Treatment of pancreatic cancer xenografts with erbitux (IMC-C225) anti-EGFR antibody, gemcitabine, and radiation
Treatment of pancreatic cancer xenografts with erbitux (IMC-C225) anti-EGFR antibody, gemcitabine, and radiation
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DOI：
10.1016/s0360-3016(02)03788-4
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发表时间：
2002-11-15
影响因子：
7
通讯作者：
Raisch, KP
中科院分区：
文献类型：
--
作者：
Buchsbaum, DJ;Bonner, JA;Raisch, KP
目的：研究爱必妥联合治疗人胰腺癌细胞系和异种移植物（IMC-C225）抗表皮生长因子受体（EGFR）抗体、吉西他滨和放射。BxPC-3和MiaPaCa-2人胰腺癌细胞在体外用顶G-C225处理24小时（5 μ g/mL），然后暴露于表皮生长因子（EGF）（10 mM）5 min。免疫印迹筛选EGFR表达和IMC-C225阻断EGF诱导的EGFR酪氨酸磷酸化的能力。在第0天用IMC-C225（5 μ g/mL）处理细胞，在第1天用IC 50剂量的吉西他滨处理24小时，然后在第2天用3戈伊（CO）-C-60照射，或每种试剂的组合。对于细胞增殖，在第4天计数细胞，对于细胞凋亡，用膜联蛋白V-FITC和碘化丙啶染色细胞，然后通过FACS分析。用相同的单次或多次处理处理细胞，并在克隆形成细胞存活测定中进行分析。测定顶C-C225、吉西他滨和放射对BxPC-3和MiaPaCa-2肿瘤异种移植物生长的影响。无胸腺裸鼠，皮下接种已建立的直径为6-8 mm的肿瘤异种移植物接受6周的IMC-C225（每3天1 mg × 6）单独治疗或与吉西他滨（每6天120 mg/kg静脉内注射× 6）联合治疗，并在吉西他滨给药后的日子接受6次每周一次的3戈伊放射。结果：BxPC-3和MiaPaCa-2细胞株表达低水平的EGFR。IMC-C225抑制EGF诱导的EGF受体的酪氨酸磷酸化。用IMC-C225 +吉西他滨+辐射的组合处理细胞在体外产生最高的凋亡诱导和增殖抑制。IMC-C225、吉西他滨和放射的组合治疗产生了超过250天的MiaPaCa-2肿瘤的100%完全消退，并且与任何单一或双重治疗相比，BxPC-3肿瘤的生长抑制最大。法团校董会-C225联合吉西他滨化疗和放疗的疗效在统计学上显著高于单药和双药联合治疗。治疗这种形式的多模式治疗显示出在人类胰腺癌治疗中的潜在临床应用。(C)2002年爱思唯尔科技有限公司
Purpose: To investigate treatment of human pancreatic cancer cell lines and xenografts with combinations of Erbitux (IMC-C225) anti-epidermal growth factor receptor (EGFR) antibody, gemcitabine, and radiation.Methods and Materials: BxPC-3 and MiaPaCa-2 human pancreatic carcinoma cells were treated in vitro for 24 h with IMG-C225 (5 mug/mL), then exposed to epidermal growth factor (EGF) (10 mM) for 5 min. Immunoblots were screened for EGFR expression and the ability of IMC-C225 to block EGF-induced tyrosine phosphorylation of EGFR. Cells were treated with IMC-C225 (5 muglmL) on Day 0, the IC50 dose of gemcitabine on Day I for 24 h, followed by 3 Gy (CO)-C-60 irradiation on Day 2, or the combination of each agent. For cell proliferation, cells were counted on Day 4, and for apoptosis, cells were stained with annexin V-FITC and propidium iodide, then analyzed by FACS. Cells were treated with the same single or multiple treatments and analyzed in a clonogenic cell survival assay. The effect of IMC-C225, gemcitabine, and radiation on the growth of BxPC-3 and MiaPaCa-2 tumor xenografts was determined. Athymic nude mice bearing established s.c. tumor xenografts of 6-8 mm diameter received 6 weeks of treatment with IMC-C225 (I mg every 3 days X 6) alone or in combination with gemcitabine (120 mg/kg i.v. every 6 days X 6), and 6 weekly fractions of 3 Gy radiation on the days after gemcitabine administration. Tumor growth was measured with Vernier calipers.Results: BxPC-3 and MiaPaCa-2 cell lines expressed low levels of EGFR. IMC-C225 inhibited EGF-induced tyrosine phosphorylation of the EGF receptor on both cell lines. Treatment of cells with a combination of IMC-C225 + gemcitabine + radiation produced the highest induction of apoptosis and inhibition of proliferation in vitro. Combination treatment with IMC-C225, gemcitabine, and radiation produced 100% complete regression of MiaPaCa-2 tumors for more than 250 days, and the greatest growth inhibition of BxPC-3 tumors compared to any single or dual treatments.Conclusions: The IMC-C225 therapy in combination with gemcitabine chemotherapy and radiation therapy demonstrated statistically significantly greater efficacy over the single and double combination therapies. This form of multimodality treatment shows potential clinical application in the treatment of pancreatic cancer in humans. (C) 2002 Elsevier Science Inc.