Biomedical subjects

M R Hellmich

Publications and source records attributed to M R Hellmich.

41 records · Page 3Linked to original sources

PubMedDate not supplied

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.

Analysis of Variance↗

PubMedDate not supplied

Prevention of mucosal atrophy: role of glutamine and caspases in apoptosis in intestinal epithelial cells.

Glutamine starvation induces apoptosis in enterocytes; therefore glutamine is important in the maintenance of gut mucosal homeostasis. However, the molecular mechanisms are unknown. The caspase family of proteases constitutes the molecular machinery that drives apoptosis. Caspases are selectively activated in a stimulus-specific and tissue-specific fashion. The aims of this study were to (1) identify specific caspases activated by glutamine starvation and (2) determine whether a general caspase inhibitor blocks glutamine starvation-induced apoptosis in intestinal epithelial cells. Rat intestinal epithelial (RIE-1) cells were deprived of glutamine. Specific caspase activation was measured using fluorogenic substrate assay. Apoptosis was quantified by DNA fragmentation and Hoechst nuclear staining. Glutamine starvation of RIE-1 cells resulted in the time-dependent activation of caspases 3 (10 hours) and 2 (18 hours), and the induction of DNA fragmentation (12 hours). Caspases 1 and 8 remained inactive ZVAD-fluoromethyl ketone, a general caspase inhibitor, completely blocked glutamine starvation-induced caspase activation, DNA fragmentation, and nuclear condensation. These results indicate that glutamine starvation selectively activates specific caspases, which leads to the induction of apoptosis in RIE-1 cells. Furthermore, inhibition of caspase activity blocked the induction of apoptosis, suggesting that caspases are potential molecular targets to attenuate apoptotic responses in the gut.

Amino Acid Chloromethyl Ketones↗

PubMedDate not supplied

Glucagon-like peptide 2 is a potent growth factor for small intestine and colon.

Factors that stimulate gut mucosal proliferation may be beneficial during periods of gut disuse or atrophy. Recently glucagon-like peptide 2 (GLP-2) has been shown to stimulate small bowel growth. The purpose of our study was to compare the trophic effects of GLP-2 with those of neurotensin (NT), a potent gut trophic factor. Mice were randomized to receive either GLP-2, NT, or saline solution (control) for 10 days. The mice were killed on day 11, at which time the jejunum, ileum, and colon were removed, weighed, and DNA and protein content measured. Mice treated with GLP-2 showed a significant increase in the weight of the jejunum, ileum, and colon compared to both control and NT-treated mice. DNA content, a marker of cellular hyperplasia, was significantly increased in the small bowel and colon by treatment with GLP-2 and NT compared to control tissues. Small intestinal protein content, an indicator of cellular hypertrophy, was significantly increased by GLP-2 compared to both NT and control; protein content of the colon was greater in each of the treatment groups compared with control mice. We have demonstrated, for the first time, that GLP-2 stimulates colonic growth. In addition, GLP-2 is a potent trophic factor of normal small intestine with proliferative effects that are equal to or greater than those of NT. Administration of GLP-2 may be useful clinically to enhance small intestinal regeneration and adaptation during periods of disease and in the early phases of the short bowel syndrome.

Adaptation, Physiological↗

PubMedDate not supplied

Enterotrophic effects of glucagon-like peptide 2 are enhanced by neurotensin.

Combination therapy with enterotrophic agents may be useful in patients with the short bowel syndrome. The gut hormones neurotensin (NT) and glucagon-like peptide 2 (GLP-2) are potent enterotrophic factors when administered alone; however, their combined effects are not known. Using a GLP-2-producing tumor (STC-1), we determined whether administration of NT enhances the effect of GLP-2 on intestinal growth. Athymic mice were injected with STC-1 cells (6 x 10(6)) subcutaneously. Twenty-three days after STC-1 implantation, mice received either NT (300 microg/kg or 600 microg/kg) or saline solution (control) subcutaneously three times a day for 6 days. Two groups of tumor-free mice received either saline or NT for 6 days. At sacrifice, jejunum and ileum were collected, weighed, and analyzed for DNA and protein content. In the jejunum, NT combined with GLP-2 (from STC-1) increased weight, protein content (markers of mucosal hypertrophy), and DNA content (a marker of mucosal hyperplasia), compared to either NT or GLP-2 alone. In the ileum, the combination of NT and GLP-2 significantly increased weight and/or protein content compared to NT or GLP-2 alone. Administration of NT enhances the enterotrophic effects of GLP-2, augmenting hypertrophy of the entire small bowel and hyperplasia of the jejunum. The combination of NT and GLP-2 may be useful to enhance intestinal growth in patients with the short bowel syndrome.

Analysis of Variance↗

PubMedDate not supplied

JMV1155: a novel inhibitor of glycine-extended progastrin-mediated growth of a human colon cancer in vivo.

BACKGROUND: Glycine-extended progastrin (G-17-Gly), the immediate biosynthetic precursor to gastrin (G-17), stimulates growth of some gastrointestinal cancers in vitro. The purpose of this study was twofold: to evaluate the effects of G-17-Gly on a human colon cancer (DLD-1) in vivo and to determine whether the novel gastrin-receptor antagonist, JMV1155, inhibits G-17-Gly-mediated growth. METHODS: DLD-1 cells (2 x 10(6)) were injected subcutaneously (s.c.) at a single site in athymic nude mice. Mice were randomized to four groups (n = 6/group) to receive injections, s.c., tid of either saline (control), G-17-Gly, JMV1155, or G-17-Gly + JMV1155 for 28 days. Tumors were measured biweekly until sacrifice at which time tumors were weighed and analyzed for DNA and protein content. RESULTS: JMV1155 significantly inhibited G-17-Gly-stimulated growth of DLD-1 tumors by 14 days of treatment, producing a 56% decrease in tumor size by 28 days. JMV1155 also significantly decreased G-17-Gly-mediated increases in tumor weight (by 64%), DNA content (by 61%), and protein content (by 65%). CONCLUSIONS: We have demonstrated, for the first time, that the novel gastrin-receptor antagonist, JMV1155, blocks G-17-Gly-induced growth of a transplanted human colon cancer in vivo. Hormonally based therapy with JMV1155 potentially could be employed for some patients with colon carcinoma.

Animals↗