mitoguazone and Carcinoma

Methylglyoxal bis(guanylhydrazone) (MGBG) a structural analogue of spermidine produced a dose-dependent induction of cytosolic spermidine/spermine N1-acetyltransferase (N1-SAT) in the human breast carcinoma cell line, T47-D. Intracellular accumulation of MGBG was found to be saturable and the drug produced characteristic effects on intracellular polyamines, decreasing spermidine and spermine content, with concomitant increases in putrescine levels. The MGBG-induced increase in N1-SAT activity was potentiated by both tetronasin, a calcium ionophore, and felodipine, a calcium channel blocking agent. Only tetronasin was an active inducer of the enzyme when used alone. Both drugs influenced intracellular MGBG content but in opposite directions: tetronasin increased MGBG content while felodipine decreased it. Therefore, the potentiation of N1-SAT induction is not simply the result of increased intracellular accumulation of MGBG but is more likely to be related to the concentration of intracellular free calcium in these cells.

Topics: Acetyltransferases; Breast Neoplasms; Calcium; Carcinoma; Cytosol; Dose-Response Relationship, Drug; Enzyme Induction; Felodipine; Furans; Humans; Mitoguazone; Polyamines; Tumor Cells, Cultured

Antitumor therapies using polyamine antimetabolites combined with 1-(4-amino-2-methyl-5-pyrimidyl)methyl-3(2-chloroethyl)-3-nitrosourea (ACNU) or fluorinated pyrimidines for human gastric cancer xenotransplanted into nude mice were studied to determine inhibiting post-therapeutic regrowth of the tumor after cessation of antitumor treatments with polyamine antimetabolites alone. ACNU 20 mg/kg, fluorinated pyrimidine, 5-FU 52.8 mg/kg and 5'-deoxy-5-fluorouridine (5'-DFUR) 100 mg/kg as well as polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) 1000 mg/kg and methylglyoxal-bis-guanylhydrazone (MGBG) 50 mg/kg were given intraperitoneally for 5 successive days. When DFMO and MGBG were combined with ACNU, the post-therapeutic regrowth was definitely inhibited, while combined treatments with 5-FU or 5'-DFUR did not inhibit the regrowth. Post-therapeutic DNA biosynthesis was suppressed in mice given DFMO, MGBG plus ACNU. On the contrary, in mice treated with DFMO, MGBG plus 5-FU or 5'-DFUR, suppression of DNA biosynthesis was not observed. Tumor tissue spermine levels in the DFMO, MGBG plus 5-FU or 5'-DFUR group remained unchanged, compared to those in the DFMO + MGBG group. In mice given DFMO, MGBG plus ACNU, however, spermine levels were markedly depressed; and the ACNU alone depressed also the tissue spermine levels. These different results between nitrosourea and fluorinated pyrimidines may relate to mechanisms of action of these antitumor drugs.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Carcinoma; Eflornithine; Floxuridine; Fluorouracil; Mice; Mice, Inbred BALB C; Mice, Nude; Mitoguazone; Neoplasm Transplantation; Nimustine; Nitrosourea Compounds; Ornithine; Stomach Neoplasms

Transplantable prostate adenocarcinoma were treated with polyamine biosynthetic inhibitors. alpha-difluoromethylornithine (alpha-DFMO), an inhibitor of ornithine decarboxylase and by s-methylglyoxal-bisguanylhydrazone (MGBG), an inhibitor of s-adenosylmethionine decarboxylase. The therapeutic regimen of 0.8-1.11 g/kg DFMO reduced the tumor growth by 40% whilst the combination with 10.5 mg/kg MGBG completely destroyed the prostate adenocarcinomas in the tumor-bearing animals. The polyamine content of spermidine and spermine in the cancerous tissues is significantly lower whereas the putrescine levels remain unchanged. The MGBG therapy distinctly stimulates the activity of ornithine decarboxylase and increases the putrescine concentration up to toxic levels. The application of alpha-DFMO prevented the toxic accumulation of putrescine and allowed higher doses of MGBG. Clinical trials with polyamine antimetabolites appeared useful due to pathological polyamine excretion of patients with metastatic prostate cancer. The therapy with 0.2-0.3 g/kg DFMO in patients with hormone-resistent prostate cancer and metastasis displayed a moderate anti-tumor activity following 2 months additional treatment. High levels of side effects, however, were registered and were similar to those of other cytotoxic compounds. A combined therapy with DFMO/MGBG in a patient with metastatic anaplastic prostate cancer did not improve the survival rate but showed regressive effects of the histological pattern.

Topics: Adenocarcinoma; Adenosylmethionine Decarboxylase; Animals; Antineoplastic Agents; Carboxy-Lyases; Carcinoma; Eflornithine; Estrogens; Humans; Male; Mitoguazone; Neoplasm Metastasis; Ornithine; Ornithine Decarboxylase Inhibitors; Prostatic Hyperplasia; Prostatic Neoplasms; Prostatitis; Putrescine; Rats; Spermidine; Spermine

We have tested methyl glyoxal bis-guanyl hydrazone (NSC 32946) for antitumor activity in patients with colorectal carcinoma and non-small cell bronchogenic carcinoma. The drug dose was 500 mg/m2 administered by single weekly injection, and with a provision dose escalation. No responses were seen in 38 evaluable patients with colorectal cancer, including 17 who had received no prior chemotherapy. Three responses were seen among 42 patients with bronchogenic carcinoma. These included one each with epidermoid carcinoma, adenocarcinoma and large cell anaplastic carcinoma. None of these responders had received prior chemotherapy. Toxicity of the drug was predominantly gastrointestinal, namely nausea, vomiting and diarrhea, and tended to increase with repeated drug doses. Neurologic symptoms of various sorts were also prominent. We conclude that methyl-G is of marginal benefit in this dose and schedule to patients with bronchogenic carcinoma.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma; Carcinoma, Bronchogenic; Colonic Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Gastrointestinal Diseases; Guanidines; Humans; Lung Neoplasms; Male; Middle Aged; Mitoguazone; Rectal Neoplasms

Topics: Animals; Antineoplastic Agents; Carcinoma; Carcinoma 256, Walker; Chemistry, Pharmaceutical; Guanidine; Guanidines; Leukemia L1210; Mice; Mitoguazone; Pharmacology; Propane; Pyruvaldehyde; Rats; Research