Background & Aims: The hypothesis that progastrin- cleotides and complementary DNA (cDNA) inhibited derived peptides act as autocrine growth factors for proliferation of the human colorectal carcinoma cell lines colorectal carcinomas has generated considerable in- LIM 1215 and HCT 116, respectively. 3, 4 Similarly, pro-terest. However, the influence of autocrine gastrins on liferation of the human colorectal carcinoma cell lines nontumorigenic colonic cells has not been investi- COLO 205 and SW613-S was stimulated by IGF-II and gated. This study tested the above hypothesis in the inhibited by antibodies against IGF-II or the IGF-I re-nontumorigenic, conditionally immortalized mouse co-ceptor. 5, 6 lon cell line YAMC. Methods: The effects of expression Much of the controversy over the existence of an auto-of antisense or sense gastrin messenger RNA, treat-crine proliferative loop involving gastrin in colorectal ment with antibodies against progastrin-derived pep-carcinomas has arisen because interest initially focused on tides, or treatment with gastrin receptor antagonists mature C-terminally amidated gastrins. For many years, on YAMC cell proliferation were measured. Results: amidation of gastrin was thought to be an essential pre-YAMC clones expressing antisense gastrin messenger

RNA had reduced levels of immunoreactive progastrin- requisite for biological activity, but recent data indicate derived peptides and a reduced rate of proliferation, that nonamidated gastrins can also stimulate prolifera-relative to vector only–transfected cells. Glycine- tion both in vitro7, 8 and in vivo. 9 All gastrins are derived extended gastrin17, but not amidated gastrin17, re- from the 80–amino acid precursor progastrin by a series versed the antisense-induced inhibition of proliferation of proteolytic cleavages followed, in the case of amidated and stimulated the proliferation of sense-or vector