose of this study is to evaluate the improved method of arterial infusion therapy of SMANCS (SX) with lipiodol under the angiotensin-induced hypertensive state for various difficult-to-treat solid tumors. Most patients were unresectable with no other therapeutic options, recurrence after resection, or patients do not respond to common treatments. The new method utilizes angiotensin II (AT) to induce hypertension (e.g. approximately 15-30 mmHg above norm) for 15-20 min. This method was successfully applied to metastatic liver cancer, cholangiocarcinoma, massive renal cell carcinoma, pancreatic and other abdominal solid cancers. This AT-induced hypertension resulted in remarkably enhanced tumor delivery accompanied by improved therapeutic response, and a shorter time to achieve 50% regression of tumor size with least toxicity. We demonstrated clinically herein improved therapy for various advanced solid tumors with SX by elevating the tumor blood flow selectively. This is the first clinical proof that modulations of vascular pathophysiology can uniquely accomplish enhanced tumor selective delivery of polymeric drugs and thus yielded better clinical outcome.

Topics: Adenocarcinoma; Adult; Aged; Angiotensin II; Antineoplastic Agents; Blood Pressure; Carcinoma, Renal Cell; Cholangiocarcinoma; Drug Delivery Systems; Female; Humans; Hypertension; Infusions, Intravenous; Japan; Kidney Neoplasms; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Neoplasm Staging; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Polystyrenes; Vasoconstrictor Agents; Zinostatin

Topics: Adult; Antineoplastic Agents; Hepatic Artery; Humans; Infusions, Intra-Arterial; Insulinoma; Liver Neoplasms; Male; Maleic Anhydrides; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Polystyrenes; Splenic Artery; Zinostatin

Topics: Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Humans; Immunotoxins; Injections, Intralesional; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Zinostatin

Techniques which can increase the expression level of tumor-associated antigens may improve immunotargeting therapy. We studied the reactivity of MAb A7 toward an antigen expressed on the surface of the human pancreatic cancer cell line HPC-YS after treatment with various antitumoral agents. When we applied 1 microg/ml mitomycin C (MMC) or 0.1 microg/ml neocarzinostatin (NCS) for 1 h, A7 recognizing antigen expression was enhanced until 24 h after the treatments. At a dose that completely suppressed cell growth, increased antigen expression was maintained for 96 h. Therefore, this study suggests that the combined application of an anticancer drug and MAb A7 may be useful for immunotargeting chemotherapy.

Topics: Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antigens, Neoplasm; Carcinoma; Cell Count; Cell Cycle; Humans; Mitomycin; Pancreatic Neoplasms; Tumor Cells, Cultured; Zinostatin

Topics: Animals; Antibodies, Monoclonal; Carcinoma, Squamous Cell; Humans; Immunotoxins; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Zinostatin

Murine monoclonal antibodies (mAbs) such as A7 administered to humans induce a human anti-mouse antibody response. Moreover, because Fab fragments of mAbs are able to penetrate target tumors easily, they may be more suitable than intact mAb to be carriers of anticancer agents such as neocarzinostatin (NCS), which are rapidly inactivated in the blood. To address these problems, chimeric A7 Fab fragment-NCS conjugate (chA7Fab-NCS) was produced. However, large amounts of 125I-labeled chA7Fab-NCS accumulate in the kidney and can lead to renal dysfunction. To decrease renal accumulation of chA7Fab-NCS, chA7Fab was biotinylated and administered with a subsequent injection of avidin. Human pancreatic carcinoma-bearing nude mice were injected with 125I-labeled biotinylated chA7Fab-NCS with or without subsequent administration of avidin. The accumulation of 125I-labeled biotinylated chA7Fab-NCS in tissue samples was measured at appropriate time intervals. 125I-labeled biotinylated chA7Fab-NCS was cleared more rapidly from the blood and the kidney with the administration of avidin than without it. There was no difference between tumor accumulation in these groups. The tumor/blood ratio of radioactivity of 125I-labeled biotinylated chA7Fab-NCS was significantly higher with subsequent administration of avidin than without avidin. The administration of biotinylated chA7Fab-NCS followed by avidin may enhance safety and permit the administration of larger doses of NCS without the subsequent development of renal failure. A larger amount of 125I-labeled biotinylated chA7Fab-NCS was retained in the liver and spleen with the subsequent administration of avidin than without avidin.

