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).