Stephan Susann, Datta Kaustubh, Wang Enfeng, Li Jinping, Brekken Rolf A, Parangi Sareh, Thorpe Philip E, Mukhopadhyay Debabrata
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Clin Cancer Res. 2004 Oct 15;10(20):6993-7000. doi: 10.1158/1078-0432.CCR-04-0808.
The overall 5-year survival of patients with pancreatic cancer remains <5%. Novel therapeutic strategies are needed. We examined the effect of rapamycin, alone and in combination with antiangiogenesis therapy, on pancreatic cancer in vivo.
Human pancreatic cancer AsPC-1 cells were orthotopically injected into severe combined immunodeficient/beige mice to evaluate primary tumor growth and liver metastasis after treatment with rapamycin alone or in combination with anti-vascular endothelial growth factor antibody 2C3. Tumor cell proliferation was determined by bromodeoxyuridine incorporation. To detect tumor cell apoptosis, the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used. Tumor angiogenesis was investigated by using a monoclonal anti-CD31 antibody. All statistical tests were two-sided.
Rapamycin, alone and in combination with 2C3, strongly inhibited primary and metastatic tumor growth in an orthotopic pancreatic cancer animal model. Furthermore, the combination therapy significantly improved the effect on liver metastasis compared with single treatment with either rapamycin (P = 0.0128) or 2C3 (P = 0.0099). Rapamycin alone inhibited pancreatic tumor cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Nevertheless, the combination therapy showed a significant, stronger inhibition of tumor cell proliferation (P = 0.0002 versus rapamycin alone and P < 0.0001 versus 2C3 alone). The induction of apoptosis was significantly higher than in the rapamycin-treated group (P = 0.0039). Additionally, the combination therapy further improved suppression of tumor cell angiogenesis compared with rapamycin treatment (P = 0.029)
Our studies propose new therapeutic strategies to inhibit both primary and metastatic tumor growth in pancreatic cancer. Considering the fact that liver metastasis is a crucial problem in advanced stages of pancreatic cancer, the combination therapy of rapamycin plus anti-vascular endothelial growth factor antibody 2C3 is a significant advantage compared with single treatment with rapamycin.
胰腺癌患者的总体5年生存率仍低于5%。需要新的治疗策略。我们在体内研究了雷帕霉素单独及与抗血管生成疗法联合应用对胰腺癌的影响。
将人胰腺癌细胞AsPC-1原位注射到严重联合免疫缺陷/米色小鼠体内，以评估单独使用雷帕霉素或与抗血管内皮生长因子抗体2C3联合治疗后原发性肿瘤生长和肝转移情况。通过溴脱氧尿苷掺入法测定肿瘤细胞增殖。使用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法检测肿瘤细胞凋亡。使用单克隆抗CD31抗体研究肿瘤血管生成。所有统计检验均为双侧检验。
雷帕霉素单独及与2C3联合应用，在原位胰腺癌动物模型中均强烈抑制原发性和转移性肿瘤生长。此外，与单独使用雷帕霉素（P = 0.0128）或2C3（P = 0.0099）相比，联合治疗显著改善了对肝转移的疗效。单独使用雷帕霉素可抑制胰腺肿瘤细胞增殖、诱导凋亡并减少肿瘤血管生成。然而，联合治疗对肿瘤细胞增殖的抑制作用更显著（与单独使用雷帕霉素相比，P = 0.0002；与单独使用2C3相比，P < 0.0001）。凋亡诱导率显著高于雷帕霉素治疗组（P = 0.0039）。此外，与雷帕霉素治疗相比，联合治疗进一步改善了对肿瘤细胞血管生成的抑制作用（P = 0.029）。
我们的研究提出了抑制胰腺癌原发性和转移性肿瘤生长的新治疗策略。鉴于肝转移是晚期胰腺癌的一个关键问题，与单独使用雷帕霉素相比，雷帕霉素加抗血管内皮生长因子抗体2C3的联合治疗具有显著优势。
