mitoguazone and doxifluridine

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

A combined efficacy of the polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG) with two fluorinated pyrimidines was studied. DFMO, MGBG, 5-FU and 5'-deoxy-5-fluorouridine (5'-DFUR) were administered intraperitoneally to BALB/c nu/nu mice bearing xenotransplanted human gastric cancer for 5 consecutive days. Similar antitumor efficacies were observed in 3 groups treated with DFMO plus MGBG, DFMO, MGBG plus 5-FU as well as DFMO, MGBG plus 5'-DFUR. The two groups on 5-FU or 5'-DFUR alone did not differ in antitumor effects from the control, although reasonable levels of 5-FU were involved in tumor tissues. Hepatic and splenic 5-FU levels after 5-FU administration were significantly higher than those after 5'-DFUR, and marked decrease in mouse body weight was caused by 5-FU alone as well as 5-FU plus polyamine antimetabolites for 5 consecutive days. DNA biosynthesis and spermine levels in the tumor tissues on day 2 after cessation of the treatments dropped in 3 groups with DFMO plus MGBG, DFMO, MGBG plus 5'-DFUR as well as DFMO, MGBG plus 5-FU, while on day 6 there was little difference between the control and treated groups. These data suggest that combination with 5-FU or 5'-DFUR does not enhance the antitumor activity of polyamine antimetabolites by this experimental regimen.

Topics: Animals; DNA Replication; Drug Therapy, Combination; Eflornithine; Floxuridine; Fluorouracil; Mice; Mice, Nude; Mitoguazone; Ornithine; Polyamines; Spermine; Stomach Neoplasms