Indirect inhibitory effect of a neurotensin receptor antagonist on human colon cancer (LoVo) growth.

The effect of the nonpeptide neurotensin (NT) receptor antagonist SR48692 on NT-mediated growth of xenografted human colon cancers (LoVo) was determined. Sixty-four athymic nude mice, inoculated with LoVo cells at a single site, were randomized into four groups of 16 mice each to receive either vehicle NT (600 microg/kg), SR48692 (2 mg/kg) or NT+SR48692 administered s.c., t.i.d., for 25 days. Treatment with NT significantly stimulated LoVo tumour growth, weight, DNA and protein content; SR48692 blocked this NT-mediated effect but had no effect when administered as a single agent. In addition, normal jejunum and ileum were removed and assessed. Similar to the effects on LoVo tumours, NT stimulated jejunal and ileal growth; SR48692 blocked this NT-mediated effect. In contrast to our in vivo findings, NT had no effect on LoVo cell growth in vitro. Also, Northern blot analysis demonstrated no expression for the NT receptor in either LoVo tumour cells or xenografted tumours. Our findings suggest that the trophic effect of NT on LoVo may be through an indirect effect; one possibility is that administration of NT may stimulate the release of other trophic factors which then stimulate tumour growth. The nonpeptide NT receptor antagonist SR48692 will be a useful agent to delineate the specific effects of NT on neoplastic as well as normal gastrointestinal tissues.