mitoguazone and Brain-Neoplasms

This article covers chemotherapy of malignant astrocytomas, ependymoma, and medulloblastoma. The future direction of anticancer drugs is discussed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Brain Neoplasms; Brain Stem; Child; Eflornithine; Ependymoma; Fluorouracil; Glioblastoma; Humans; Hydroxyurea; Lomustine; Medulloblastoma; Methotrexate; Mitoguazone; Mitolactol; Neoplasm Recurrence, Local; Ornithine; Prednisone; Risk; Thioguanine; Vincristine

Eflornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, and mitoguazone (MGBG), a competitive inhibitor of S-adenosylmethionine decarboxylase, were evaluated in a phase I-II study for patients with primary recurrent malignant brain tumors. All patients had failed prior radiation therapy and most had also failed prior chemotherapy. Two dose schedules were used, with the second schedule (Group II) a modification of the first schedule (Group I). The Group II schedule, with different dose levels, was better tolerated than the Group I schedule. Gastrointestinal and myelotoxicity were dose-limiting in most patients, and tinnitus was dose-limiting in two patients. Nineteen of 33 evaluable patients had anaplastic gliomas, in whom response was observed in 21%, stable disease in 53%, and immediate progression after one course of therapy in 26%. Of six patients with glioblastoma multiforme, two had brief stabilization of disease. An additional patient with brainstem glioma and ependymoma also had disease stabilization. Four patients with medulloblastoma, a spinal cord mixed glioma, and one with oligodendroglioma failed DFMO-MGBG. Based on this study, we believe that a combination of DFMO and MGBG is well-tolerated and deserves further evaluation for patients with anaplastic gliomas, particularly those that appear to be biologically slow growing.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Drug Evaluation; Eflornithine; Humans; Leukopenia; Middle Aged; Mitoguazone; Nausea; Neoplasm Recurrence, Local; Thrombocytopenia; Tinnitus; Vomiting

The continuous human medulloblastoma cell line TE-671 was grown as s.c. and intracranial xenografts in athymic nude mice. Tumor-bearing animals were treated with chemotherapeutic agents at the 10% lethal dose; s.c. xenografts were sensitive to melphalan, 1-(2-chloroethyl)-3-(2,6-dioxo-1-piperidyl)-1-nitrosourea, and 5-azacytidine. No consistent response could be demonstrated to 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate, and no response to methylglyoxal bis(guanyl hydrazone), N-trifluoroacetyl adriamycin-14-valerate, or to 1-beta-D-arabinofuranosylcytosine was observed. Melphalan produced a significant (P = less than or equal to 0.007) increase in the median survival of mice bearing intracranial xenografts, whereas no response was seen to 1-(2-chloroethyl)-3-(2,6-dioxo-1-piperidyl)-1-nitrosourea or 5-azacytidine. This model will allow analysis of the chemotherapeutic profile of human medulloblastoma, and provides a means to differentiate cellular sensitivity and resistance from drug access to the intracranial site.

Topics: Animals; Azacitidine; Brain Neoplasms; Cell Line; Cytarabine; Doxorubicin; Humans; Medulloblastoma; Melphalan; Mice; Mice, Nude; Mitoguazone; Neoplasm Transplantation; Nitrosourea Compounds; Skin Neoplasms; Vidarabine Phosphate

