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 mechanism of the enhancemdnt 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 administered, 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 highdose 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.

Prognostic Significance of Tumor-infiltrating CD8^＋ or CD3^＋ T Lymphocytes and Interleukin-2 Expression in Radically Resected Non-small Cell Lung Cancer

Background：Altered immunoresponse is associated with tumorigenesis and cancer progression.This study assessed the levels of tumor-infiltrating CD3^＋ or CD8^＋ T lymphocytes and interleukin-2 （IL-2） protein in radically resected non-small cell lung cancer （NSCLC） tissues to predict overall survival （OS） of the patients.Methods：Paraffin-embedded tissue specimens from 129 NSCLC patients were retrospectively collected for immunostaining of CD8^＋,CD3^＋,and IL-2 expression.Clinicopathological and survival data were collected and analyzed using the Chi-squared test,Kaplan-Meier curves,and the log-rank test or the Cox regression model.Results：The data showed a significant inverse association between CD8^＋ T lymphocyte levels and IL-2 expression （r =-0.927; P =0.000） and between the levels of CD8^＋ and CD3^＋ T lymphocytes （r =-0.722; P =0.000）,but a positive association between CD3^＋ T lymphocyte levels and IL-2 expression （r =0.781; P =0.000） in NSCLC tissues.Furthermore,the levels of CD3^＋ and CD8^＋ T lymphocytes and IL-2 expression were associated with tumor stage （P =0.023,0.006,and 0.031,respectively） and the level of CD8^＋ T lymphocytes was associated with the patient gender （P =0.024）.In addition,the levels of CD8^＋ T lymphocytes were associated with an unfavorable 5-year OS,whereas patients with high levels of CD3^＋ T lymphocytes in tumor lesions and IL-2-expressing tumors had significantly better 5-year OS rates than patients with low levels.Conclusions：The levels of CD8^＋ T cells in tumor lesions and IL-2 expression were both independent predictors of OS for these NSCLC patients.Thus,the detection of tumor-infiltrating CD3^＋ or CD8^＋ T lymphocytes and IL-2 expression could be useful to predict the prognosis of radically resected NSCLC patients.