Antitumor efficacy of capecitabine and celecoxib in irradiated and lead-shielded, contralateral human BxPC-3 pancreatic cancer xenografts: Clinical implications of abscopal effects
Antitumor efficacy of capecitabine and celecoxib in irradiated and lead-shielded, contralateral human BxPC-3 pancreatic cancer xenografts: Clinical implications of abscopal effects
复制标题
DOI：
10.1158/1078-0432.ccr-05-0627
复制
发表时间：
2005-12-15
影响因子：
11.5
通讯作者：
Johnson, MR
中科院分区：
文献类型：
--
作者：
Blanquicett, C;Saif, MW;Johnson, MR
目的：X线治疗（XRT）仍然是治疗局部晚期胰腺癌的主要方法之一。然而，XRT对照射野外转移性肿瘤的影响（远位效应）在很大程度上仍然未知。在当前的研究中，我们检查了XRT单独和与卡培他滨和/或塞来昔布联合在辐照和铅屏蔽对侧BxPC-3胰腺癌异种移植物中的作用。根据我们对胰腺癌的分子分析，选择了这种放化疗方案。实验设计：无胸腺小鼠双侧注射BxPC-3细胞，并在植入后28天开始治疗。在XRT期间（2戈伊，连续5天，在第0天和第24天给药），照射一侧胁腹，而身体的其余部分（包括对侧肿瘤）进行铅屏蔽。在第0 - 13天和第24 - 37天给予卡培他滨（350 mg/kg）。塞来昔布以100 ppm（相当于20 mg/kg/d p.o.）结果：卡培他滨和XRT在放射性移植瘤中显示出协同的抗肿瘤作用（P = 0.008），而塞来昔布的加入进一步提高了这种作用（P < 0.001）。在对侧屏蔽异种移植物中，观察到远位效应。尽管XRT单药治疗显示辐照异种移植物的肿瘤面积显著减少，但相对于未处理的肿瘤，相同动物中对侧铅屏蔽肿瘤的生长促进了23%（P < 0.001）。有趣的是，当给予卡培他滨时，尽管在照射野之外，但在这些对侧肿瘤中发生协同抗增殖功效（P < 0.001）。添加塞来昔布进一步抑制肿瘤生长（P < 0.001）。这种三模式组合最有效地稳定了屏蔽和辐照肿瘤中的疾病;然而，没有观察到肿瘤根除。在照射或铅屏蔽的肿瘤中，胸苷磷酸化酶、二氢嘧啶脱氢酶或环氧合酶-2 mRNA水平没有显著变化，表明不能仅从这些先前确定的反应指标预测疗效。免疫组织化学检查增殖标记Ki-67显示一致性与肿瘤反应在辐照和对侧屏蔽xenograft.Conclusions：这些结果有影响的合理设计的治疗模式，胰腺癌转移性疾病仍然是患者发病的主要原因，并在肿瘤的辐射领域以外的远位效应可能会影响肿瘤的反应。
Purpose: X-ray therapy (XRT) remains one of the major modalities used to treat patients diagnosed with locally advanced pancreatic adenocarcinoma. However, the effect of XRT on metastatic tumors outside the field of irradiation (abscopal effect) remains largely unknown. In the current study, we examined the effect of XRT alone and in combination with capecitabine and/or celecoxib in both irradiated and lead-shielded contralateral BxPC-3 pancreatic cancer xenografts. This chemoradiation regimen was chosen based on our molecular analysis of pancreatic adenocarcinoma.Experimental Design: Athymic mice were injected bilaterally with BxPC-3 cells and treatment was initiated 28 days postimplant. During XRT (2 Gy for 5 consecutive days, administered on days 0 and 24), one flank was irradiated whereas the rest of the body (including the contralateral tumor) was lead shielded. Capecitabine (350 mg/kg) was administered on days 0 to 13 and 24 to 37. Celecoxib was initiated in the diet at 100 ppm (equivalent to 20 mg/kg/d p.o.) and administered throughout the study.Results: In irradiated xenografts, capecitabine and XRT showed synergistic anitiumor efficacy (P = 0.008), which was further improved with the addition of celecoxib (P < 0.001). In contralateral shielded xenografts, abscopal effects were observed. Whereas monotherapy with XRT showed significant reduction in tumor area in irradiated xenografts, growth was promoted by 23% (P < 0.001) in contralateral lead-shielded tumors in the same animals relative to untreated tumors. Interestingly, synergistic antiproliferative efficacy occurred in these contralateral tumors when capecitabine was administered (P < 0.001), despite being outside the irradiated field, The addition of celecoxib further inhibited tumor growth (P < 0.001). This trimodal combination most effectively stabilized disease in both shielded and irradiated tumors; however, tumor eradication was not observed. There were no significant changes in thymidine phosphorylase, dihydropyrimidine dehydrogenase, or cyclooxygenase-2 mRNA levels in irradiated or lead-shielded tumors, suggesting that efficacy cannot be predicted solely from these previously identified indicators of response. Immunohistochemistry examining the proliferation marker Ki-67 showed concordance with tumor response in both irradiated and contralateral shielded xenografts.Conclusions: These results have implications in the rational design of treatment paradigms for pancreatic cancer where metastatic disease remains the primary cause of patient morbidity and abscopal effects in tumors outside the field of irradiation may affect tumor response.