zinostatin and Leukemia

This article describes previous studies on a unique protein antitumor antibiotic, neocarzinostatin. Namely, its chemical nature, mode of action at molecular and cellular levels, toxicity and pharmacology, and recent results in clinical trials obtained primarily in Japan have been reviewed briefly.

Topics: Amino Acid Sequence; Animals; Antibiotics, Antineoplastic; Clinical Trials as Topic; DNA, Neoplasm; Dogs; Drug Evaluation; Humans; Lethal Dose 50; Leukemia; Mice; Neoplasms; Rabbits; Rats; Zinostatin

Topics: Altretamine; Aminoacridines; Amsacrine; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Daunorubicin; Doxorubicin; Female; Gallium; Humans; Ifosfamide; Leukemia; Vinblastine; Vindesine; Zinostatin

Topics: Animals; Antibiotics, Antineoplastic; Bone Marrow; Digestive System; DNA, Single-Stranded; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Leukemia; Neoplasms; Neoplasms, Experimental; 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

Topics: Adolescent; Cell Survival; Female; Humans; Leukemia; Leukocyte Count; Lymphocytes; Neutrophils; Time Factors; Zinostatin

This article describes previous studies on a unique protein antitumor antibiotic, neocarzinostatin. Namely, its chemical nature, mode of action at molecular and cellular levels, toxicity and pharmacology, and recent results in clinical trials obtained primarily in Japan have been reviewed briefly.

Topics: Amino Acid Sequence; Animals; Antibiotics, Antineoplastic; Clinical Trials as Topic; DNA, Neoplasm; Dogs; Drug Evaluation; Humans; Lethal Dose 50; Leukemia; Mice; Neoplasms; Rabbits; Rats; Zinostatin

Topics: Altretamine; Aminoacridines; Amsacrine; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Daunorubicin; Doxorubicin; Female; Gallium; Humans; Ifosfamide; Leukemia; Vinblastine; Vindesine; Zinostatin

Topics: Acetaminophen; Acute Disease; Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Child; Clinical Trials as Topic; Diphenhydramine; Drug Evaluation; Female; Humans; Infusions, Parenteral; Leukemia; Male; Middle Aged; Zinostatin

Recent advances in molecular cytogenetics of leukemia is reported with special reference to the pathogenesis, diagnosis, prognosis, and potential gene therapy. Regarding leukemogenesis, we found that neocarzinostatin induced a variety of deletions and reciprocal translocations. Among these random chromosome abnormalities, two reciprocal translocations which were specific for certain leukemias could be observed; t(11;14)(q13;q32) and t(7;11)(p15p13). This fact suggests that a translocation carrying oncogene rearrangement may be of potential relevance to the leukemogenesis. The success in making a subgroup (FAB classification) identified a number of subtype-specific translocations in leukemias. It has been suggested that an initiation or progression-associated event is mediated through a gross chromosomal change. The molecular characterization of chromosomal rearrangement leads to the identification of genes involved in leukemia. Our recent works in molecular cytogenetics of chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), FAB-M3 and -M4 were shown in this article. Since rearrangement of relevant genes were cloned, PCR made it feasible to detect minimal residual disease at 10(-6) level after intensive treatment or bone marrow transplantation for CML, Ph-positive ALL, M3 and approximately half of childhood leukemia. Recently developed fluorescent in situ hybridization (FISH) using specific probes can visualize certain chromosomes or chromosomal segments. Ph translocation, for instance, is now demonstrated as three spot-signals in interphase nuclei using YAC (yeast artificial chromosome)-BCR clone. Lastly, the use of antisense oligonucleotides for the BCR-ABL junctions should result in the inhibition of growth of CML clone. The strategy using antisense molecules may be very powerful tool in the gene-targeting therapy for human neoplasms.

Topics: DNA Damage; Gene Rearrangement; Genetic Therapy; Humans; Leukemia; Mutation; Polymerase Chain Reaction; Prognosis; Translocation, Genetic; Zinostatin

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Leukemia; Male; Methotrexate; Middle Aged; Prednisolone; Vincristine; Zinostatin