Topics: Adenocarcinoma; Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Bacterial Proteins; Biotin; Humans; Immunoglobulin Fab Fragments; Immunotoxins; Iodine Radioisotopes; Kidney; Liver; Mice; Pancreatic Neoplasms; Spleen; Streptavidin; Transplantation, Heterologous; Tumor Cells, Cultured; Zinostatin

Topics: Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Humans; Immunoglobulin Fab Fragments; Immunotoxins; Mice; Mice, Nude; Pancreatic Neoplasms; Zinostatin

Two types of fragments of MAb A7 were produced to improve the efficacy and safety in targeting chemotherapy with neocarzinostatin. In this study, 125I-labeled F(ab')2 and Fab fragments of MAb A7 and 125I-labeled MAb A7 were injected intravenously into mice with pancreatic carcinoma xenografts, and the accumulation of each antibody in the tumors was compared. A greater amount of the 125I-labeled Fab fragments of MAb A7 localized in the tumor 2 h following the injection than was observed with the other probes. Relatively less 125I-labeled MAb A7 localized in the tumor 2 h following the injection than was observed with the other two probes. Moreover, reaction of rabbit antimouse IgC with the Fc portion, which is the most immunopotent region of the Fab and F(ab')2 fragments of MAb A7 and MAb A7, was determined by ELISA; the weakest reaction was observed with the Fab fragments of MAb A7. These results suggest that the Fab fragments of MAb A7 may be more suitable carriers of an anticancer drug that is inactivated rapidly in the blood, such as NCS, in targeting chemotherapy than either intact MAb A7 or the F(ab')2 fragments of MAb A7.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antigen-Antibody Reactions; Enzyme-Linked Immunosorbent Assay; Humans; Immunoconjugates; Immunoglobulin Fab Fragments; Iodine Radioisotopes; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Tumor Cells, Cultured; Zinostatin

Neocarzinostatin (NCS) was bound covalently to human/mouse chimeric Fab fragments of MAb A7 (chA7Fab) directed against human pancreatic carcinoma. The anti-tumour effect of chA7Fab-NCS was tested in a nude mouse model on pancreatic carcinoma and compared with A7-NCS or NCS alone. The anti-tumour effect of chA7Fab-NCS increased in a dose-dependent manner and was significantly greater than either A7-NCS or NCS. Tumour growth was completely suppressed after the administration of chA7Fab-NCS. An enzyme-linked immunosorbent assay with rabbit anti-mouse immunoglobulin was performed to examine the antigenicity of chA7Fab. ChA7Fab had less reactivity with rabbit anti-mouse immunoglobulin than either whole antibody A7 or murine Fab fragments of A7. Thus, chA7Fab-NCS can inhibit human pancreatic cancer growth in an animal and may be useful for targeting chemotherapy to pancreatic cancer in humans.

Topics: Animals; Antibodies, Anti-Idiotypic; Carcinoma, Squamous Cell; Humans; Immunotoxins; Mice; Mice, Nude; Neoplasms, Experimental; Pancreatic Neoplasms; Recombinant Fusion Proteins; Transplantation, Heterologous; Zinostatin

We have developed chimeric Fab fragments of MAb A7 (chA7Fab) and have reported on their potential usefulness as a carrier of neocarzinostatin (NCS). However, a large amount of chA7Fab accumulates in the kidneys which might cause renal failure. This was one of the major side-effects of the chA7Fab-NCS immunoconjugate administered to humans. To decrease the kidney accumulation of chA7Fab, chA7Fab was biotinylated and administered with a subsequent injection of avidin to nude mice with pancreatic cancer. The accumulation of biotinylated chA7Fab in the blood and the kidneys decreased significantly after the injection of avidin. In a separate experiment with biotinylated chA7Fab-NCS, the blood and kidney accumulation decreased significantly after the injection of avidin. These findings suggest that the injection of biotinylated chA7Fab complexed with NCS followed by avidin may be safer and may permit the administration of larger doses of NCS without the subsequent development of renal failure.

