zinostatin and Fever

Lipiodol, an oily contrast medium, is utilized to deliver the anticancer agent SMANCS to the target tumor in which the tumor selective delivery of 2,500 fold more than plasma was confirmed with prolonged retention in the tumor tissue. This unique tumor targeting is accomplished by the arterial injection of the oily formulation of the drug. The method utilizes unique vascular properties of tumor tissue. SMANCS is a derivative of neocarzinostatin conjugated with copolymer of styrene and maleic acid. It has much propronounced lipophilicity, stability against various harsh environments and exerts a potent cytotoxicity. Therapeutic effect of the drug to unresectable primary hepatoma is much better than the conventional method. For Child A category patients with intrahepatic metastasis in no more than three area, a 3 yr survival rate is more than 87%. When the Child's A and B are combined with no distant metastasis, 1-, 2- and 3-year survival rates are 87%, 50%, and 35%, respectively. The side effect of this treatment [SMANCS/Lipiodol, i.p.] is minimal; transitory low grade fever is the commonest one (40-50% of cases) which can be controlled by a routine protocol. No liver or marrow toxicity was observed. Procedural limitations for the lung cancer etc. are discussed.

Topics: Adult; Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Evaluation; Fever; Furans; Humans; Injections, Intra-Arterial; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Middle Aged; Polystyrenes; Survival Rate; Zinostatin

Neocarzinostatin is a new anticancer drug developed by Japanese investigators. In order to delineate the potential usefulness of this drug, we have reviewed the preclinical data and summarized the Japanese clinical data on 462 patients. The bulk of these patients had carcinoma of the stomach or pancreas and acute leukemia. Neocarzinostatin was administered intravenously in a daily dose of 2-3 mg for five to 15 day periods. Significant antitumor activity was observed in acute leukemia. A few responses were also reported in pancreatic adenocarcinoma, but the drug was inactive against gastric carcinoma. The side effects observed included nausea, vomiting, myelosuppression, fever, and occasional hypersensitivity reactions. The Investigational Drug Branch of the National Cancer Institute has recently sponsored an investigational new drug application with the Food and Drug Administration, and phase I studies are expected to begin soon in the United States.

Topics: Amino Acids; Animals; Antibiotics, Antineoplastic; Cell Division; Chemical Phenomena; Chemistry; Diarrhea; DNA Replication; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Eruptions; Fever; Humans; Hypotension; Kidney Diseases; Leukopenia; Molecular Weight; Nausea; Neoplasms; Neoplasms, Experimental; Temperature; Templates, Genetic; Thrombocytopenia; Zinostatin

We report a Phase I/II clinical trial of poly-(styrene-co-maleyl-half-n-butylate)-neocarzinostatin (SMANCS) for intra-arterial treatment of hepatoma. Early patients received 4 or 8 mg SMANCS dissolved in Lipiodol; later patients were treated according to tumour size and degree of filling achieved. SMANCS/Lipiodol drained rapidly from normal liver but was retained within tumour interstitium. Tumour nodules filled with SMANCS/Lipiodol usually stabilised and often regressed. No UICC criteria-defined responses were achieved, partly due to difficulties of filling several lesions simultaneously. Signs of therapeutic activity suggest a more extensive clinical study is warranted.

Topics: Abdominal Pain; Adult; Aged; alpha-Fetoproteins; Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Evaluation; Drug Hypersensitivity; Female; Fever; Humans; Hypotension; Injections, Intra-Arterial; Liver; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Radiography; Syncope; Treatment Outcome; Zinostatin

A phase II study of YM 881 (zinostatin stimalamer) to determine the response and safety was conducted in patients with hepatocellular carcinoma by injecting a suspension of the drug into the hepatic artery. Repeated doses of 4 to 6 mg of the drug were given every 4 weeks so that the tumor tissues were filled with the suspension. Of the 195 registered patients, 15 were ineligible for the study, 8 dropped out, and data were missing for 5. A total of 167 patients completed the study. Response was assessed in the 167 patients who completed the study. CR was found in one, PR in 59, MR in 25, NC in 67, and PD in 15, with a response rate of 35.9. The safety of the drug was assessed in 177, excluding ineligible patients and 3 who dropped out because of the concurrent use of other drugs. Adverse reactions were found in 93.2% of the patients, and abnormal values in clinical laboratory tests in 60.5%. Major unwanted symptoms included fever, nausea, vomiting, and anorexia. Major abnormal changes in laboratory tests were elevated total bilirubin and LDH and abnormal hepatic function. About half the patients had malaise and pain related to the intra-arterial infusion therapy. The one year survival rate was 56.9%, and the duration of survival of 50% of the patients was 407 days.

Topics: Adult; Aged; alpha-Fetoproteins; Anorexia; Carcinoma, Hepatocellular; Drug Administration Schedule; Drug Evaluation; Female; Fever; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Nausea; Polystyrenes; Survival Rate; Zinostatin

A phase I study of YM-881 (zinostatin stimalamer), neocarzinostatin combined with butylesterified styrene maleate, suspended in iodized poppy oil ethyl ester, was conducted in patients with hepatocellular carcinoma by giving single intra-arterial infusions via catheters inserted by Seldinger's method. Four dose levels, 2, 4, 6, and 8 mg, were tested. Major adverse reactions were fever, anorexia, nausea, vomiting, and abnormal hepatic function. Both the incidence and severity of adverse reactions tended to increase with the 8 mg dose. Tumor regression of 50% or more occurred in one receiving 2 mg and one receiving 4 mg. The results of the study suggest that doses of 6 mg or less may be appropriate for the phase II studies.

Topics: Adult; Aged; Anorexia; Carcinoma, Hepatocellular; Drug Administration Schedule; Drug Evaluation; Female; Fever; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Nausea; Polystyrenes; Zinostatin

Neocarzinostatin (NCZ), an acidic polypeptide antibiotic, was given to 47 patients with cancer and leukemia, and tolerance to two schedules, a single dose given as a 2 hour infusion and a continuous infusion over 5 days was investigated. Immediate reactions, including fever, chills, rigor, hypertension and mental confusion, were dose-limiting for the 2 hour infusion schedule, occurring at 3000 U/m2 and higher. Continuous administration for 5 days eliminated the immediate reactions and then hematological toxicity--often prolonged leukopenia and thrombocytopenia--became dose-limiting. Other toxicities of NCZ at both dose schedules included anemia, fever and chills, anorexia, nausea and vomiting, hepatic dysfunction, azotemia, hypophosphatemia, aminoaciduria, stomatitis, phlebitis and/or cellulitis at the venous infusion site and pruritus. Patients with solid tumors who had received little or no prior chemotherapy and had good bone marrow reserve tolerated up to 6000 U/m2/24 hours X 5 days. One patient with previously treated acute myelocytic leukemia was induced into a good partial remission lasting 10 weeks.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Bone Marrow; Child; Drug Administration Schedule; Drug Evaluation; Drug Tolerance; Female; Fever; Humans; Hyperbilirubinemia; Infusions, Parenteral; Leukemia; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasms; Remission, Spontaneous; Uremia; Zinostatin