An analysis of prognostic factors was performed on a series of 50 adult patients with acute leukemia, treated in our department in the Tokai university Hospital between July, 1975 and June, 1980. The diagnosis was made in all cases on the basis of May-Grünwald-Giemsa-stained smears of peripheral blood and bone marrow. The patients were treated with two successive protocols. One course of induction chemotherapy consisted of 40 units/kg/day of neocarzinostatin, 1.2-1.6 mg/kg/day of cytosine arabinoside, 0.6-0.8 mg/kg/day of daunorubicin and 0.8-1.6 mg/kg/day of prednisolone on days 1-4 for acute nonlymphocytic leukemia, and the other consisted of 0.04 mg/kg/day of vincristine on day 1, 0.6-0.8 mg/kg/day of daunorubicin on days 1-4, 0.8-1.6 mg/kg/day of prednisolone on days 1-4 for acute lymphocytic leukemia. Consolidation and intensification therapies were given every 1-2 months after complete remission, and the protocols were basically the same as those of the induction therapy. Maintenance therapy consisted of 1.2-1.6 mg/kg/day of cytosine arabinoside, twice a week or 2 mg/kg/day of 6 MP orally. Risk factor leading to poor prognosis of acute leukemia were considered to be (1) advanced age (older than 50 years, P less than 0.05), (2) M5 (monocytic leukemia), (3) thrombocytopenia (less than 50,000 cmm-1), and (4) chromosome abnormalities of blast cells.

Topics: Acute Disease; Adolescent; Adult; Aged; Chromosome Aberrations; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Middle Aged; Prednisolone; Prognosis; Vincristine; Zinostatin

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Agents; Cytarabine; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Middle Aged; Prednisolone; 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

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

Topics: Acute Disease; Adult; Antineoplastic Agents; Azacitidine; Blood Transfusion; Cytarabine; Daunorubicin; Dexamethasone; Etoposide; Granulocytes; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Patient Isolation; Platelet Transfusion; Pneumonia; Prednisone; Pyrimethamine; Remission, Spontaneous; Thioguanine; Vincristine; Zinostatin

Neocarzinostain (NCS) was first used by Hiraki and his colleagues for induction chemotherapy in acute leukemia. This new anti-tumor agent is a polypeptide with a high molecular weight of 10,700 daltons. Anti-NCS antibody was produced in rabbits administered NCS intramuscularly with or without adjuvant. The production of anti-NCS antibody in patients treated with NCS was investigated. Forty three leukemia cases of various types were examined totally 65 times. Two mg of NCS for four consecutive days by intravenous drip infusion followed by 7 to 10 days of pause was repeatedly administered. The total amounts ranged 8 to 174 mg and the total periods 4 to 87 days. The methods used to measure the antibody titer are the passive hemagglutination (PHA) test on microplate and the passive cutaneous anaphylaxis (PCA) reaction in guinea pigs. The sera of all patients showed only non-specific agglutination at less than 2(3) dilution by PHA test, and to confirm these results four patient sera were tested by PCA reaction. The production of anti-NCS antibody was not detected in patients by PHA test and PCA reaction. The anaphylactic reaction and other adverse reactions due to anti-NCS adtibody production were not demonstrated in patients. Anti-NCS antibody was not detected by these experiments in the dose schedule administered.

Topics: Anaphylaxis; Animals; Antibiotics, Antineoplastic; Antibodies, Anti-Idiotypic; Antibody Formation; Hemagglutination Inhibition Tests; Hemagglutination Tests; Humans; Leukemia; Rabbits; Zinostatin

Topics: Acute Disease; Adolescent; Adult; Aminobiphenyl Compounds; Antineoplastic Agents; Asparaginase; Bone Marrow; Cell Survival; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia; Leukocyte Count; Male; Mercaptopurine; Mesylates; Methotrexate; Middle Aged; Neutrophils; Prednisolone; Time Factors; Zinostatin

Topics: Acute Disease; Antineoplastic Agents; Azacitidine; Cytarabine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Guanazole; Humans; Leukemia; Lomustine; Peptichemio; Podophyllotoxin; Razoxane; Zinostatin

Topics: Aged; Busulfan; Drug Administration Schedule; Drug Therapy, Combination; Humans; Leukemia; Leukemia, Myeloid; Mitobronitol; Zinostatin

Topics: Acute Disease; Antibiotics, Antineoplastic; Drug Evaluation; Humans; Leukemia; Middle Aged; Remission, Spontaneous; Zinostatin

Topics: Acute Disease; Adolescent; Adult; Antibiotics, Antineoplastic; Child; Female; Humans; Infant; Leukemia; Male; Middle Aged; Zinostatin

Topics: Acute Disease; Antibiotics, Antineoplastic; Drug Therapy, Combination; Humans; Leukemia; Middle Aged; Zinostatin

Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Ascites; Leukemia; Leukemia, Experimental; Mice; Molecular Weight; Pharmacology; Research; Sarcina; Sarcoma 180; Staphylococcus; Streptomyces; Tissue Culture Techniques; Zinostatin