mitoguazone and Nausea

Initial clinical trials of methyl-GAG (MGBG) showed that repetitive daily administration produced severe, occasionally fatal, toxic reactions. After two decades of neglect, recent studies have shown that doses of 500-600 mg/sq m administered every 7-14 days are very well tolerated. Moreover, current results indicate that MGBG has useful antitumor activity in patients with advanced malignant lymphoma and carcinomas of the head and neck, esophagus, and lung (non-small cell). The drug's mechanism of cytotoxic action and its toxic effects are not shared by most other cancer chemotherapeutic drugs. Furthermore, Phase II and Phase III evaluation are required to determine the therapeutic potential of this unique agent.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Eruptions; Drug Therapy, Combination; Eflornithine; Esophageal Neoplasms; Guanidines; Head and Neck Neoplasms; Humans; Kidney Neoplasms; Leukemia; Leukemia L1210; Lung Neoplasms; Mice; Mitoguazone; Muscular Diseases; Nausea; Neoplasms; Ornithine; Polyamines; Stilbamidines; Structure-Activity Relationship

Initial clinical trials of methyl-GAG (MGBG) showed that repetitive daily administration produced severe, occasionally fatal, toxic reactions. After two decades of neglect, recent studies have shown that doses of 500-600 mg/sq m administered every 7-14 days are very well tolerated. Moreover, current results indicate that MGBG has useful antitumor activity in patients with advanced malignant lymphoma and carcinomas of the head and neck, esophagus, and lung (non-small cell). The drug's mechanism of cytotoxic action and its toxic effects are not shared by most other cancer chemotherapeutic drugs. Furthermore, Phase II and Phase III evaluation are required to determine the therapeutic potential of this unique agent.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Eruptions; Drug Therapy, Combination; Eflornithine; Esophageal Neoplasms; Guanidines; Head and Neck Neoplasms; Humans; Kidney Neoplasms; Leukemia; Leukemia L1210; Lung Neoplasms; Mice; Mitoguazone; Muscular Diseases; Nausea; Neoplasms; Ornithine; Polyamines; Stilbamidines; Structure-Activity Relationship

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

Methylglyoxal bis (guanylhydrazone) (MGBG) is an inhibitor of polyamine synthesis. In vitro studies demonstrate the accumulation of some tumor cells in S and G2 phases of the cell cycle. Nineteen patients with advanced head and neck cancer were entered in a Phase II trial of MGBG. MGBG, 500 mg/M2, was administered as a brief intravenous infusion weekly for 4 weeks, then every 2 weeks. Dose modifications were based on cumulative toxicity after 2 weekly treatments. All but three patients had prior exposure to chemotherapy for disease recurrence. Of 17 patients evaluable for response and toxicity, one brief partial response was observed. The most common toxicities were mild to moderate nausea, vomiting, diarrhea, and stomatitis. Myelosuppression occurred in three patients. Dose modifications were required in four patients; a maximum dose of 700 mg/M2 was tolerated. The results of four other Phase II single and combination chemotherapy trials of MGBG in head and neck cancer are reviewed. The single agent response rate in 59 patients was 22% (range, 6%-41%). The poor response rate observed in this trial was similar to that in other trials in which a heavily pretreated group of patients was evaluated. It is concluded that single agent MGBG is not a useful drug in heavily pretreated recurrent disease patients. However, because of its biochemical effects, further testing in combination with cycle specific agents and in larger numbers of patients with minimal prior treatment may be warranted.

Topics: Aged; Animals; Cats; Diarrhea; Drug Evaluation; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mitoguazone; Nausea; Vomiting

Fourteen patients with metastatic renal cell carcinoma received methyl-G weekly at a starting dose of 600 mg/m2 (five patients) and 500 mg/m2 (nine patients) intravenously. All 14 patients are evaluable for response and toxicity. No antitumor responses were observed. Six patients achieved stabilization of disease for 8 to 42 weeks. Toxicity was nonhematologic and included nausea or vomiting (35%), fever with shaking chills (28%), diarrhea (21%), myalgia (63%), paresthesia (49%), and bilateral foot drop (7%). Methyl-G does not appear to have activity against renal cell carcinoma.

Topics: Adenocarcinoma; Adult; Aged; Dose-Response Relationship, Drug; Drug Evaluation; Drug Resistance; Female; Guanidines; Humans; Male; Middle Aged; Mitoguazone; Nausea; Neoplasm Metastasis; Neoplasms; Paresthesia; Vomiting