zinostatin and Drug-Hypersensitivity

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

SV40-transformed ataxia-telangiectasia (SV40-AT) fibroblasts were cotransfected with a plasmid carrying the neomycin-resistance gene as well as DNA from primary mouse embryo fibroblasts. The transfected fibroblasts were seeded under selective conditions and neomycin-resistant (neor) colonies were obtained and tested for the effect of the carcinogen neocarzinostatin (NCS) on DNA synthesis. Whereas the primary A-T and SV40-transformed A-T fibroblasts did not respond to carcinogen treatment and continued to synthesize DNA on damaged templates, normal fibroblasts stopped DNA synthesis after NCS treatment. Among the neomycin-resistant colonies, cells of two colonies responded to NCS treatment by the cessation of DNA synthesis like normal fibroblasts. When DNA from such a colony was transfected into SV40-AT cells, four neor colonies were isolated of which one had regained the normal phenotype. This study provides the first clue that mouse DNA can partly correct the A-T genetic defect expressed in SV40-transformed fibroblasts. Two of the neor colonies with the corrected phenotype expressed a 3.5 kb fibronectin RNA that was detectable by a rat fibronectin DNA probe but not by the human fibronectin DNA probe containing the cell attachment sequence. The latter probe did not detect fibronectin mRNA in the SV40-AT cells but detected expression of the 8.6 kb fibronectin RNA in the two neor colonies of transfected SV40-AT fibroblasts in which the response to NCS was repressed. The results suggest that "correction" of the A-T gene defect in SV40-AT fibroblasts might be associated with regulation of human fibronectin gene(s) expression.

Topics: Animals; Ataxia Telangiectasia; Cell Line, Transformed; DNA Replication; Drug Hypersensitivity; Drug Resistance, Microbial; Fibroblasts; Fibronectins; Gene Expression; Humans; Mice; Neomycin; Plasmids; RNA, Messenger; Simian virus 40; Transfection; Zinostatin

Neocarzinostatin, a polypeptide antibiotic, was administered by both continuous and intermittent intravenous infusion to 76 patients with a variety of malignant diseases. Doses ranged from 500 to 6500 units/m2 X 5 days. With levels greater than or equal to 1800 units/m2, bone marrow suppression (particularly thrombocytopenia) was the dose-limiting toxicity. Delayed bone marrow recovery was less dose-dependent and occurred in 58% of initial treatment courses in solid tumor patients. Allergic reactions were more frequent with intermittent than with continuous infusions (20% vs. 2% of courses). No complete or partial remissions were observed among solid tumor patients although clinical improvement was noted in one patient with mycosis fungoides and one patient with multiple myeloma. One complete and two partial remissions were noted among 21 patients with acute leukemia. There was one complete remission in a patient with chronic leukemia. Leukemic patients on intermittent therapy evidenced greater change in bone marrow cellularity than those treated by continuous infusion. Although neocarzinostatin has some activity in the treatment of acute leukemia, continuous infusion offers no advantage over intermittent therapy.

Topics: Antibiotics, Antineoplastic; Bone Marrow; Drug Administration Schedule; Drug Evaluation; Drug Hypersensitivity; Female; Humans; Infusions, Parenteral; Leukemia; Neoplasms; Zinostatin

Twenty-three children with advanced cancer refractory to conventional therapy received weekly iv doses of neocarzinostatin for 5 weeks. Doses were escalated from 500 to 6750 units/m2/week. Four types of toxic manifestations occurred: acute reactions consisting of shaking chills with or without fever and cyanosis (rigor), hypersensitivity, vomiting, and marrow depression. Evidence of oncolytic activity was limited to patients with acute leukemia in whom phase II trials at doses between 3000 and 4500 units/m2 appear warranted.

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Bone Marrow; Child; Child, Preschool; Drug Evaluation; Drug Hypersensitivity; Humans; Infant; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Neoplasms; Remission, Spontaneous; Shivering; Vomiting; Zinostatin