zinostatin and Adenocarcinoma

Polyanionid copolymer of divinyl ether and maleic anhydride (DIVEMA) with narrow molecular weight distribution was synthesized and tested of its antitumor activity. DIVEMA showed a significant antitumor activity against colon 26 adenocarcinoma and FSaI fibrosarcoma transplanted in syngenic mice. Furthermore, DIVEMA was used as a polymeric drug carrier of antitumor drugs to reduce side effects and enhance the antitumor activity of the drugs. Adriamycin and neocarzinostatin were attached covalently to DIVEMA and the polymeric conjugates showed higher antitumor activity than the corresponding mother drugs against P 388 leukemic mice.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Chemical Phenomena; Chemistry; Colonic Neoplasms; Doxorubicin; Drug Carriers; Humans; Leukemia P388; Macromolecular Substances; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Polyelectrolytes; Polymers; Pyran Copolymer; 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

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

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

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

For targeting chemotherapy of colorectal carcinoma, mitomycin C (MMC) and neocarzinostatin (NCS) were covalently bound to monoclonal antibody A7 which is highly specific to human colon cancer. The in vitro cytotoxic effects of the conjugates A7-MMC and A7-NCS on SW1116 were 77 times and 4 times stronger than those of the free MMC and free NCS, respectively. An in vivo study in nude mice bearing human colon carcinoma revealed that monoclonal antibody A7 alone had no effect, and that A7-MMC and A7-NCS had greater inhibitory effects than the free MMC and NCS, respectively. Thirty-five patients with carcinoma of the colon and rectum including 6 with postoperative liver metastasis, one with postoperative lung metastasis and one with postoperative peritoneal metastasis, were given the A7-NCS conjugate consisting of between 15 and 90 mg of antibody and between 1,000 and 6,000 units of NCS. Immunoperoxidase study of resected specimens revealed selective localization of NCS in the cancer cells. The conjugate had no serious adverse effects. Five of the six patients with postoperative liver metastasis responded favorably to the conjugate, showing a decrease in tumor size on CT scan or relief of pain. The conjugate was of no benefit to patients with multiple lung metastasis or peritoneal metastasis. The effect on other patients with surgically resected carcinoma remains to be determined by a follow-up study.

Topics: Adenocarcinoma; Aged; Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Colonic Neoplasms; Female; Humans; Immunotoxins; Male; Mice; Mice, Nude; Middle Aged; Mitomycin; Mitomycins; Rectal Neoplasms; Zinostatin

Twenty-four patients with various solid tumors including metastatic liver cancer and cancer of the lung, gallbladder, and pancreas were treated with a lipophilic macromolecular drug, copoly(styrene-maleic acid) conjugated neocarzinostatin (SMANCS). The drug was dissolved in a lipid contrast medium Lipiodol and administered by catheterizing the respective feeding arteries under x-ray monitoring. The advantages of this therapy include: (1) selective deposition of Lipiodol with the anti-cancer drug in the target tumor, (2) a pronounced and long-lasting anti-cancer effect, (3) enhanced visualization of the tumor on x-ray examinations for a prolonged period which also facilitated the long-term follow-up, (4) semiquantitative evaluation of the dosage regimen by x-ray examination before further administration, (5) general applicability due to procedural simplicity, and (6) little side effect. Since the amount of Lipiodol and SMANCS used per administration for a patient (1.0-5.0 ml; 1.0-5.0 mg) was far less than the anticipated toxicity (LD50 of Lipiodol = 95 ml/60 kg, dog, intravenously; and that of SMANCS = 3.4 mg/kg, mouse, IV), no deleterious effects to such critical organs as the brain, heart, lung, liver, or kidneys were observed upon radiologic and general clinical examination.

Topics: Adenocarcinoma; Aged; Antibiotics, Antineoplastic; Carcinoma, Squamous Cell; Contrast Media; Female; Follow-Up Studies; Gastrointestinal Neoplasms; Humans; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Radiography; 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