Märten Angela, Zeiss Nina, Serba Susanne, Mehrle Stefan, von Lilienfeld-Toal Marie, Schmidt Jan
Uniklinik Heidelberg, Im Neuenheimer Feld 350, Heidelberg, Germany.
Mol Cancer Ther. 2008 Nov;7(11):3624-31. doi: 10.1158/1535-7163.MCT-08-0393.
The purpose of the present study was to evaluate the potency of the proteasome inhibitor bortezomib +/- gemcitabine in vitro and in vivo in pancreatic carcinoma. It could be shown that bortezomib induced apoptosis and inhibited proliferation of pancreatic carcinoma very efficiently in vitro. In contrast, in an orthotopic pancreatic adenocarcinoma mouse model, gemcitabine treatment inhibited tumor growth, whereas bortezomib promoted it. Bortezomib-treated animals showed significantly higher tumor burden compared with gemcitabine-treated and control animals, although bortezomib was locally active and induced a decrease of proteasome activity, which was most pronounced following the simultaneous administration of gemcitabine. Also, tumor progression was not caused by immunosuppression as a result of proteasome inhibition. Interestingly, anti-CD31 staining of tumors showed that angiogenesis was significantly increased in the tumors of bortezomib-treated mice compared with the tumors of control animals. In addition, bortezomib resulted an increase of pericytes, vascular endothelial growth factor, RGS-5, and hypoxia-inducible factor-1alpha in the tumor. Although this study supports efficacy of bortezomib against pancreatic carcinoma in vitro, it strongly indicates that bortezomib therapy has a significant tumor-promoting effect in vivo by induction of angiogenesis. The data are in accordance with the complete failure of bortezomib in a phase II trial for this indication. Choosing the right schedule of gemcitabine and bortezomib showed some synergistic effects, but the gain might not be big enough to compensate the potentially detrimental effects.
本研究的目的是评估蛋白酶体抑制剂硼替佐米联合/不联合吉西他滨在体外和体内对胰腺癌的疗效。结果表明，硼替佐米在体外能非常有效地诱导胰腺癌细胞凋亡并抑制其增殖。相反，在原位胰腺腺癌小鼠模型中，吉西他滨治疗可抑制肿瘤生长，而硼替佐米则促进肿瘤生长。与吉西他滨治疗组和对照组动物相比，硼替佐米治疗组动物的肿瘤负荷显著更高，尽管硼替佐米具有局部活性并能诱导蛋白酶体活性降低，这在同时给予吉西他滨后最为明显。此外，肿瘤进展并非由蛋白酶体抑制导致的免疫抑制引起。有趣的是，肿瘤的抗CD31染色显示，与对照组动物的肿瘤相比，硼替佐米治疗组小鼠肿瘤中的血管生成显著增加。此外，硼替佐米导致肿瘤中周细胞、血管内皮生长因子、RGS - 5和缺氧诱导因子-1α增加。尽管本研究支持硼替佐米在体外对胰腺癌的疗效，但强烈表明硼替佐米治疗在体内通过诱导血管生成具有显著的促肿瘤作用。这些数据与硼替佐米在该适应症的II期试验中完全失败一致。选择吉西他滨和硼替佐米的合适给药方案显示出一些协同作用，但获益可能不足以弥补潜在的有害影响。
