mitoguazone and Body-Weight

The polyamines, putrescine, spermidine and spermine are small cationic molecules essential for DNA synthesis and cell replication. Because the cytotoxicity of most anti-cancer drugs can be attributed to inhibitory effects on DNA synthesis and cell replication it led to speculation that inhibition of polyamine synthesis could be a useful tool in the control of neoplastic growth. In 1978 alpha-difluoromethylornithine (DFMO), a powerful inhibitor of ornithine decarboxylase, the rate limiting enzyme in polyamine synthesis, was synthesized by Metcalf. Since then numerous investigators have tested the potential of DFMO and other polyamine antimetabolites as chemotherapeutic agents in experimental animals and cell cultures. The accumulated knowledge is now being evaluated in the treatment of human proliferative disorders and cancer.

Topics: Animals; Antimetabolites; Antineoplastic Agents; Body Weight; Cell Division; Cell Line; Child; Drug Interactions; Eflornithine; Female; Humans; Mice; Mitoguazone; Neoplasms; Neoplasms, Experimental; Ornithine; Ornithine Decarboxylase Inhibitors; Polyamines; Rats

The aim of the present study was to evaluate a new anticancer treatment for gastrointestinal cancer, using a combination of polyamine antimetabolites, an anticancer agent and a low-polyamine state. Two polyamine antimetabolites, given as either 40 mg/kg of methylglyoxal-bis-guanylhydrazone (MGBG) or ethylglyoxal-bis-guanylhydrazone (EGBG) and a normal diet (ND), or 20 mg/kg of each drug and a low polyamine diet (LPD), together with 1,000 mg/kg of alphadifluoromethylornithine (DFMO) were administered ip to nude mice for six consecutive days. Mitomycin C (MMC) at 2 mg/kg was then given ip for 3 alternate days. The combination of MGBG or EGBG with DFMO plus MMC resulted in an enhanced antitumor efficacy on LPD. However, the combination which included EGBG was much more enhanced than that which included MGBG and there was no evidence of any tumor regrowth. Weight loss was minimal or nil in the mice given the combination with EGBG, but was evident in those given the combination with MGBG. These results led to the conclusion that in mice, the combined therapy of EGBG with DFMO plus MMC and LPD is a safe and effective regimen for the treatment of gastric cancer.

Topics: Adenosylmethionine Decarboxylase; Animals; Body Weight; Cell Division; Combined Modality Therapy; Diet; DNA, Neoplasm; Drug Therapy, Combination; Eflornithine; Mice; Mice, Inbred BALB C; Mice, Nude; Mitoguazone; Mitomycin; Neoplasm Transplantation; Polyamines; Stomach Neoplasms

The aim of the present study was to investigate the influence of different stages of leukemia P388 on the pharmacokinetics of the antineoplastic agent mitoguazone in mice. It could be shown that, independent of the tumor stage investigated, the total clearance of mitoguazone is slightly reduced reflecting a moderate increase of AUC in the serum of leukemia-bearing animals. Furthermore, in an advanced tumor stage the drug levels in kidneys, liver, spleen and serum were found to be elevated to some extent in comparison to tumor-free controls in contrast to an earlier stage of leukemia. In conclusion, the tumor stage has to be considered as an important factor to which extent a neoplasia may alter the pharmacokinetics of drugs used for anticancer chemotherapy.

Topics: Animals; Body Weight; Female; Leukemia P388; Leukemia, Experimental; Mice; Mice, Inbred Strains; Mitoguazone; Neoplasm Transplantation; Organ Size

Topics: Animals; Body Weight; Female; Melanoma, Experimental; Mice; Mitoguazone; Organ Size; Tissue Distribution

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

Recent in vitro evidence suggests that polyamines play an important role in the growth of the N-nitrosomethyl-urea (NMU)-induced rat mammary tumor, and that they may be involved in mediating the effect of estrogens on tumor growth. In support of this hypothesis, we here show that inhibition of polyamine biosynthesis with alpha-difluoromethyl-ornithine (DFMO) blocks the mitogenic effect of estradiol-17 beta (E2) added to NMU-mammary tumors grown in soft agar in the presence of the antiestrogen tamoxifen (Tam). Exogenous polyamine administration reversed the inhibitory effect of DFMO and restored E2 action. Administration of polyamine inhibitors to NMU-tumor-bearing rats induced significant inhibition of tumor growth, although tumor ornithine decarboxylase (ODC) was not consistently suppressed. Under our experimental conditions, such treatment did not potentiate the antitumor effect of Tam. Tam alone was found to suppress tumor ODC, suggesting a possible involvement of the polyamine pathway in its antitumor action. These data suggest that the polyamines may play an important role in the hormonal control of the growth of this experimental breast cancer.