Uptake characteristics and growth-inhibitory effects of methylglyoxal bis(guanylhydrazone) (MGBG), a competitive inhibitor of S-adenosylmethionine decarboxylase, were investigated in 9L rat brain tumor cells and in V79 hamster lung cells. Proliferation of 9L cells was only slightly inhibited by treatment with 40 microM MGBG alone, but when used in combination with 0.5 mM alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, proliferation was much more effectively inhibited. The intracellular concentration of MGBG was approximately 2-fold higher 4 days after cells were treated with both DFMO and MGBG, either simultaneously or when MGBG was added after a 48-hr DFMO pretreatment, than that in cells treated with MGBG alone. Polyamine levels in DFMO- and MGBG-treated cells correlated with the antiproliferative effects of the drugs. Used either alone or in combination with 1 mM DFMO, 0.5 microM MGBG inhibited the growth of and eventually killed V79 cells. Simultaneous or sequential treatment with DFMO and MGBG increased intracellular concentrations of MGBG at 4 days by 2- and 3-fold, respectively, compared to treatment with MGBG alone. Intracellular polyamine levels did not correlate with the antiproliferative effect of the two drugs in V79 cells. In both cell lines, polyamines and MGBG share a common transport system. The net transport of polyamines and MGBG was more temperature dependent and up to 10-fold more active in V79 cells than in 9L cells. The Km and Vmax values for spermidine and MGBG measured 10 sec after addition (initial permeation) were not affected by DFMO pretreatment in either cell line. However, 1 hr after administration, the Vmax values for spermidine and MGBG uptake were doubled in V79 cells pretreated for 48 hr with DFMO; no significant change occurred in 9L cells. Mitochondrial function, assessed by pyruvate oxidation, was substantially impaired by MGBG in V79 cells but not in 9L cells when the intracellular concentrations of MGBG were equal in each cell line. Pretreatment with DFMO did not increase MGBG-induced inhibition of pyruvate oxidation in V79 cells. These results show that, compared with V79 cells, the decreased sensitivity of 9L cells to MGBG may be related to decreased intracellular MGBG accumulation but not to cellular permeation such as carrier transport. Results of measurements of both polyamine levels and mitochondrial function indicate that V79 cells may be more susceptible to nonpolya

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line; Eflornithine; Guanidines; Kinetics; Mitochondria; Mitoguazone; Ornithine; Putrescine; Pyruvates; Pyruvic Acid; Rats; Spermidine; Temperature; Time Factors

Growth characteristics, polyamine levels, and distribution of cells in the cell cycle were determined for 9L rat brain tumor cells treated for various periods with 1 mM dicyclohexylamine sulfate (DCHA). Continuous treatment of cells with DCHA caused growth inhibition at 2 days of treatment. After 2 days of treatment the growth rate of cells increased to approximately the same rate as control cells, even though treatment was continuous. Levels of spermidine were depleted to less than 10% of control levels, spermine levels were essentially unchanged, and putrescine levels were elevated to more than 350% of control levels after 9L cells were treated with DCHA for 2 days. In contrast to results found for the polyamine biosynthesis inhibitor alpha-difluoromethylornithine, treatment of 9L cells with DCHA did not potentiate the cytotoxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea. To mimic the effects on polyamine levels caused by treatment with DCHA, 9L cells were treated with 5 mM putrescine alone or with 5 mM putrescine and 1 mM DCHA after treatment with 1 mM alpha-difluoromethylornithine. Results of these experiments suggest that treatment with DCHA alone does not potentiate the cytotoxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea because elevated levels of putrescine caused by treatment counteract the effects of decreased spermidine levels.

Topics: Animals; Brain Neoplasms; Carmustine; Cell Cycle; Cell Survival; Cyclohexylamines; Eflornithine; Mitoguazone; Ornithine; Polyamines; Putrescine; Rats; Spermidine Synthase; Transferases

Sixteen patients with primary malignant brain tumors, recurrent or progressive after surgery and radiation therapy, were treated with mitoguazone. Starting dose was 500 mg/m2 iv on a weekly schedule. In 15 evaluable patients no tumor regressions were observed. Four patients had stabilization of disease.

Topics: Adult; Brain Neoplasms; Drug Evaluation; Female; Guanidines; Humans; Hyperglycemia; Leukopenia; Male; Middle Aged; Mitoguazone; Pulmonary Embolism; Stomatitis; Thrombocytopenia

In the last decade, advances in the treatment of primary neuroglial tumors of the central nervous system in adults have been modest. Theories regarding their resistance to treatment have changed little, although now the heterogeneity of anaplastic astrocytomas is recognized. The most effective chemotherapeutic agents--the nitrosoureas and procarbazine--have been used for more than a decade, with no comparably active drugs identified in the meantime. The authors have initiated clinical trials using inhibitors of polyamine synthesis and augmentation of the known effectiveness of irradiation. These programs will be described with preliminary observations.

