mitoguazone and Leukemia--Myeloid--Acute

Topics: Aminoacridines; Amsacrine; Antineoplastic Agents; Azacitidine; Clinical Trials as Topic; Daunorubicin; Doxorubicin; Drug Evaluation; Drug Therapy, Combination; Etoposide; Humans; Leukemia, Myeloid, Acute; Mitoguazone; Recurrence

Topics: Bone Marrow Examination; Cytarabine; Daunorubicin; Drug Therapy, Combination; Guanidines; Humans; Intensive Care Units; Leukemia, Myeloid, Acute; Leukocyte Count; Mitoguazone; Remission, Spontaneous; Thioguanine; Time Factors

A combined eflornithine-MGBG treatment was studied in patients with acute myeloid leukemia (AML) or blastic transformation of chronic myeloid leukemia (BT CML). The first ten patients (5 AML, 5 BT CML) received i.v. or p.o. eflornithine 6 g m-2 day-1 and i.v. MGBG 500 mg/m2 once a week. The duration of treatment was 5-37 days (median 15) with one to five MGBG infusions (median 2). The results were complete response (CR) in one patient, partial response (PR) in four, minimal response (MR) in one and failure (F) in four. Pronounced side effects, including severe mucositis, gastrointestinal disturbances and skin infiltration, were observed in eight patients. As the four PRs were achieved in patients with BT CML, it was decided also to study ten patients with this indication. In attempts to decrease the incidence and severity of unwanted effects, lower doses of eflornithine-MGBG were used, i.e., eflornithine 4 g m-2 day-1 and MGBG 200 mg m-2 once a week. The duration of treatment was 9-110 days (median 46), with 2-14 MGBG infusions (median 6). Responses observed were CR in two patients (in one of whom it was only transient), transient PR in two, transient MR in four, and F in two. Treatment at lower doses was better tolerated, thus allowing a longer duration of treatment. Five of ten patients had moderate or severe gastrointestinal disturbances and one patient had a severe subjective hearing loss. The eflornithine-MGBG combination may prove to be a useful alternative treatment for AML and BT CML, but comparative trials will ultimately be necessary for a more definitive assessment of the combination.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Eflornithine; Female; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphocyte Activation; Male; Middle Aged; Mitoguazone

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Combinations; Drug Evaluation; Female; Humans; Leukemia, Myeloid, Acute; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Middle Aged; Mitoguazone; Prednisone; Thioguanine; Vincristine

Ten patients with AML refractory to anthracyclines and cytosine arabinoside were treated with vincristine 1.4 mg/m2 and methotrexate (MTX) 2.5 gm/m2 by intravenous (IV) bolus on day 1 [citrovorum factor (CF) rescue began 24 h later], BCNU 80 mg/m2, and cyclophosphamide 900 mg/m2 IV 36 h after MTX and MGBG 300 mg/m2 IV over 1-2 h on days 3, 4, and 5. Bone marrow aplasia was achieved in all patients by day 12. Five patients (50%) achieved complete remission (CR). Two patients died of sepsis during induction. The median duration of remission was 24 weeks (range 8-38). Maintenance therapy was employed in three patients (high-dose MTX-CF in 2 and MGBG plus BCNU in 1), but did not appear to significantly increase the duration of remission. Nausea and vomiting occurred in eight patients. Five patients developed moderate stomatitis and one developed a moderately severe cutaneous reaction. This pilot experience demonstrates that patients with refractory AML can achieve CR after aggressive treatment with so-called second-line drugs. and may indicate that collateral sensitivity to MTX exists in cells which have become resistant to anthracyclines, a situation we previously described in an experimental cell line.

Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Child; Cyclophosphamide; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Methotrexate; Middle Aged; Mitoguazone; Vincristine

A high-pressure liquid chromatographic method was utilized to determine the concentration of the antileukemic agent methylgloxal bis(guanylhydrazone) (MGBG, NSC-32946) in tissue samples obtained at autopsy from patients who received MGBG. In a patient with cholangiocarcinoma who received one course of MGBG (500 mg/m2), the highest drug concentration was found in normal liver tissue. However, the drug concentration in intrahepatic tumor tissue was only 10% of that found in uninvolved liver. In a patient with acute myelogenous leukemia (AML) who received 12 courses of MGBG therapy, highly infiltrated lymph node tissue was found to contain the highest concentration of MGBG. High concentrations of the drug were also found in liver, spleen, kidney, adrenal, and thyroid. The drug penetrated well into normal brain tissue. After repeated administration, high drug concentrations were found in cerebral and cerebellar gray matter. These studies suggest that there is no selective uptake of MGBG into solid tumors early after drug administration and provide a pharmacologic rationale for testing this agent against endocrine and intracerebral tumors in man.

Topics: Absorption; Adenoma, Bile Duct; Adolescent; Bile Duct Neoplasms; Brain; Chromatography, High Pressure Liquid; Female; Guanidines; Humans; Leukemia, Myeloid, Acute; Liver; Lymph Nodes; Middle Aged; Mitoguazone; Tissue Distribution

Sequential administration of alpha-difluoromethyl ornithine and methylglyoxal bis(guanylhydrazone), two differently acting inhibitors of the biosynthesis of natural polyamines, produced a rapid and distinct therapeutic response in four children with advanced lymphoblastic and in one with myeloblastic leukemia. The synergism between the action of the two compounds was based upon a unique drug interaction; a preceding treatment with difluoromethyl ornithine greatly increased the uptake of subsequently administered methylglyoxal bis(guanylhydrazone) as verified by the actual determinations of the latter drug in the circulating leukemia cells. The side-effects associated with the combined drug regiment were either absent or mild.

Topics: Antineoplastic Agents; Child; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Eflornithine; Female; Guanidines; Humans; Infant; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Mitoguazone; Ornithine

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoguazone; Remission, Spontaneous; Vincristine

Topics: Drug Therapy; Guanidines; Humans; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Mercaptopurine; Mitoguazone; Pyruvaldehyde; Toxicology

Topics: Amidines; Antineoplastic Agents; Humans; Hydrazines; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Mitoguazone; Pyruvaldehyde