Insulin-Enhanced Antitumor Effect of 5-Fluorouracil in vivo

OBJECTIVE To determine if insulin treatment can enhance the antitumor effect of 5-fluorouracil(5-FU),and to explore the mech- anism of the enhancement of insulin. METHODS S180 sarcoma,H22 liver cancer and human Eca-109 esophageal cancer cells were transplanted into nude mice to evaluate the inhibitory effect on tumor growth of insulin alone or in combination with 5-FU.The levels of serum insulin-like growth factor-I(IGF-I)and insulin-like growth factor binding protein-3 (IGFBP-3)were determined. RESULTS Compared with 5-FU treatment alone,the tumor weight of H22 liver cancer and S180 sarcoma was reduced further with high,medium and low-dose insulin(0.09,0.06,0.03 U/20 g) +5-FU treatment.When a high dosage of insulin+5-FU was ad- ministered,tumor weight was significantly reduced(P<0.05).The inhibitory rate of growth of S180 sarcoma and H22 liver cancer reached 50.2% and 51.4%,respectively,which was significantly higher than 24.9% and 27.9% in the group receiving 5-FU alone (P<0.05).High,medium and low-dose insulin combined with 5-FU significantly inhibited the growth of Eca-109 cancer cells (P<0.05).Compared with the control group,the level of serum IGF-1 decreased(P<0.05),whereas the level of serum IGFBP-3 slightly increased in the 5-FU±insulin groups(P>0.05).In mice with H22 liver cancer and S180 sarcoma the IGF-1 level with high- dose insulin+5-FU treatment was significantly lower compared to treatment with 5-FU alone(P<0.05),but the difference was not significant in mice transplanted with esophageal cancer cells. CONCLUSION Insulin can enhance the anti-tumor effect of 5-FU without significantly increasing 5-FU toxicity.Although changes in the serum IGF-1 or IGFBP-3 level do not explain the mechanism of the insulin-induced enhancement on 5-FU on growth,a decrease in the level of serum IGF-1 and an increase in serum IGFBP-3 may be important in the chemotherapeutic response.