Topics: Brachytherapy; Brain Neoplasms; Bromodeoxyuridine; Eflornithine; Humans; Hyperthermia, Induced; Iodine Radioisotopes; Mitoguazone; Ornithine; Polyamines

Methylglyoxal-bis(guanylhydrazone) (MGBG), a potent inhibitor of the spermidine and spermine biosynthetic enzyme S-adenosyl-L-methionine decarboxylase, enhanced the cytotoxicity of 1,3-bis-(2-chlorethyl)-1-nitrosourea in 9L rat brain tumor cells in vitro, as measured by a colony-forming efficiency assay, by an amount that was approximately the same as the potentiation caused by the ornithine decarboxylase inhibitor alpha-difluoromethylornithine. Dose enhancement ratios at 10, 1 and 0.1% survival levels were approximately 1.3 for both inhibitors. 9L cells that were treated for 48 hr with 40 microM MGBG had putrescine, spermidine and spermine levels that were 112, 41 and 21%, respectively, of polyamine levels in control cells. MGBG treatment does not increase intracellular levels of decarboxylated S-adenosyl-L-methionine (AdoMet) as alpha-difluoromethylornithine treatment does. Elevated levels of decarboxylated AdoMet could modify intracellular methylation reactions and could affect the cytotoxicity of a chloroethylnitrosourea. Despite the fact that MGBG treatment caused a slight increase in intracellular levels of AdoMet, it is unlikely that this elevation will increase the amount of intracellular methylation. Thus it appears that effects caused by the decrease in polyamine levels are responsible for the potentiation of chloroethylnitrosourea cytotoxicity against 9L cells.

Topics: Adenosylmethionine Decarboxylase; Animals; Brain Neoplasms; Carboxy-Lyases; Carmustine; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Synergism; Guanidines; Mitoguazone; Putrescine; Rats; Spermidine; Spermine

Methylglyoxal bis(guanylhydrazone) (MGBG; NSC 32946) is currently being reevaluated for its clinical antineoplastic activity against both hematological and solid tumors. MGBG (100 to 200 mg/sq m) was administered by slow infusion over 3 hr to six patients during surgical resection of intracerebral tumors. Excised tumor tissue and plasma were assayed for MGBG by high-pressure liquid chromatography. In all cases, MGBG penetrated rapidly into brain tumor tissue. Viable tumor tissue contained greater concentrations of MBGB than did necrotic tumor tissue. In two patients with glioblastoma multiforme, MBGB concentrations in brain tumor tissue were five- to 19-fold higher than concurrent plasma samples. However, MGBG did not penetrate well into the cerebrospinal fluid of two patients with Ommaya reservoirs given i.v. MGBG (200 mg/sq m). The highest MGBG concentration in cerebrospinal fluid reached only 22% of the concurrent plasma levels. These studies suggest that MGBG may be a useful agent in the treatment of intracerebral tumors but may not be effective against meningeal leukemia and meningeal carcinomatosis.

Topics: Blood-Brain Barrier; Brain Neoplasms; Guanidines; Humans; Meningeal Neoplasms; Mitoguazone

Topics: Animals; Brain Neoplasms; Cell Line; Cell Survival; Cells, Cultured; DNA; DNA, Neoplasm; Eflornithine; Guanidines; Mitoguazone; Ornithine; Polyamines; Putrescine; Radiation Tolerance; Rats; Spermidine; Spermine; X-Rays

Topics: Animals; Brain Neoplasms; Cell Cycle; Cells, Cultured; Guanidines; Mitoguazone; Putrescine; Rats; Spermidine; Spermine