Ram Z, Culver K W, Oshiro E M, Viola J J, DeVroom H L, Otto E, Long Z, Chiang Y, McGarrity G J, Muul L M, Katz D, Blaese R M, Oldfield E H
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892, USA.
Nat Med. 1997 Dec;3(12):1354-61. doi: 10.1038/nm1297-1354.
Intratumoral implantation of murine cells modified to produce retroviral vectors containing the herpes simplex virus-thymidine kinase (HSV-TK) gene induces regression of experimental brain tumors in rodents after ganciclovir (GCV) administration. We evaluated this approach in 15 patients with progressive growth of recurrent malignant brain tumors. Antitumor activity was detected in five of the smaller tumors (1.4 +/- 0.5 ml). In situ hybridization for HSV-TK demonstrated survival of vector-producing cells (VPCs) at 7 days but indicated limited gene transfer to tumors, suggesting that indirect, "bystander," mechanisms provide local antitumor activity in human tumors. However, the response of only very small tumors in which a high density of vector-producing cells had been placed suggests that techniques to improve delivery and distribution of the therapeutic gene will need to be developed if clinical utility is to be achieved with this approach.
向小鼠细胞中导入经过修饰的基因，使其产生含有单纯疱疹病毒胸苷激酶（HSV-TK）基因的逆转录病毒载体，然后将这些细胞瘤内植入。在给予更昔洛韦（GCV）后，可使啮齿类动物实验性脑肿瘤消退。我们对15例复发性恶性脑肿瘤呈进行性生长的患者评估了这种方法。在5个较小的肿瘤（体积为1.4±0.5 ml）中检测到了抗肿瘤活性。对HSV-TK进行原位杂交显示，产生载体的细胞（VPC）在7天时仍存活，但表明基因向肿瘤的转移有限，这提示间接的“旁观者”机制在人类肿瘤中提供了局部抗肿瘤活性。然而，只有那些植入了高密度产生载体细胞的非常小的肿瘤出现了反应，这表明如果要通过这种方法实现临床应用，还需要开发改善治疗基因递送和分布的技术。
