[无蛋氨酸静脉氨基酸溶液（AO-90）增强大鼠5-氟尿嘧啶抗肿瘤作用的机制]

[The mechanism of potentiation of the antitumor effect of 5-fluorouracil by methionine-free intravenous amino acid solution (AO-90) in rats].

作者信息

Hibino Y, Kawarabayashi Y, Kohri H, Ueda N, Tsukagoshi S

机构信息

Nutrition Research Institute, Otsuka Pharmaceutical Factory, Inc.

出版信息

Gan To Kagaku Ryoho. 1994 Sep;21(12):2021-8.

PMID:8085853

Abstract

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).

摘要

AO - 90是一种不含蛋氨酸的静脉注射氨基酸溶液（7.43%），在吉田肉瘤（YS）荷瘤大鼠的全胃肠外营养（TPN）中作为氮源与5 - 氟尿嘧啶（5 - FU）同时使用时，显示出增强5 - FU抗肿瘤作用的效果。在本实验中，通过测定接受AO - 90（第1天氮含量0.73g/kg，其余6天为1.46g/kg）TPN给药1周的YS荷瘤唐利大鼠的血清蛋氨酸水平和肿瘤亚甲基四氢叶酸（CH2FH4）含量，研究了这种增强作用机制。在TPN开始前3天，将大鼠背部皮下接种10⁴个YS细胞。还评估了在接种10⁶个肿瘤细胞的情况下，TPN给予AO - 90（第1天氮含量0.68g/kg，其余6天为1.36g/kg）并每日腹腔注射5 - FU（10mg/kg）后肿瘤组织中胸苷酸合成酶活性的抑制情况。将结果与接受含蛋氨酸的市售氨基酸溶液TPN的荷瘤大鼠的结果进行比较。在TPN第5天，接受AO - 90的荷瘤大鼠血清蛋氨酸水平显著低于对照大鼠：分别为101±11μmol/L和29±14μmol/L（p<0.01）；肿瘤中CH2FH4含量更高：分别为7.0±2.8pmol/g蛋白质和23.7±16.6pmol/g蛋白质（p<0.05）。AO - 90组胸苷酸合成酶抑制率为81.2±5.1%，对照组为30.9±26.3%（p<0.01）。本研究结果表明，AO - 90通过生化调节增强5 - FU的抗肿瘤作用。AO - 90与5 - FU同时给药7天不仅在同种异体肿瘤模型中有效，而且在先前分别接种10⁶个同基因KDH - 8肝癌细胞和SST - 2腺癌细胞的WKAH和SHR大鼠中也有效。TPN期后，AO - 90组SHR大鼠的SST - 2腺癌重量显著小于接受含蛋氨酸TPN和5 - FU的对照大鼠：分别为2.66±0.91和5.12±2.11（p<0.05）。