Combination of conditionally replicative adenovirus and standard chemotherapies shows synergistic antitumor effect in pancreatic cancer.
Combination of conditionally replicative adenovirus and standard chemotherapies shows synergistic antitumor effect in pancreatic cancer.
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DOI：
10.1111/j.1349-7006.2009.01289.x
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发表时间：
2009-11
期刊：
影响因子：
5.7
通讯作者：
Yamamoto M
中科院分区：
文献类型：
--
作者：
Nelson AR;Davydova J;Curiel DT;Yamamoto M
由于胰腺癌的预后很差，因此需要新的治疗方法。我们正在为我们开发的条件复制型腺病毒（CRAD）的人体临床试验做准备。虽然目标人群中的大多数患者正在接受吉西他滨或5-氟尿嘧啶化疗，但尚未研究与CRAd的联合治疗。本研究旨在评估CRAd和目前标准化疗方案在胰腺癌中的联合治疗。当在体外测试组合疗法时，吉西他滨预处理在四种细胞系中的两种中显示出协同效应，而CRAd随后吉西他滨在一种细胞系中显示出协同效应。与5-氟尿嘧啶，5-氟尿嘧啶预处理产生了协同效应，在三个细胞系，而后处理是协同作用，只有一个细胞系。这些影响不能完全解释诱导环氧合酶（考克斯）2活性或腺病毒受体与化疗药物。在Hs 766 T异种移植物的体内分析中，5-氟尿嘧啶略微改善CRAd抗肿瘤作用，但不显著。与吉西他滨单药治疗相比，吉西他滨预治疗表现出显著的肿瘤缩小。当在第12天用5/3COX 2CRAdF和随后的吉西他滨处理肿瘤时，发生最显著的抗肿瘤作用（P = 0.001 vs单独的吉西他滨，P = 0.012 vs单独的5/3COX 2CRAdF）。在MIA Paca-2中，在CRAd注射前给予5-氟尿嘧啶或吉西他滨预处理可改善CRAd治疗效果（分别为P = 0.03和P = 0.01）。这些实验表明了联合治疗的可能益处，因此在接受CRAd治疗时没有必要中断化疗。（Cancer Sci 2009）; 00：000-000）
Due to devastating prognosis, novel therapies are needed for pancreatic cancer. We are in preparation for a human clinical trial of a conditionally replicative adenovirus (CRAd) we developed. While most patients in the target population are receiving either gemcitabine or 5-fluorouracil chemotherapy, the combination with CRAd has not yet been studied. This study was designed to evaluate combination therapies with CRAd and current standard chemotherapies in pancreatic cancer. When the combination therapy was tested in vitro, gemcitabine pretreatment showed a synergistic effect in two out of four cell lines whereas CRAd followed by gemcitabine exhibited a synergistic effect in one cell line. With 5-fluorouracil, pretreatment with 5-fluorouracil produced a synergistic effect in three cell lines whereas post-treatment was synergistic in only one cell line. These effects were not fully explained by either induction of cyclooxygenase (Cox) 2 activity or adenoviral receptors with chemotherapeutics. In in vivo analyses with Hs766T xenograft, 5-fluorouracil slightly improved the CRAd antitumor effect but it was not significant. Pretreatment with gemcitabine embodied a significant tumor reduction compared with single therapy with gemcitabine. The most significant antitumor effect occurred when tumors were treated with 5/3COX2CRAdF and subsequent gemcitabine (P = 0.001 vs gemcitabine alone, P = 0.012 vs 5/3COX2CRAdF alone) at day 12. In MIA Paca-2, pretreatments with either 5-fluorouracil or gemcitabine improved the CRAd therapeutic effect when administered before CRAd injection (P = 0.03 and P = 0.01, respectively). These experiments indicate the possible benefit of combination therapies, and thus it is not necessary to interrupt chemotherapeutics when receiving CRAd therapy. (Cancer Sci 2009); 00: 000–000)