Lamfers Martine L M, Idema Sander, Bosscher Lisette, Heukelom Stan, Moeniralm Sharif, van der Meulen-Muileman Ida H, Overmeer Renée M, van der Valk Paul, van Beusechem Victor W, Gerritsen Winald R, Vandertop W Peter, Dirven Clemens M F
Department of Neurosurgery, VU University Medical Center, Amsterdam, the Netherlands.
Clin Cancer Res. 2007 Dec 15;13(24):7451-8. doi: 10.1158/1078-0432.CCR-07-1265.
The integrin-targeted conditionally replicating adenovirus Ad5-delta 24RGD has been shown to possess strong oncolytic activity in experimental tumors and is currently being developed toward phase I clinical evaluation for ovarian cancer and malignant glioma. Previously, we reported that combination therapy of Ad5-delta 24RGD with irradiation led to synergistic antitumor activity in s.c. glioma xenografts. In the current study, the underlying mechanism of action to this synergy was studied and the effects of combined therapy were assessed in an orthotopic glioma model.
Sequencing studies in U-87 monolayers showed that delivery of irradiation before Ad5-delta 24RGD infection led to a greater oncolytic effect than simultaneous delivery or infection before irradiation. This effect was not due to enhanced virus production or release. Experiments using a luciferase-encoding vector revealed a small increase in transgene expression in irradiated cells. In tumor spheroids, combination therapy was more effective than Ad5-delta 24RGD or irradiation alone. Staining of spheroid sections showed improved penetration of virus to the core of irradiated spheroids. Mice bearing intracranial tumors received a combination of Ad5-delta 24RGD with 1 x 5 Gy total body irradiation or with 2 x 6 Gy whole brain irradiation. In contrast to the in vitro data and reported results in s.c. tumors, addition of radiotherapy did not significantly enhance the antitumor effect of Ad5-delta 24RGD.
Combined treatment with Ad5-delta 24RGD and irradiation shows enhanced antitumor activity in vitro and in s.c. tumors, but not in an orthotopic glioma model. These differential results underscore the significance of the selected tumor model in assessing the effects of combination therapies with oncolytic adenoviruses.
靶向整合素的条件性复制腺病毒Ad5-δ24RGD已显示在实验性肿瘤中具有强大的溶瘤活性，目前正朝着卵巢癌和恶性胶质瘤的I期临床评估方向发展。此前，我们报道Ad5-δ24RGD与放疗联合治疗可在皮下胶质瘤异种移植模型中产生协同抗肿瘤活性。在本研究中，我们研究了这种协同作用的潜在作用机制，并在原位胶质瘤模型中评估了联合治疗的效果。
对U-87单层细胞进行测序研究表明，在Ad5-δ24RGD感染前进行放疗比同时进行放疗或在放疗前进行感染产生更大的溶瘤效果。这种效果并非由于病毒产生或释放增加所致。使用编码荧光素酶的载体进行的实验显示，受照射细胞中的转基因表达略有增加。在肿瘤球体中，联合治疗比单独使用Ad5-δ24RGD或放疗更有效。球体切片染色显示病毒向受照射球体核心的渗透有所改善。携带颅内肿瘤的小鼠接受了Ad5-δ24RGD与1×5 Gy全身照射或2×6 Gy全脑照射的联合治疗。与体外数据和皮下肿瘤的报道结果相反，放疗的加入并未显著增强Ad5-δ24RGD的抗肿瘤效果。
Ad5-δ24RGD与放疗联合治疗在体外和皮下肿瘤中显示出增强的抗肿瘤活性，但在原位胶质瘤模型中并非如此。这些不同的结果强调了所选肿瘤模型在评估溶瘤腺病毒联合治疗效果方面的重要性。
