Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity
Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity
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DOI：
10.1038/sj.cgt.7700835
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发表时间：
2005-08-01
影响因子：
6.4
通讯作者：
Yu, DC
中科院分区：
文献类型：
--
作者：
Dilley, J;Reddy, S;Yu, DC
选择性地在肿瘤细胞中复制而不是在正常细胞中复制的连续复制腺病毒正在被探索作为癌症的病毒治疗剂。一种前列腺特异性溶瘤腺病毒，CG 7870目前正在评估用于治疗前列腺癌的1/2期临床试验。为了降低CG 7870的有效剂量，进一步提高其治疗效果，本研究探索了病毒治疗与放射治疗的联合应用。CG 7870是一种溶瘤腺病毒，其中肿瘤特异性启动子驱动E1 A和E1 B蛋白的表达。在细胞毒性和病毒产率测定中测定用CG 7870和辐射联合处理对培养细胞的影响。在建立的裸鼠皮下LNCaP异种移植物中评价了CG 7870（1 × 10（7）颗粒/mm（3）肿瘤）、10戈伊局部放射或两者的抗肿瘤功效。在体外，双重药剂处理在次优剂量的辐射和病毒下导致协同增强的效力。相对于未照射细胞中的产量，照射细胞中的病毒产量增加，而不损害载体对其靶细胞类型的特异性。在体内，单独使用CG 7870治疗可抑制肿瘤生长并延长肿瘤非进展时间。在治疗后39天，仅用CG 7870和仅用放射治疗的组的平均肿瘤体积分别为基线的121%和126%。单次给药后39天，联合治疗组的平均肿瘤体积为基线的34%。在任何给药组中均未观察到显著体重减轻。联合用药组的血清前列腺特异性抗原（PSA）水平较单独用药组显著下降。在仅用CG 7870或仅用辐射处理的小鼠中，到研究第46天，血清PSA水平分别变为基线的26%和383%。相比之下，用CG 7870加辐射处理的小鼠中的PSA水平在研究第46天降低至低于基线的11%。从组合组收集的肿瘤切片的组织学分析揭示了增强的坏死和更多的凋亡细胞。CG 7870与放射治疗的组合与单独的任一药剂相比显著增加抗肿瘤功效。这些结果表明，CG 7870与放射组合在较低剂量下具有改善的抗肿瘤功效，并且没有额外的副作用。
Conditionally replicating adenoviruses that selectively replicate in tumor cells, but not in normal cells, are being explored as virotherapeutic agents for cancer. A prostate-specific oncolytic adenovirus, CG7870 is currently being evaluated in phase 1/2 clinical trials for the treatment of prostate cancer. To decrease the effective dose and further increase the therapeutic efficacy of CG7870, the combination of virotherapy with radiation therapy was explored in this study. CG7870 is an oncolytic adenovirus in which tumor-specific promoters are driving the expression of E1A and E1B proteins. The effects of combined treatment with CG7870 and radiation on cultured cells were determined in cytotoxicity and virus yield assays. The antitumor efficacy of CG7870 ( 1 x 10(7) particles/mm(3) of tumor), 10 Gy of local radiation or both was evaluated in established subcutaneous LNCaP xenografts in nude mice. In vitro, the dual agent treatment resulted in synergistically enhanced potency at suboptimal doses of radiation and virus. Virus yield in irradiated cells increased relative to yield in nonirradiated cells without compromising the specificity of the vector for its target cell types. In vivo, CG7870 treatment alone suppressed tumor growth and extended tumor nonprogression time. The average tumor-volume of the groups treated with CG7870 only and radiation only was 121 and 126% of baseline, respectively, 39 days after treatment. The average tumor-volume of the combination group was 34% of baseline 39 days after a single dose of treatment. No significant body weight loss was observed in any treatment group. There was a significant drop in serum level of prostate-specific antigen (PSA) in the combination group compared to the group treated with either agent alone. In mice treated with CG7870 only or radiation only, serum PSA levels changed to 26 and 383% of baseline, respectively, by study day 46. In contrast, PSA levels in mice treated with CG7870 plus radiation decreased to less than 11% of baseline by study day 46. Histological analysis of tumor sections collected from the combination group revealed enhanced necrosis and more apoptotic cells. Combination of CG7870 with radiotherapy significantly increased antitumor efficacy compared to either agent alone. These results suggest that CG7870 in combination with radiation has improved antitumor efficacy at lower doses and with no additional side effects.