Topics: Animals; Antibodies, Monoclonal; Avidin; Biotin; Drug Carriers; Humans; Immunoglobulin Fab Fragments; Iodine Radioisotopes; Kidney; Male; Mice; Mice, Nude; Pancreatic Neoplasms; Recombinant Fusion Proteins; Time Factors; Tissue Distribution; Transplantation, Heterologous; Zinostatin

In order to investigate the efficacy of the intra-tumoural administration of an anticancer drug-monoclonal antibody conjugate in athymic nude mice bearing xenografts of a human pancreatic carcinoma, we examined the clearance of the murine monoclonal antibody A7 from the xenografts after intravenous or intra-tumoural administration and measured the antitumour effect of neocarzinostatin conjugated to MAb A7 following intravenous or intra-tumoural injection. Compared with 125I-labelled normal mouse IgG, a larger amount of 125I-labelled A7 remained in the tumour after both intravenous and intra-tumoural injection, and a significantly larger amount of 125I-labelled A7 remained in the tumour after intra-tumoural injection than that after intravenous injection. Moreover, a larger amount of 125I-labelled A7-NCS localized in the tumour after intra-tumoural injection than that after intravenous injection. Neocarzinostatin conjugated to MAb A7 showed greater activity against human pancreatic cancer than neocarzinostatin alone after both intravenous and intra-tumoural administration. Tumour growth was suppressed completely by the intra-tumoural administration of A7-NCS at a dose that did not suppress tumour growth via the intravenous route. These observations suggest that the intra-tumoural injection of neocarzinostatin conjugated to MAb A7 offers promise in treating pancreatic carcinoma.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Humans; Immunotoxins; Infusions, Intravenous; Injections, Intralesional; Iodine Radioisotopes; Mice; Mice, Nude; Pancreatic Neoplasms; Transplantation, Heterologous; Tumor Cells, Cultured; Zinostatin

The anticancer agent neocarzinostatin (NCS) was bound covalently to human/mouse chimeric Fab fragments of the monoclonal antibody A7 to form the conjugate chA7Fab-NCS. The antitumor effect of chA7Fab-NCS was tested by measuring the inhibition of 3H-thymidine incorporation into human pancreatic carcinoma cells. The chA7Fab-NCS was approximately 2.3 times as effective as free NCS against human pancreatic carcinoma cells which reacted with the monoclonal antibody A7. The antitumor activity of chA7Fab-NCS was inhibited by excess chA7Fab. ChA7Fab-NCS had an antitumor effect equivalent to free NCS on human pancreatic carcinoma cells which did not react with the monoclonal antibody A7. ChA7Fab-NCS appears to be a potentially useful conjugate for immunotargeting chemotherapy against pancreatic carcinoma.

Topics: Animals; Antibodies, Monoclonal; Drug Carriers; Humans; Immunoconjugates; Immunoenzyme Techniques; Immunoglobulin Fab Fragments; Mice; Pancreatic Neoplasms; Tumor Cells, Cultured; Zinostatin

In this study, we conjugated chimeric Fab fragments of the monoclonal antibody (MAb) A7, which reacts with pancreatic cancers, to the antitumor drug neocarzinostatin (chA7Fab-NCS) and intravenously injected 125I-labeled chA7Fab-NCS into nude mice bearing a human pancreatic cancer xenograft. We compared the tumor localization of 125I-labeled chA7Fab-NCS with that of conventional 125I-labeled A7-NCS, which was produced by conjugation of MAb A7 and NCS. 125I-Labeled chA7Fab-NCS accumulated in the tumor earlier than 125I-labeled A7-NCS, and significantly larger amounts of 125I-labeled chA7Fab-NCS had accumulated in the tumor 1 hour after injection. The results suggest that chA7Fab may be a suitable carrier for NCS in immunotargeting therapy against pancreatic cancer.

Topics: Animals; Antibodies, Monoclonal; Humans; Immunoglobulin Fab Fragments; Injections, Intravenous; Iodine Radioisotopes; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Recombinant Proteins; Transplantation, Heterologous; Tumor Cells, Cultured; Zinostatin

We investigated the following in athymic nude mice with xenografts of a human pancreatic carcinoma: 1) clearance of the murine monoclonal antibody A7 from the carcinoma; and 2) the antitumor effect of neocarzinostatin conjugated to MAb A7 (A7-NCS) on the carcinoma following intratumoral injection. Compared with 125I-labeled normal mouse IgG, a significantly larger amount of 125I-labeled A7 remained in the tumor after intratumoral injection. Neocarzinostatin conjugated to MAb A7 showed a greater antitumor activity against human pancreatic cancer than neocarzinostatin alone after intratumoral administration. The conjugate completely suppressed tumor growth macroscopically during the experiment. Tumor tissue in mice became necrotic 32 days after injection with A7-NCS. These observations suggest that the intratumoral injection of A7-NCS offers promise in treating pancreatic carcinoma.

