[The mechanism of potentiation of the antitumor effect of 5-fluorouracil by methionine-free intravenous amino acid solution (AO-90) in rats].
AO-90, a methionine-free intravenous amino acid solution (7.43%) showed to potentiate the antitumor effect of 5-fluorouracil (5-FU) when concomitantly used as the nitrogen source in total parenteral nutrition (TPN) in Yoshida sarcoma (YS)-bearing rats. In the present experiment, this potentiation mechanism was studied by determining the serum methionine level and tumor methylenetetrahydrofolate (CH2FH4) content in YS-bearing Donryu rats given AO-90 (nitrogen 0.73g/kg on the 1st day and 1.46g/kg for the remaining 6 days) by TPN for 1 week. The rats were subcutaneously inoculated with 10(4) YS cells in the dorsum 3 days before the start of TPN. Inhibition of thymidylate synthase activity in tumor tissue after dosing of AO-90 (nitrogen 0.68g/kg on the 1st day and 1.36 g/kg for the remaining 6 days) by TPN along with daily intraperitoneal dosing of 5-FU (10 mg/kg) was also evaluated with the inoculation of 10(6) tumor cells. The results were compared with those in tumor-bearing rats given TPN with a commercially available amino acid solution containing methionine. On day 5 of TPN, the tumor-bearing rats given AO-90 showed a significantly lower serum methionine level than the control rats: 101 +/- 11 mumol/l versus 29 +/- 14 mumol/l (p < 0.01); and a higher CH2FH4 content in tumor: 7.0 +/- 2.8 pmol/g protein versus 23.7 +/- 16.6 pmol/g protein (p < 0.05). Thymidylate synthase inhibition was 81.2 +/- 5.1% in the AO-90 group and 30.9 +/- 26.3% in the control group (p < 0.01). The results of the present study suggest that AO-90 potentiate the antitumor effect of 5-FU by biochemical modulation. AO-90 concomitantly given with 5-FU for 7 days was effective not only in the allogeneic tumor model, but also in WKAH and SHR rats previously inoculated with 10(6) of syngeneic KDH-8 hepatoma cells and SST-2 adenocarcinoma cells, respectively. Weight of SST-2 adenocarcinoma in SHR rats after the TPN period was significantly smaller in the AO-90 group than in the control rats given methionine-containing TPN and 5-FU: 2.66 +/- 0.91 versus 5.12 +/- 2.11 (p < 0.05).
Hibino
Y
Y
Nutrition Research Institute, Otsuka Pharmaceutical Factory, Inc.
Kawarabayashi
Y
Y
Kohri
H
H
Ueda
N
N
Tsukagoshi
S
S
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000097:blood; D010289:Parenteral Nutrition, Total; D051381:Rats; D012517:Sarcoma, Yoshida / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013940:Thymidylate Synthase / Q000378:metabolism
C068810:AO 90; D000596:Amino Acids; D008715:Methionine; D013940:Thymidylate Synthase; D005472:Fluorouracil