zinostatin and Leukemia--Lymphoid

Topics: Antibiotics, Antineoplastic; Antibodies; Antibodies, Monoclonal; Antibody Specificity; Cell Line; Cytotoxicity, Immunologic; Humans; Immunoglobulins; Leukemia, Lymphoid; Ricin; Zinostatin

An alkaline elution procedure was used to study the nature of DNA damage induced by auromomycin, an antitumor protein, in human leukemic lymphoblasts (CCRF-CEM cells). The filter elution of drug-treated cells at pH 12.2 and 9.6 showed induction of both single and double strand DNA breaks. The DNA strand scission activities were linear in relation to drug concentration. The frequency of single strand breaks was higher than that of the double strand breaks. Protein-associated DNA single strand breaks were also detected in alkaline elution of drug-treated cells when a proteinase K digestion step was included in the assay protocol. The auromomycin-induced single strand breaks were repaired to almost completion within 8 h of postincubation of DNA-damaged cells whereas the repair of double strand breaks was not detected.

Topics: Anti-Bacterial Agents; Antibiotics, Antineoplastic; Apoproteins; Cell Line; DNA Repair; DNA, Neoplasm; Endopeptidase K; Endopeptidases; Gamma Rays; Humans; Leukemia, Lymphoid; Molecular Weight; Peptides; Structure-Activity Relationship; Zinostatin

The establishment of permanent acute lymphocytic leukemia (ALL) lines of different phenotypes permits the study of their sensitivity to chemotherapeutic agents. The sensitivity of four ALL cell lines, two T-cell lines and one each of B- and non-T/non-B cell lines, to eight chemotherapeutic agents was studied by means of clonogenic assay. Response data were analyzed by two criteria--one based on concentrations obtainable from the elimination phase and the other based on peak concentration--both derived from pharmacokinetic studies in man. The overall correlation between the two criteria was good and only in 5 of 32 occasions were there major discrepancies. A retrospective analysis of the clinical course of the four donor patients showed that although the one set of criteria gave a positive correlation of asparaginase response in vivo, the other positively correlated the daunorubicin response, but not vice versa. No new cut-off line could be drawn to satisfy completely in vitro/in vivo correlation for all the drugs. Although the possibility exists that a leukemic cell line may not actually be predictive of chemotherapeutic responsiveness in the donor patients, our data indicate a need to reexamine the in vitro system in predictive testing of antileukemic agents.

Topics: Adult; Antineoplastic Agents; Asparaginase; Cell Survival; Cells, Cultured; Child; Colony-Forming Units Assay; Daunorubicin; Dexamethasone; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Hydrocortisone; Leukemia, Lymphoid; Male; Middle Aged; Tumor Stem Cell Assay; Vinblastine; Vincristine; Zinostatin

The in vivo antitumor activity of NCS-immune immunoglobulin G (IgG) [Neocarzinostatin (NCS) conjugated with rabbit IgG antibody against a human leukemia cell line (NALL-1)] was evaluated in immunosuppressed newborn Syrian hamsters into which a transplantable human leukemia cell line, BALL-1 was implanted. After intraperitoneal (i.p.) injection of the conjugate, hamsters preinoculated i.p. with BALL-1 cells survived longer than hamsters treated with control solutions (p less than 0.01). The control solutions were NCS, immune IgG, a mixture of NCS and immune IgG, NCS-normal IgG conjugate and physiological saline. There was no change in body weight in the NCS-immune IgG-treated hamsters. The growth of subcutaneously (s.c.) implanted BALL-1 tumors was also inhibited by i.p. administration of NCS-immune IgG; however, the degree of inhibition was not significantly different from that obtained by administration of NCS alone, a mixture of NCS and immune IgG or NCS-normal IgG conjugate. These results indicate that NCS-immune IgG was effective against i.p. BALL-1 tumors, but was less effective against s.c. implanted tumors.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies, Neoplasm; Cell Line; Cricetinae; Humans; Immunoglobulin G; Leukemia, Experimental; Leukemia, Lymphoid; Mesocricetus; Neoplasm Transplantation; 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

Topics: Antibiotics, Antineoplastic; Humans; Immunoglobulin G; In Vitro Techniques; Leukemia, Lymphoid; Lymphoma; Picibanil; 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

Neocarzinostatin is a protein antitumor antibiotic isolated from cultures of Streptomyces carzinostaticus var.F41. The drug has undergone extensive clinical trial in Japan, and has been reported active against a variety of human tumors. A phase I and preliminary phase II evaluation of the drug has been performed, using an iv bolus daily x 5 schedule. Ninety-six patients have been treated at doses from 500 to 2250 units/m2/day. Courses were repeated at 4-week intervals if allowed by bone marrow recovery. Dose-limiting toxicity was myelosupppression, which occurred late (median nadir, Day 27). Myelosuppression was more pronounced in patients who had received previous chemotherapy. In nine patients (9%) thrombocytopenia was prolonged (greater than or equal to 45 days) or irreversible. Acute administration of the drug was associated with rigors in approximately half the patients. Gastrointestinal side effects were mild. Three patients had a severe acute reaction resembling anaphylaxis. The maximally tolerated dose for this dose schedule is approximately 2250 units/m2/day. Antitumor activity has been seen in hepatoma and hematologic malignancies. Activity in lung and colorectal carcinoma appears limited with this dose schedule.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Bone Marrow; Carcinoma, Hepatocellular; Child; Drug Evaluation; Female; Humans; Leukemia, Lymphoid; Liver Neoplasms; Male; Middle Aged; Neoplasms; Remission, Spontaneous; Thrombocytopenia; Zinostatin

Neocarzinostatin (NCS) is an acidic protein (molecular weight, 10,700) isolated from Streptomyces carzinostaticus that has antitumor activity both in model rodent systems and in humans. In vitro it inhibits the growth of a human lymphoblastic leukemic cell line (CCRF-CEM) at a very low concentration (the amount of drug that causes a 50% inhibition of growth compared to control cultures as extrapolated from a dose-response curve (ID50), 2.4 X 10(-9) M). We covalently coupled NCS to the N-hydroxysuccinimide ester of agarose and obtained a product that, by a variety of biochemical and immunological criteria, has been demonstrated to be devoid of any free or loosely bound NCS. Agarose-bound NCS, which is unable to enter cells because of its size, retains a significant amount of inhibitory activity (ID50, 6 to 15 X 10(-9) M) and is also capable of inhibiting tritiated deoxythymidine incorporation into CCRF-CEM cells. Since agarose-bound NCS cannot enter mammalian cells, the above findings indicate that NCS is able to exert its toxic effects by binding to or reacting with receptors on the cell membrane.

Topics: Animals; Antibiotics, Antineoplastic; Cell Division; Cell Line; Cell Membrane; Humans; Leukemia, Experimental; Leukemia, Lymphoid; Sepharose; 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

Topics: Adolescent; Adult; Cytarabine; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Middle Aged; Prednisolone; Statistics as Topic; Vincristine; Zinostatin