Topics: Animals; Antibodies, Monoclonal; Carcinoma, Intraductal, Noninfiltrating; Drug Carriers; Humans; Immunoenzyme Techniques; Injections, Intralesional; Iodine Radioisotopes; Male; Mice; Mice, Inbred BALB C; Pancreatic Neoplasms; Tumor Cells, Cultured; Zinostatin

The anti-cancer drug neocarzinostatin (NCS) was bound covalently to the monoclonal antibody A7 to form the conjugate A7-NCS. This antibody was produced by fusing the spleen cells of a mouse immunized against human colonic carcinoma with murine myeloma cells and reacts with a high percentage of human pancreatic carcinoma cell lines and with no normal human pancreas tissue by immunoperoxidase staining. The cytotoxic effect of A7-NCS was tested by measuring the inhibition of 3H-thymidine incorporation into human pancreatic carcinoma cells. The A7-NCS was approximately 2.7 times as effective as free NCS against human pancreatic carcinoma cells which reacted with the monoclonal antibody A7. A7-NCS had almost the same cytotoxicity a free NCS on human pancreatic carcinoma cells which did not react with the monoclonal antibody A7. A7-NCS appeared to be potentially useful as a conjugate for immunotargeting chemotherapy against pancreatic carcinoma.

Topics: Antibiotics, Antineoplastic; Antibodies, Monoclonal; Cell Survival; Drug Screening Assays, Antitumor; Humans; Immunoenzyme Techniques; Pancreatic Neoplasms; Tumor Cells, Cultured; Zinostatin

Monoclonal antibody-drug conjugate, A7-NCS, was applied for 73 patients with colorectal and pancreatic cancer, including metastasis of liver, lung and peritoneum. Monoclonal antibody A7, from a mouse splenocyte immunized against human colon cancer was bound covalently to Neocarzinostatin (NCS), Mitomycin C (MMC) and Adriamycin (ADM) to form A7-NCS, A7-MMC and A7-ADM, respectively. Fifty-four patients with colon cancer, fifteen patients with postoperative liver metastasis of colorectal cancer and one patient with advanced pancreatic cancer were given A7-NCS intra-arterially. Two patients with postoperative lung metastasis of colon cancer were injected intra-venously and one patient with postoperative peritoneal metastasis of colon cancer was given it intraperitoneally. Three patients with liver metastasis showed evidence of tumor reduction on CT scan and three claimed pain relief. Postoperative survival of the patients with distant metastasis exhibited slightly higher survival rate in the patients with A7-NCS, as compared with the patients without A7-NCS. There was no serious adverse effect in the patients given A7-NCS. Human anti-mouse antibody (HAMA) was detected in all patients given the conjugate. Repeated injections of A7-NCS for several consecutive days following the first injection brought about the same A7 pattern as the first injection.

Topics: Aged; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Colorectal Neoplasms; Doxorubicin; Drug Administration Schedule; Female; Humans; Immunotoxins; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Pancreatic Neoplasms; Prognosis; Survival Rate; Zinostatin

At the time of pancreatoduodenal cancer resection, Neocarzinostatin (NCS) was injected into the duodenal sub-serosa, as perioperative adjuvant chemotherapy for metastatic lymph nodes and cancer cells released into the lymphatic system. NCS content in the lymph nodes was measured after administration, and usefulness of the chemotherapy was investigated.. NCS (4,000 units) was administered into the duodenal sub-serosa of 18 adult mongrel dogs. NCS contents in the lymph nodes (those in the root of the mesentery and around the aorta) and pancreatic tissues were measured. NCS content in the pancreatic tissues decreased significantly 3 hours after administration, while that in the lymph nodes did not decreased even 3 hours later. Consequently, NCS is considered to be remain in the lymph nodes.. NCS (10,000 units) was administered into the duodenal sub-serosa in 18 resectable cases of pancreatoduodenal cancer. NCS content in the dissected lymph nodes was measured. The total number of dissected lymph nodes was 176, and the mean NCS content was 0.62 mu/g. The number of lymph nodes positive for metastasis was 14, and much content of NCS was observed in the specimens (mean NCS content: 1.25 mu/g). Examination according to site revealed the most content in the lymph nodes in pancreatic head closest to the site of administration, followed by the lymph nodes in the root of the mesentery and those in the hepatoduodenal ligament in the direction of lymphatic flow. Moreover, some distal lymph nodes also showed much content. NCS content in the lymph nodes showed time-related increase after administration, and significant correlation was observed within 2 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Animals; Combined Modality Therapy; Dogs; Duodenal Neoplasms; Female; Humans; Injections; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Pancreatic Neoplasms; Serous Membrane; Zinostatin

