mitoguazone and Neoplasm-Metastasis

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Doxorubicin; Esophageal Neoplasms; Etoposide; Fluorouracil; Humans; Lomustine; Methotrexate; Mitoguazone; Mitomycin; Mitomycins; Neoplasm Metastasis; Postoperative Care; Preoperative Care; Vinblastine; Vindesine

The antitumor and antimetastatic effects of alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, combined with an inhibitor of S-adenosylmethionine decarboxylase, either methylglyoxal bis(guanylhydrazone) (MGBG) or ethylglyoxal bis(guanylhydrazone) (EGBG), were studied in mice bearing P388 leukemia or Lewis lung carcinoma. Although EGBG is a more specific inhibitor of polyamine biosynthesis than the widely used MGBG, the antitumor effect of the DFMO-EGBG combination on P388 leukemia-bearing mice was less than that of the DFMO-MGBG combination. The prolongation of survival time by the DFMO(1000 mg/kg)-MGBG(25 mg/kg) combination was 2.65-fold, while that of the DFMO(1000 mg/kg)-EGBG(50 mg/kg) combination was 1.34-fold. When mice were fed a polyamine-deficient diet, stronger antitumor effects were exerted; the prolongation of survival time by the DFMO-MGBG and the DFMO-EGBG combinations was 2.89-fold and 2.03-fold, respectively. The antitumor effect of combined use of the two polyamine antimetabolites with mice on normal and polyamine-deficient diets correlated with a decrease of polyamine charge contents in the tumor cells. The above in vivo results were confirmed clearly in the KB cell culture system. The antimetastatic activity of DFMO on Lewis lung carcinoma-bearing mice was strengthened by the addition of MGBG or EGBG. The antimetastatic activity of the DFMO-MGBG or DFMO-EGBG combination did not parallel the polyamine charge contents in the primary tumor and blood.

Topics: Adenosylmethionine Decarboxylase; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carboxy-Lyases; Eflornithine; Female; Leukemia P388; Leukemia, Experimental; Lung Neoplasms; Mice; Mitoguazone; Neoplasm Metastasis; Polyamines; Tumor Cells, Cultured

Mice and rats of various ages (3, 10-12, and 18-19 months) were inoculated with the transplantation tumours murine melanoma B16 (B16), mammary adenocarcinoma 755 (Ca-755), leukemia P388 (P388), and rat rhabdomyosarcoma RA-2 (RA-2). Subcutaneous (sc) growth of B16 was not markedly affected by the age of the syngeneic host whereas intravenously (iv) inoculated 12 months old C57BL/6 mice developed more pulmonary metastases than animals 3 months of age. Median survival time (MST) of 18 months old mice bearing Ca-755 was significantly shorter than that of younger individuals. In contrast, old rats that had been injected RA-2 iv survived longer than controls. Survival of DBA/2 mice inoculated intraperitoneally (ip) with P388 cells was not influenced by the age of the host. The antineoplastic activity of ambazone and, to a less extent, of 5-fluorouracil against P388 was drastically lower in 12 months old mice than in 3 months old tumour bearers. Likewise a graduate loss of antineoplastic activity of ambazone against Ca-755 was observed with increasing age of the mice, whereas the effect of ambazone and 5-fluorouracil against RA-2 did not depend on the age of the rats. It is suggested that tumour-host interactions as well as pharmacokinetics of a given drug may underlie age-related changes.

Topics: Adenocarcinoma; Aging; Animals; Antineoplastic Agents; Cell Division; Female; Fluorouracil; Leukemia P388; Leukemia, Experimental; Male; Mammary Neoplasms, Experimental; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mitoguazone; Neoplasm Metastasis; Rats; Rhabdomyosarcoma

Topics: Aged; Drug Evaluation; Humans; Male; Mitoguazone; Neoplasm Metastasis; Prostatic Neoplasms

Forty-two patients with epidermoid carcinoma of the esophagus were treated with the three-drug combination of cisplatin, vindesine, and mitoguazone (DVM). Twenty patients had locoregional disease and 22 had extensive disease. Of 39 patients evaluable for response, 16 (41%) had complete or partial remission (95% confidence limits, 26%-56%). Of 14 patients with locoregional disease treated prior to surgery, 12 (86%) had resectable disease. There was one death associated with surgery (7.1%). Six of these 14 patients remain alive and free of disease. The median duration of remission for patients with extensive disease was 3 months (range, 2-8). As was the case for an earlier study involving cisplatin, vindesine, and bleomycin, the dose-limiting toxic effect for DVM was leukopenia (median wbc count nadir, 1800/mm3). No clinical evidence of pulmonary toxicity was seen. DVM had moderate activity in esophageal cancer, with acceptable toxicity. Although the risks of pulmonary damage were decreased, the substitution of mitoguazone for bleomycin did not improve the major dose-limiting toxicity of myelosuppression.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Esophageal Neoplasms; Female; Humans; Leukopenia; Male; Middle Aged; Mitoguazone; Neoplasm Metastasis; Vindesine

