Garver R I, Goldsmith K T, Rodu B, Hu P C, Sorscher E J, Curiel D T
Division of Pulmonary and Critical Care Medicine, UAB School of Medicine 35294, USA.
Gene Ther. 1994 Jan;1(1):46-50.
Carcinomas are malignancies derived from epithelial cells that frequently respond poorly to conventional chemotherapy. Selective expression or transduction of toxin genes to carcinomas, i.e. molecular chemotherapy, may offer important advantages over conventional chemotherapy. As one approach to developing a means of selectively expressing toxin genes, the transcriptional regulatory sequences of a gene expressed in multiple carcinomas were used to direct expression of the herpes simplex virus thymidine kinase (HSVtk) coding sequences. The secretory leukoprotease inhibitor (SLPI) gene was found to be expressed in lung, breast, oropharyngeal, bladder, endometrial, ovarian and colorectal carcinomas. The tissue-specific transcriptional regulatory sequences were isolated and used to construct a chimeric gene in which the SLPI sequences directed HSVtk expression. SLPI-expressing carcinomas were reduced in number by transduction of the SLPI-directed toxin plasmid plus ganciclovir, but the same treatment had no effect on a cell line that did not express SLPI. These results suggest that SLPI-directed therapeutic genes could be used for directing toxicity to carcinoma tissues, especially if combined with other targeting strategies.
癌是源自上皮细胞的恶性肿瘤，通常对传统化疗反应不佳。将毒素基因选择性表达或转导至癌组织，即分子化疗，可能比传统化疗具有重要优势。作为开发选择性表达毒素基因方法的一种途径，在多种癌中表达的一个基因的转录调控序列被用于指导单纯疱疹病毒胸苷激酶（HSVtk）编码序列的表达。发现分泌型白细胞蛋白酶抑制剂（SLPI）基因在肺癌、乳腺癌、口咽癌、膀胱癌、子宫内膜癌、卵巢癌和结直肠癌中表达。分离出组织特异性转录调控序列并用于构建嵌合基因，其中SLPI序列指导HSVtk表达。通过转导SLPI导向的毒素质粒加更昔洛韦，表达SLPI的癌数量减少，但相同处理对不表达SLPI的细胞系没有影响。这些结果表明，SLPI导向的治疗基因可用于将毒性导向癌组织，特别是如果与其他靶向策略联合使用。