As an intraoperative chemotherapy treatment for the regional lymph nodes in resectable cases of pancreatoduodenal cancer, Neocarzinostatin (NCS) was administered in the duodenal subserosa and the NCS concentration was measured in the resected lymph nodes.. NCS 4,000 units (n = 4), or 10,000 units (n = 4) was administered into the duodenal subserosa of mongrel dogs, and 2 hours after administration, the lymph nodes of the mesentery root were resected. The NCS concentration in the lymph nodes was 0.21 U/g in the 4,000-U group and 1.39 U/g in the 10,000-U group.. NCS 10,000 U was administered into the duodenal subserosa in 6 cases of pancreatoduodenal cancer. The total number of resected lymph nodes was 49 and the mean NCS concentration was 5.65 U/g. According to site, the highest concentration was measured in lymph nodes from the anterior and posterior region of the pancreas head, which were near to the administration site. Also, NCS was well distributed in the lymph nodes in the hepatoduodenal ligament and mesentery root which lay in the direction of lymph flow. NCS concentration was high in lymph nodes resected 1 hour after administration. According to experimental reports of in vitro studies, an NCS concentration of more than 0.5 U/g is required to obtain an anticancer effect. This method is therefore considered to be useful as a form of intraoperative chemotherapy for the regional lymph nodes in pancreatoduodenal cancer.

Topics: Animals; Antibiotics, Antineoplastic; Dogs; Duodenal Neoplasms; Duodenum; Intraoperative Period; Liver; Lymph Nodes; Pancreatic Neoplasms; Serous Membrane; Zinostatin

The present study was designed to evaluate the efficacy of chemotherapy by NCS for advanced and/or recurrent carcinoma of the pancreas, mainly nonresectable cases in which exploratory laparotomy or construction of biliary fistula were performed. Three hundred fifty seven cases were available for the study. Of the 357 cases, 116 were treated with NCS alone 5-FU. In the former, the efficacy rate was higher in cases with 2,000 mu/body of NCS every day than in those with 4,000 mu/body of NCS intermittently 2-3 times for a week. 19.6% of the cases treated with more than 40,000 mu of NCS alone in total were interpreted as effective clinically by Karnofsky's criteria of I-A over. In the latter, the efficacy rate was higher in cases with 2,000 mu/body of NCS combined with 250 mg of 5-FU every day than in those with 4,000 mu of NCS combined with 500 mg of 5-FU intermittently, 22.5% of the cases given more than 40,000 mu of NCS in total were interpreted as effective clinically by Karnofsky's criteria of I-A over. The major adverse effects of NCS such as anorexia, vomiting and nausea were observed in 20% of total cases respectively, leucopenia in 10% and fever in 15% of them.

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

By applying an en bloc resection of the pancreas with adjacent soft tissue, regional lymph nodes and pertinent vascular structures, a better prognosis could be made for patients with stages I or II carcinoma of the pancreas. The patients with stages III or IV of carcinoma of the pancreas could only be treated to a certain degree of effectiveness by using systemic combination chemotherapy with a very limited prognosis. Recent development of slow releasing anticancer agents would give more positive aspect for the management of persistent pains due to carcinoma of the pancreas with the absence of systemic side effect.

Topics: Adult; Aged; Delayed-Action Preparations; Drug Therapy, Combination; Female; Fluorouracil; Humans; Male; Middle Aged; Mitomycin; Mitomycins; Pancreatectomy; Pancreatic Neoplasms; Zinostatin

Topics: Aged; Amylases; Animals; Antibiotics, Antineoplastic; Bicarbonates; Humans; Middle Aged; Pancreatic Neoplasms; Rats; Zinostatin