Differential effects of gut hormones on pancreatic and intestinal growth during administration of an elemental diet.

Liquid elemental diets (ED) will, in time, cause atrophy of the gut. Pentagastrin (PG), neurotensin (NT), and bombesin (BBS) are peptides that have trophic effects on the gut of normal rats. This study examined the effect of these three agents on gut atrophy produced by ED. Four groups of rats were given an ED and injected with either saline (control), PG (250 micrograms/kg), NT (300 micrograms/kg), or BBS (10 micrograms/kg) subcutaneously every 8 hours for 5 or 10 days. A fifth group was fed rat chow ad libidum. The rats were killed on day 6 or 11; the pancreas and segments of small intestine were removed. Atrophy of ileal mucosa was apparent on days 6 and 11, and atrophy of jejunal mucosa was manifest by day 11. Bombesin prevented jejunal mucosal atrophy and significantly increased ileal mucosal growth (compared with control). Neurotensin prevented the jejunal, but not the ileal, mucosal atrophy produced by ED. Pentagastrin had no effect on gut mucosa. Bombesin and PG, but not NT, stimulated pancreatic growth. Neurotensin stimulates pancreaticobiliary secretions (PBS), which are known to stimulate gut growth. Jejunoileal bypass was performed to determine whether trophic effects of NT on gut mucosa were mediated through stimulation of PBS. After 1 week treatment, animals were killed and segments of intestine removed. As expected NT was trophic for gut mucosa in continuity with the luminal stream; furthermore NT produced significant stimulation of growth of gut mucosa in the bypassed segment. We conclude that both BBS and NT are trophic for intestinal mucosa of rats given ED; both agents have a more pronounced effect on jejunum. The trophic effect of NT is mediated, in part, by a mechanism unrelated to stimulation of PBS. Bombesin and NT may have important regulatory functions in the adaptive growth of small bowel mucosa and in the maintenance of gut mucosal integrity.     

Bombesin stimulates mucosal growth in jejunal and ileal Thiry-Vella fistulas.

OBJECTIVE: The authors determined whether the trophic effects of bombesin (BBS) on the small bowel mucosa are mediated by either nonluminal factors or endogenous luminal secretion. SUMMARY BACKGROUND DATA: The gut hormone bombesin stimulates growth of small bowel mucosa. The mechanisms responsible for this trophic effect are not known. METHODS: Rats underwent construction of a Thiry-Vella fistula (TVF) of either the jejunum or ileum. On postoperative day 10, the two groups were subdivided to receive either saline (control) or bombesin (10 micrograms/kg, subcutaneously, three times a day). After 14 days, rats were killed and the TVF was removed. The mucosa was scraped and weighed, and DNA and protein content was determined. RESULTS: Bombesin significantly increased mucosal weight and DNA and protein content of both the jejunal and ileal TVF compared with the control rats. CONCLUSIONS: Bombesin-mediated stimulation of small bowel mucosal growth is mediated by factors that are independent of luminal contents and pancreaticobiliary secretion. Bombesin may prove to be an important enterotrophic factor for gut mucosal proliferation.     

Role of bombesin on gut mucosal growth.

OBJECTIVE: The authors examined the effects of exogenous bombesin (BBS) on gut mucosal growth in chow-fed rats and the mucosal regeneration after gut atrophy brought about by feeding an elemental diet and after intestinal injury produced by methotrexate (MTX). SUMMARY BACKGROUND DATA: Bombesin is one of many gastrointestinal peptides implicated in the regulation of gut mucosal growth. Although BBS is known to stimulate growth of normal pancreatic tissue, the trophic effect of BBS on gut mucosa is less clear and its exact role in gut mucosal regeneration and repair is not known. METHODS: Rats were fed a regular chow diet (control) or an elemental diet plus either saline or BBS (10 micrograms/kg). In another experiment, rats fed a chow diet and treated with saline or BBS were given MTX (20 micrograms/kg) or a single intraperitoneal injection. In all experiments, small and large bowel mucosa and pancreas were removed and analyzed for BBS-mediated proliferation. RESULTS: Bombesin produced significant mucosal proliferation of the small bowel at day 14, but not at day 7, in rats fed regular chow. In contrast, BBS treatment for 7 days produced significant proliferation in both the atrophic and injured gut mucosa of rats given elemental diet or MTX. CONCLUSIONS: Bombesin may be an important enterotrophic factor for normal mucosal proliferation and may be clinically beneficial as an agent to restore or maintain gut mucosa during periods of atrophy or injury.     

Gastrin stimulates growth of colon cancer

Gastrin is trophic for normal gastric and colonic mucosa. We examined the potential trophic effects of chronic gastrin administration on the growth of mouse colon adenocarcinoma (MC-26). Thirty-three mice bearing transplantable MC-26 colon cancers were treated with varying doses (125, 250, or 500 micrograms/kg/day) of pentagastrin. Significant increases in tumor weight and DNA content were observed. Fundic mucosal weight and DNA content in these mice showed a dose-related trophic response. The weight of control fundic mucosa was 10 mg and rose to 20, 45, and 65 mg with increasing doses of gastrin. The DNA content of control fundic mucosa was 155 micrograms and rose to 220, 340, and 480 micrograms as the dose of gastrin was increased. Pentagastrin stimulated growth of the MC-26 colon cancer, but the threshold for gastrin-stimulated tumor growth was different from that of normal mucosal growth. The hyperplastic response of the fundic mucosa was increased by increasing gastrin doses; whereas, colon cancer hyperplasia was maximal at the lowest dose tested (125 micrograms/kg/day) and did not increase further with increasing doses of hormone. Mice bearing gastrin-stimulated tumors died at a significantly greater rate than did mice with untreated tumors (80% of control mice and none of the treated mice were alive at day 55). The effects of gastrin treatment on the growth of MC-26 colon cancer persist after treatment is discontinued; mice with tumors that were treated with gastrin for either 7 or 14 days and in which the treatment was stopped were all dead by 35 or 28 days, respectively, after the end of treatment.     

