Strategy for achieving selective killing of carcinomas.
Strategy for achieving selective killing of carcinomas.
复制标题
实现选择性杀死癌症的策略。
作者：
R. Garver;K. Goldsmith;B. Rodu;P. Hu;E. Sorscher;D. Curiel
癌是源自上皮细胞的恶性肿瘤，通常对常规化疗反应不佳。选择性表达或转导毒素基因到肿瘤，即分子化疗，可能提供比传统化疗更重要的优势。作为开发一种选择性表达毒素基因的方法，在多种癌中表达的一个基因的转录调控序列被用来指导单纯疱疹病毒胸苷激酶（HSVtk）编码序列的表达。分泌性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均有表达。分离出组织特异性转录调控序列，并利用SLPI序列构建了一个嵌合基因，其中SLPI序列指导HSVtk的表达。通过SLPI导向的毒素质粒和更昔洛韦的转导，表达SLPI的癌细胞数量减少，但同样的处理对不表达SLPI的细胞系没有影响。这些结果表明，slpi导向的治疗基因可以用于指导对癌组织的毒性，特别是如果与其他靶向策略结合使用。
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.