Gefitinib does not enhance radiation caused lung injury in vivo
WANG Xiao-zhen*, JI Wei, JIANG Heng, ZHAO Lu-jun, YANG Wei-zhi, WANG Lü-hua
*Department of Radiation Oncology, Cancer Hospital (Insititute), Chinese Academy of Medical Sciences, Peking Union Medical College,Beijing 100021, China Corresponding author:WANG Lü-hua,Email:wlhwq@yahoo.com
Abstract：Objective To evaluate the effect on lung injury of gefitinib or/and radiation. Methods Totally 160 mice were divided into five groups:control (C);gefitinib (G);radiation (R);gefitinib followed by irradiation (G+R);and R+G. 12 Gy irradiation was delivered. Gefitinib fed by 200 mg/kg once daily for 3 weeks. Mice were sacrificed on 1, 2, 4 or 6 months after radiation. Macrophage count of lung lavage fluid and hydroxyproline assessed, lung fibrosis scored. and plasma TGF-β1 concentration assayed. One-way ANOVA was used to test the significance. Results The lung lavage macrophage cell number were significantly higher in group R, R+G and G+R than group C (q=2.95－8.61,all P<0.05) on 4 and 6 months, yet no significant difference between the three groups (q=0.37－3.49,all P<0.05);The macrophage was significantly lower in month 1, 4 and 6 in group G than R, R+G and G+R (q=3.37－6.25,all P<0.05). The hydroxyproline content and the fibrosis score of G, R, R+G and G+R were significantly higher than C (q=3.14－4.76,all P<0.05), but no significant difference between the four groups (q=0.70－4.19,all P>0.05).The TGF-β1 concentration of R, G+R, R+G at all time points and TGF-β1 concentration of G at 1st and 2nd months were significantly higher than C (q=3.76－8.09,all P<0.05). Conclusions Gefitinib could cause lung fibrosis in vivo in BalB/C mouse. The combination of gefitinib and radiation did not significantly exacerbate lung injury caused byeither alone. The mechanism of lung fibrosis caused by gefitinib might be different from that by radiation which needs further research.
WANG Xiao-zhen*,JI Wei,JIANG Heng et al. Gefitinib does not enhance radiation caused lung injury in vivo[J]. Chinese Journal of Radiation Oncology, 2012, 21(4): 388-391.
[1] Ready N, Herndon J, Vokes E, et al. Initial cohort toxicity evaluation for chemoradiotherapy (CRT) and ZD1839 in stage Ⅲ non-small cell lung cancer (NSCLC):a CALGB stratified phase Ⅱ trial. Proc Am Soc Clin Oncol,2004,23:632. [2] RischinD, Burmeister B, Mitchell P, et al. Phase Ⅰ trial of gefitinib (ZD1839) in combination with concurrent carboplatin, paclitaxel and radiation therapy in patients with stage Ⅲ non-small cell lung cancer. Proc Am Soc Clin Oncol,2004,23:632. [3] Mauer A, Haraf D, Hoffman PC, et al. A phase Ⅰ trial of OSI 774 in combination with chemoradiation (CRT) for unresectable, locally advanced non-small cell lung cancer (NSCLC).Proc Am Clin Oncol,2003,22:651. [4] Hotta K, Harita S, Bessho A, et al. Interstitial lung disease (ILD) during gefitinib treatment in Japanese patients with non-small cell lung cancer (NSCLC):Okayama lung cancer study group. Proc Am Soc Clin Oncol.2004,24:629. [5] Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol,1988,41:467-470. [6] Schmidt-Ullrich RK, Valerie K, Fogleman PB, et al. Radiation-induced autophosphorylation of epidermal growth factor receptor in human malignant mammary and squamous epithelial cell. Radiat Res,1996,145:81-85. [7] Chinnaiyan P, Huang S, Vallabhaneni G, et al. Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res,2005,65:3328-3335. [8] Shintani S, Li C, Mihara M, et al. Enhancement of tumor radioresponse by combined treatment with gefitinib (Iressa, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, is accompanied by inhibition of DNA damage repair and cell growth in oral cancer. Int J Cancer,2003,107:1030-1037. [9] Huang SM, Li J, Armstrong EA, et al. Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839(Iressa). Cancer Res,2002,62:4300-4306. [10] Huang SM, Harari PM. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas:inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin Cancer Res,2000,6:2166-2174. [11] Ohyanagi F, Ando Y, Nagashima F, et al. Acute gefitinib-induced pneumonitis. Int J Clin Oncol,2004,9:406-409. [12] Seto T, Seki N, Uematsu K, et al. Gefitinib-induced lung injury successfully treated with high-dose corticosteroids. Respirology,2006,11:113-116. [13] Takano T, Ohe Y, Kusumoto M, et al. Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib. Lung cancer,2004,45:93-104. [14] Forsythe B, Faulkner K. Overview of the tolerability of gefitinib (iressa) monotherapy. Drug Safety,2004,27:1081-1092. [15] Kataoka K, Taniguchi H, Hasegawa Y, et al. Interstitial lung disease associated with gefitinib. Resp Med,2006,100:698-704. [16] Suzuki H, Aoshiba K, Yokohori N, et al. Epidermal growth factor receptor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis. Cancer Res,2003,63:5054-5059. [17] Camus P, Fanton A, Bonniaud P, et al. Interstitial lung disease induced by drugs and radiation. Respiration,2004,71:301-326. [18] Rice AB, Moomaw CR, Morgan DL, et al. Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosisi in rats. Am J Pathol,1999,155:213-221.
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