Tumour-specific arginine vasopressin promoter activation in small-cell lung cancer

Small-cell lung cancer (SCLC) can produce numerous mitogenic neuropeptides, which are not found in normal respiratory epithelium. Arginine vasopressin is detected in up to two-thirds of SCLC tumours whereas normal physiologic al expression is essentially restricted to the hypothalamus. This presents the opportunity to identify elements of the gene promoter which could be ex ploited for SCLC-specific targeting. A series of human vasopressin 5' promo ter fragments (1048 bp, 468 bp and 199 bp) were isolated and cloned upstrea m of a reporter gene. These were transfected into a panel of ten cell lines , including SCLC with high or low endogenous vasopressin transcription, non -SCLC and bronchial epithelium. All these fragments directed reporter gene expression in the five SCLC cell lines, but had negligible activity in the control lines. The level of reporter gene expression reflected the level of endogenous vasopressin production, with up to 4.9-fold (s.d. 0.34) higher activity than an SV40 promoter. The elements required for this strong, rest ricted, SCLC-specific promoter activity are contained within the 199-bp fra gment. Further analysis of this region indicated involvement of E-box trans cription factor binding sites, although tumour-specificity was retained by a 65-bp minimal promoter fragment. These data show that a short region of t he vasopressin promoter will drive strong expression in SCLC in vitro and r aise the possibility of targeting gene therapy to these tumours.