INDIRECT INHIBITORY EFFECT OF A NEUROTENSIN RECEPTOR ANTAGONIST ON HUMAN COLON-CANCER (LOVO) GROWTH

The effect of the nonpeptide neurotensin (NT) receptor antagonist SR48 692 on NT-mediated growth of xenografted human colon cancers (LoVo) wa s 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 mu g/kg), SR48692 (2 mg/kg) or NT+SR48 692 administered s.c., t.i.d., for 25 days. Treatment with NT signific antly stimulated LoVo tumour growth, weight, DNA and protein content; SR48692 blocked this NT-mediated effect but had no effect when adminis tered as a single agent. In addition, normal jejunum and ileum were re moved and assessed. Similar to the effects on LoVo tumours, NT stimula ted jejunal and ileal growth; SR48692 blocked this NT-mediated effect. In contrast to our in vivo findings, NT had no effect on LoVo cell gr owth in vitro. Also, Northern blot analysis demonstrated no expression for the NT receptor in either LoVo tumour cells or xenografted tumour s. Our findings suggest that the trophic effect of NT on LoVo may be t hrough an indirect effect; one possibility is that administration of N T may stimulate the release of other trophic factors which then stimul ate tumour growth. The nonpeptide NT receptor antagonist SR48692 will be a useful agent to delineate the specific effects of NT on neoplasti c as well as normal gastrointestinal tissues.