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

Topics: Drug Evaluation; Guanidines; Humans; Infusions, Parenteral; Male; Mediastinal Neoplasms; Mitoguazone; Neoplasm Metastasis; Neoplasms, Germ Cell and Embryonal; Prognosis; Retroperitoneal Neoplasms; Testicular Neoplasms

Methylglyoxal-bis(guanylhydrazone) (MGBG), an inhibitor of polyamine synthesis, was administered to 35 patients with hormone-resistant advanced adenocarcinoma of the prostate in doses of 500 or 600 mg/m2 per week intravenously. Of 31 patients with bidimensional measurable soft-tissue lesions, 25 had an adequate trial, defined as four or more doses. Six (24%; 95% confidence limits, 8% to 32%) patients achieved a partial remission (greater than or equal to 50% reduction in tumor size) in soft-tissue disease. Response was noted to start after one to two doses and persisted for a median of three months (range, 1 to 4 months). Toxicity was tolerable, and significant myelosuppression was not observed. The lack of response in osseous metastases may be secondary to the short duration of remission or to the presence or inducibility of the enzyme ornithine decarboxylase in bone. Since some animal prostatic cancer tumor models are sensitive to cytotoxic drugs that produce polyamine inhibition, clinical trials of MGBG combined with other inhibitors of the polyamine pathway should be explored.

Topics: Adenocarcinoma; Aged; Drug Evaluation; Guanidines; Humans; Male; Middle Aged; Mitoguazone; Neoplasm Metastasis; Prostatic Neoplasms; Tomography, X-Ray Computed

alpha-Difluoromethylornithine (DFMO) and methylglyoxal bis-(guanylhydrazone) (MGBG) were tested against a murine renal adenocarcinoma, because polyamines are necessary for neoplastic cell growth and because human renal adenocarcinomas contain higher levels of spermidine than do normal renal cells; MGBG inhibits spermidine synthesis and has some activity against human renal tumors; DFMO irreversibly inhibits ornithine decarboxylase, the first rate-limiting enzyme controlling polyamine biosynthesis; and DFMO promotes intracellular accumulation of MGBG in experimental tumor models and human leukemia. DFMO (2%) in drinking water, MGBG (15 mg/kg i.p.), or a combination of DFMO and MGBG was administered daily to BALB/c mice (n = 80) with intrarenal transplants of renal adenocarcinoma cells. At 28 days, renal carcinomas weighed 64 and 73% less, respectively, in DFMO- and DFMO-MGBG-treated mice than in control animals (p less than 0.01). MGBG alone had no antigrowth effect. DFMO-MGBG reduced the total metastatic index (total number of metastases/total number of animals) to 1.2 versus 3.6 in control animals (p less than 0.01) and increased survival by 12.3 +/- 1.5 (S.E.) days, from 30.8 to 42.5 days (p less than 0.05). Compared with control, DFMO-, or MGBG-treated animals, DFMO-MGBG exposure reduced tumor growth and the number of metastases, prevented metastases in some animals (47%), and increased survival of mice bearing renal adenocarcinomas. DFMO also appeared to selectively increase the uptake of [14C]MGBG by tumor tissue, which may help to explain the enhanced synergistic antigrowth effect of DFMO and MGBG against this murine renal adenocarcinoma.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Body Weight; Cell Division; Drug Synergism; Eflornithine; Guanidines; Kidney Neoplasms; Male; Mice; Mice, Inbred BALB C; Mitoguazone; Neoplasm Metastasis; Ornithine; Tissue Distribution

The Southwest Oncology Group has evaluated methyl-GAG on a weekly schedule among patients with metastatic breast cancer. Among 72 fully and partial evaluable patients, one complete and four partial responses were seen. Toxicity was similar to other trials with this compound except for thrombocytopenia which was more frequent and severe and probably related to tumor infiltrating marrow. In addition, one patient experienced recall dermatitis following methyl-GAG. This toxicity has not been previously reported with this compound. Methyl-GAG has minimal activity at this dose and schedule among heavily pretreated patients with breast cancer.

Topics: Adult; Aged; Breast Neoplasms; Drug Evaluation; Female; Guanidines; Humans; Middle Aged; Mitoguazone; Neoplasm Metastasis; Thrombocytopenia

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