The effects of administration of a methionine-free amino acid solution (AO-90) via total parenteral nutrition on the tumor and liver vitamin B12 dependent methionine synthase activity in Yoshida sarcoma-bearing rats

M. Wada, K. Yamada, T. Kawata, T. Tadokoro, A. Maekawa, G. Ebisu, Y. Hibino

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Abstract

AO-90 is a methionine (Met)-free intravenous amino acid solution that is intended for use in cancer therapy via total parenteral nutrition (TPN) in combination with 5 fluorouracil (5-FU) and mitomycin C. It has been reported that AO-90 enhances the anti-tumor effect of 5-FU by biochemical modulation. This potentiation by AO-90 may start with the reduction of Met levels in the tumor. This reduction will increase the activity of Met synthase (EC2.1.1.13:MS) which forms Met from homocysteine. The conversion of homocysteine into Met is coupled with folic acid metabolism. Folic acid metabolism is activated by MS and as a result the methylenetetrahydrofolate (CH2FH4) level in the tumor will increase. It has been reported that the CH2FH4 level in the tumor and the formation of a ternary complex (CH2FH4:FdUMP:TS) which leads to inhibition of thymidylate synthase (TS) are closely related. We have already reported that the administration of AO- 90 to Yoshida sarcoma-bearing rats decreased the serum Met level and increased the CH2FH4 level in tumors. In the present study, we examined the change in the tumor and liver MS activities in Yoshida sarcoma bearing rats administered AO-90 via TPN. Twelve male Donryu rats were inoculated with 1 x 104 Yoshida sarcoma cells. Three days after inoculation, the rats were divided into 3 treatment groups and were administered a TPN solution for 5 days. The AO-90 group received a solution containing AO-90, glucose, electrolytes and vitamins via TPN at a dose of 247 kcal/kg/day. The Pan-S group received the same as the AO-90 group except that a commercially available amino acid solution (Pan-Amin S) containing Met was substituted in place of AO-90. The N-free group received the same as the AO-90 group except that distilled water was substituted in place of AO-90. The administration doses of the Pan-S group and the N-free group were 250 kcal/kg/day and 210 kcal/kg/day respectively. On the 1st day of TPN, the administration dose was reduced to half the full dosage in each group. On day 5 of TPN, the rats were killed and the livers and tumors were removed for measurement of Met levels and MS activities. The tumor MS activity in the AO-90 group (11.97±0.50 pmol/min/mg protein) was significantly higher (p<0.05) than in the Pan-S group and N-free group (5.57±2.94 pmol/min/mg protein and 6.03±4.01 pmol/min/mg protein respectively). The tumor Met level in the AO-90 group (71.0± 31.2 nmol/g) was significantly lower (p<0.05) than in the Pan-S group (132.0±31.1 nmol/g). On the other hand, there was no significant difference in Met levels or MS activities in the liver among the three groups. These results demonstrate that the administration of AO-90 via TPN decreases the Met level and enhances MS activity in the tumor.

Original languageEnglish
Pages (from-to)223-230
Number of pages8
JournalJapanese Pharmacology and Therapeutics
Volume23
Issue number5
Publication statusPublished - Jan 1 1995
Externally publishedYes

Keywords

  • Methionine depletion
  • Methionine synthase
  • Rat
  • Total parenteral nutrition
  • Yoshida sarcoma

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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