Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) in combination with the Apogossypol derivative BI-97C1 (Sabutoclax) improves therapeutic efficacy in low CAR colorectal cancer cells.
Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) in combination with the Apogossypol derivative BI-97C1 (Sabutoclax) improves therapeutic efficacy in low CAR colorectal cancer cells.
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DOI：
10.1002/jcp.22947
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发表时间：
2012-05
影响因子：
5.6
通讯作者：
Fisher, Paul B.
中科院分区：
文献类型：
--
作者：
Azab, Belal;Dash, Rupesh;Das, Swadesh K.;Bhutia, Sujit K.;Shen, Xue-Ning;Quinn, Bridget A.;Sarkar, Siddik;Wang, Xiang-Yang;Hedvat, Michael;Dmitriev, Igor P.;Curiel, David T.;Grant, Steven;Dent, Paul;Reed, John C.;Pellecchia, Maurizio;Sarkar, Devanand;Fisher, Paul B.
基于腺病毒（Ad）的基因治疗代表了治疗结直肠癌的潜在可行策略。血清型5腺病毒（Ad.5）通常用作转基因递送载体，其感染性依赖于柯萨奇-腺病毒受体（CAR）。CAR表达在许多癌症中下调，从而阻止了基于Ad.5的疗法的最佳治疗效率。为了克服低CAR问题，使用血清型嵌合方法来产生重组Ad（Ad.5/3），其能够以CAR非依赖性方式经由Ad.3受体感染癌细胞。我们评估了表达黑色素瘤分化相关基因7/白细胞介素24（mda-7/IL-24）的Ad.5/3重组病毒的转基因递送和疗效，这是一种有效的广谱癌症选择性治疗药物。在低CAR的人结直肠癌细胞RKO中，表达mda-7/IL-24的野生型Ad.5病毒（Ad.5-mda-7）未能有效感染，导致缺乏MDA-7/IL-24的表达或细胞凋亡的诱导。然而，表达mda-7/IL-24的重组Ad.5/3病毒（Ad.5/3-mda-7）有效地感染RKO细胞，导致更高的MDA-7/IL-24表达和体外和裸鼠异种移植模型中的细胞生长抑制。加入新型Bcl-2家族药理学抑制剂Apogossypol衍生物BI-97 C1（Sabutoclax）显著增强了Ad.5/3-mda-7的疗效。亚最佳剂量的Ad.5/3-mda-7和BI-97 C1的组合方案在体外和体内均显著增强了RKO细胞中的细胞毒性。考虑到Ad.5-mda-7在晚期实体瘤的I期临床试验中已显示出显著的客观缓解，预计Ad.5/3-mda-7单独或与BI-97 C1联合治疗可显著改善结直肠癌患者的治疗疗效。
Adenovirus (Ad)-based gene therapy represents a potentially viable strategy for treating colorectal cancer. The infectivity of serotype 5 adenovirus (Ad.5), routinely used as a transgene delivery vector, is dependent on Coxsackie-adenovirus receptors (CAR). CAR expression is downregulated in many cancers thus preventing optimum therapeutic efficiency of Ad.5-based therapies. To overcome the low CAR problem, a serotype chimerism approach was used to generate a recombinant Ad (Ad.5/3) that is capable of infecting cancer cells via Ad.3 receptors in a CAR-independent manner. We evaluated the improved transgene delivery and efficacy of Ad.5/3 recombinant virus expressing melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), an effective wide-spectrum cancer-selective therapeutic. In low CAR human colorectal cancer cells RKO, wild-type Ad.5 virus expressing mda-7/IL-24 (Ad.5-mda-7) failed to infect efficiently resulting in lack of expression of MDA-7/IL-24 or induction of apoptosis. However, a recombinant Ad.5/3 virus expressing mda-7/IL-24 (Ad.5/3-mda-7) efficiently infected RKO cells resulting in higher MDA-7/IL-24 expression and inhibition of cell growth both in vitro and in nude mice xenograft models. Addition of the novel Bcl-2 family pharmacological inhibitor Apogossypol derivative BI-97C1 (Sabutoclax) significantly augmented the efficacy of Ad.5/3-mda-7. A combination regimen of suboptimal doses of Ad.5/3-mda-7 and BI-97C1 profoundly enhanced cytotoxicity in RKO cells both in vitro and in vivo. Considering the fact that Ad.5-mda-7 has demonstrated significant objective responses in a Phase I clinical trial for advanced solid tumors, Ad.5/3-mda-7 alone or in combination with BI-97C1 would be predicted to exert significantly improved therapeutic efficacy in colorectal cancer patients.
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影响因子：
4.4
作者：
Caudell, EG;Mumm, JB;Grimm, EA
通讯作者：
Grimm, EA
影响因子：
6.4
作者：
Korn, W. M.;Macal, M.;Ferrell, L.
通讯作者：
Ferrell, L.
影响因子：
8
作者：
Lebedeva, IV;Su, ZZ;Fisher, PB
通讯作者：
Fisher, PB
影响因子：
11.2
作者：
Dash R;Richards JE;Su ZZ;Bhutia SK;Azab B;Rahmani M;Dasmahapatra G;Yacoub A;Dent P;Dmitriev IP;Curiel DT;Grant S;Pellecchia M;Reed JC;Sarkar D;Fisher PB
通讯作者：
Fisher PB
DOI：
10.1073/pnas.0337599100
发表时间：
2003-02-18
影响因子：
11.1
作者：
Anders, M;Hansen, R;Korn, WM
通讯作者：
Korn, WM