Transplantation Laboratory, Haartman Institute and Finnish Institute of Molecular Medicine, University of Helsinki, Helsinki, Finland.
Cancer Gene Ther. 2012 Feb;19(2):126-34. doi: 10.1038/cgt.2011.76. Epub 2011 Nov 18.
Oncolytic adenoviruses are a promising treatment alternative for many advanced cancers, including colorectal cancer. However, clinical trials have demonstrated that single-agent therapy in advanced tumor masses is rarely curative. Poor spreading of the virus through tumor tissue is one of the major issues limiting efficacy. As oncolytic viruses kill preferentially cancer cells, high extracellular matrix (ECM) content constitutes potential barriers for viral penetration within tumors. In this study, the ECM-degrading proteases relaxin, hyaluronidase, elastase and macrophage metalloelastase (MME) were tested for their antitumor efficacy alone and in combination with oncolytic adenovirus. MME improved the overall antitumor efficacy of oncolytic adenovirus in subcutaneous HCT116 xenografts. In a liver metastatic colorectal cancer model, intra-tumoral treatment of primary tumors from HT29 cells with MME monotherapy or with oncolytic adenovirus inhibited tumor growth. Combination therapy showed no increased mortality in comparison with either monotherapy alone. Contradictory results of effects of MME on tumorigenesis and metastasis formation have been reported in the literature. This study demonstrates for the first time in a metastatic animal model that MME, as a monotherapy or in combination with oncolytic virus, does not increase tumor invasiveness. Co-administration of MME and oncolytic adenovirus may be a suitable approach for further optimization aiming at clinical applications for metastatic colorectal cancer.
溶瘤腺病毒是许多晚期癌症（包括结直肠癌）的一种很有前途的治疗选择。然而，临床试验表明，在晚期肿瘤中，单一药物治疗很少能治愈。病毒在肿瘤组织中的扩散不良是限制疗效的主要问题之一。由于溶瘤病毒优先杀死癌细胞，因此细胞外基质（ECM）含量高会构成病毒在肿瘤内穿透的潜在障碍。在这项研究中，单独测试了 ECM 降解蛋白酶松弛素、透明质酸酶、弹性蛋白酶和巨噬细胞金属弹性蛋白酶（MME），以及它们与溶瘤腺病毒联合应用的抗肿瘤功效。MME 提高了溶瘤腺病毒在皮下 HCT116 异种移植物中的整体抗肿瘤功效。在结直肠癌细胞系 HT29 的肝转移模型中，MME 单独治疗或联合溶瘤腺病毒治疗原发性肿瘤可抑制肿瘤生长。与单独使用任一药物相比，联合治疗并没有增加死亡率。文献中报道了 MME 对肿瘤发生和转移形成的影响存在矛盾的结果。本研究首次在转移性动物模型中证明，MME 无论是单独治疗还是与溶瘤病毒联合治疗，都不会增加肿瘤侵袭性。MME 和溶瘤腺病毒的联合给药可能是一种合适的方法，可进一步优化针对转移性结直肠癌的临床应用。