Topics: Animals; Body Weight; Cell Division; Dose-Response Relationship, Drug; Drug Interactions; Eflornithine; Estradiol; Estrogens; Female; Mammary Neoplasms, Experimental; Methylnitrosourea; Mitoguazone; Nitrosourea Compounds; Ornithine; Ornithine Decarboxylase; Polyamines; Rats; Rats, Inbred Strains; Tamoxifen

The polyamines, putrescine, spermidine, and spermine, are fundamentally related to both normal and neoplastic cell proliferation. The prostate gland and prostatic tumors in man and rodents contain large amounts of polyamines. This suggests that inhibition of polyamine biosynthetic enzymes, ornithine decarboxylase (ODC) and S-adenosyl-methionine decarboxylase (SAMDC) may retard the growth of prostatic cancer. Since alpha-difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG) are irreversible and competitive inhibitors of ODC and SAMDC, respectively, they were tested as single agents and in combination on a transplantable rapidly growing and hormone-resistant G subline of the Dunning R-3327 rat prostatic adenocarcinoma. Groups of rats bearing tumors were treated with various regimens of DFMO, MGBG, and DFMO plus MGBG, daily for 21 days. Analysis of differences in tumor growth between treatment groups and controls showed DFMO had no antitumor effect but was well tolerated, MGBG retarded growth rate significantly but resulted in drug deaths in over 50% of the animals, and the combination of DFMO and MGBG resulted in rapid decline in tumor growth rates after 5 to 9 days of treatment with reduced toxicity. At 21 days, or death, 38 of 60 (63%) rats had no viable tumor on histologic study, whereas tumor was present in each of the animals in the other groups. Alpha-difluoromethylornithine increased the intracellular uptake of MGBG and potentiated the antigrowth activity of MGBG on a hormone refractory rat prostatic tumor with less toxicity than MGBG alone.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cell Line; Drug Synergism; Eflornithine; Guanidines; Humans; Male; Mitoguazone; Neoplasm Transplantation; Ornithine; Prostatic Neoplasms; Rats; Rats, Inbred Strains

alpha-Difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG), when administered simultaneously, inhibited growth and were highly toxic to the Dunning R 3327-G hormone-resistant prostatic adenocarcinoma transplanted into Copenhagen rats. Neither DFMO (2%) nor MGBG at a nontoxic dose (15 mg/kg) inhibited tumor growth, but total (47% early cure rate) or near total suppression of growth of established tumors was observed in rats receiving both treatments.

Topics: Adenocarcinoma; Animals; Body Weight; Cell Division; Drug Therapy, Combination; Eflornithine; Guanidines; Male; Mitoguazone; Ornithine; Polyamines; Prostatic Neoplasms; Rats; Rats, Inbred Strains

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

Inhibitors of polyamine synthesis were tested for therapeutic effectiveness on transplantable prostate cancer. Inhibition of either ornithine decarboxylase or S-adenosyl-L-methionine decarboxylase (AMDC) by alpha-difluormethylornithine (DFMO) or methylglyoxal-bis[guanylhydrazone] (MGBG), respectively, was associated with significant antitumor effect. The combination of DFMO with MGBG was not only more effective but no more toxic than MGBG alone. Combination of MGBG with 9-B-D-arabinofuranosyladenine, an indirect effector of SAMDC, failed to increase therapeutic effectiveness of MGBG.

Topics: Animals; Body Weight; Drug Therapy, Combination; Eflornithine; Guanidines; Male; Mitoguazone; Neoplasm Transplantation; Neoplasms, Experimental; Ornithine; Polyamines; Prostatic Neoplasms; Rats; Vidarabine

The effect of Methyl-GAG on a transplantable murine renal cell adenocarcinoma was evaluated. Inoculation of Balb/C mice with 1 X 10(5) renal adenocarcinoma cells under the renal capsule resulted in 100% tumor growth and death of the animal in 29 +/- 5 days. In 66% of the control animals lung metastases was observed. Intraperitoneal injections of Methyl-GAG at dose levels of 200 mg/m2, 150 mg/m2, and 100 mg/m2 administered weekly failed to demonstrate any effect on local growth of the tumor. More than 50% incidence of metastatic development was noted in the treated groups. Methyl-GAG had no apparent effect on primary tumor growth or the retardation of metastatic incidence.

Topics: Adenocarcinoma; Animals; Body Weight; Guanidines; Kidney Neoplasms; Male; Mice; Mice, Inbred BALB C; Mitoguazone; Neoplasm Transplantation; Neoplasms, Experimental