Establishment of a human gastrinoma in nude mice

We report the first establishment and characterization of functioning gastrinoma from a human being transplanted into nude mice. Tissue was obtained at operation from a gastrinoma liver metastasis from a patient with the Zollinger-Ellison syndrome. The tumor was implanted subcutaneously in five athymic nude mice. Serum gastrin was measured by means of radioimmunoassay in specimens of mouse blood taken before and 5 minutes after intraperitoneal injection of secretin (100 micrograms/kg). In a second experiment serum gastrin was measured 30 minutes after injection of somatostatin analogue, SMS 201-995 (300 micrograms/kg). Studies were also done in 10 control mice. At passage, the fundus of each tumor-bearing mouse was weighed and examined microscopically. The gastrinoma (tumor line, PT) has been maintained for 34 months through four passages with a tumor doubling time of 37 to 45 days. The histology is similar to the original tumor. Immunocytochemistry showed that PT contained gastrin. In two mice metastasis developed 9 months after implantation. Gastrin levels in mice bearing PT have ranged from 216 to 12,000 pg/ml. Gastrin levels of control mice ranged from 0 to 63 pg/ml. Secretin increased gastrin levels in three of five mice tested and decreased gastrin levels in two mice. Repeat secretin tests showed identical results. SMS 201-995 decreased gastrin levels from basal values. Fundic weight of mice bearing PT (397 +/- 93 mg) was significantly greater than control fundic weight (180 +/- 26 mg). Gastrinomas growing in nude mice produce physiologically active gastrin as shown by elevated serum gastrin levels and by hyperplasia of the stomach. Two distinct subpopulations of gastrinoma cells respond differently to secretin. This model should provide important information on mechanisms of growth control and on gastrin release by gastrinomas in human beings.     

Gastrointestinal hormones and cell proliferation

There is no question that gut peptides are trophic for normal gut mucosa. Gut peptides can function in an endocrine, paracrine or autocrine fashion. We examined th effects of gut peptides on the growth of animal and human cancers of the gastrointestinal (GI) tract and pancreas in vivo and in vitro. We also examined the role of growth factors and bioamines in the regulation of growth of human endocrine tumors. Our studies have shown that gut peptides (gastrin, VIP, neurotensin, and bombesin) regulate growth of some cancers of the GI tract and pancreas. We have found that peptide action is mediated through specific receptors and that cell-specific differences in receptor expression occur. We have also begun to examine the intracellular signal-transduction pathways involved in endocrine and autocrine actions of these peptides on growth of GI cancers. We have found that cell type-specific differences exist among the various signal transduction pathways (cyclic AMP, phosphatidylinositol hydrolysis (PI), intracellular calcium ([Ca²⁺]_i) mobilization and tyrosine phosphorylation) and that different receptors for the same hormone may be linked to different signal transduction pathways depending upon cell type. We have also found that autocrine growth regulation of human pan creatic carcinoid occurs through specific receptor-mediated( signal-transduction pathways. We will discuss the mechanisms of action and potential therapeutic uses of manipulation o: gut hormone levels or hormone antagonists to inhibit the growth of GI tract cancers.     

Bombesin-induced gastroprotection

Bombesin is an endogenous gut peptide that is prominent in the stomach. In addition to its effects on modulating acid and gut peptide secretion, recent evidence indicates that bombesin is a potent gastroprotective agent. This review article examines the ability of bombesin to prevent gastric injury. Its protective actions appear to be mediated primarily via the release of endogenous gastrin, as gastroprotection is negated by blockade of gastrin receptors. Bombesin-induced gastroprotection and gastrin release are modified by somatostatin. Immunoneutralization of endogenous somatostatin increases the ability of bombesin to prevent gastric injury by increasing gastrin release. In mechanistic studies, ablation of capsaicin-sensitive afferent neurons abolishes bombesin-induced gastroprotection while cyclo-oxygenase inhibition partially reverses this effect. Nitric oxide synthase inhibition also negates bombesin-induced gastroprotection as well as the ability of bombesin to increase gastric mucosal blood flow. Taken together, the available evidence indicates that bombesin causes release of endogenous gastrin that activates sensory neurons located in the gastric mucosa. Activation of sensory neurons causes increased production of nitric oxide through activation of constitutive nitric oxide synthase, which leads to a resultant increase in gastric mucosal blood flow and renders the stomach less susceptible to damage from luminal irritants.     

Bombesin improves survival from methotrexate-induced enterocolitis.

OBJECTIVE: The authors determined whether bombesin could improve survival from methotrexate (MTX)-induced enterocolitis. SUMMARY BACKGROUND DATA: Bombesin prevents gut mucosal atrophy, which is produced by feeding rats an elemental diet. Administration of MTX produces a lethal enterocolitis in rats fed an elemental diet. METHODS: On treatment day 0, 60 rats were divided randomly into three groups and fed an elemental diet (Vivonex TEN, Sandoz, Minneapolis, MN) as the only source of nutrition. Groups were subdivided further to receive either saline or bombesin (10 micrograms/kg, subcutaneously, three times a day) beginning either on day 0 or day 14. Methotrexate (20 mg/kg, intraperitoneally) was given to all rats 14 days after the start of an elemental diet. RESULTS: Bombesin prevented the mucosal atrophy in the ileum produced by the elemental diet and significantly decreased mortality in rats given MTX (whether given as a pretreatment or at the time of MTX administration). CONCLUSION: Bombesin significantly improved survival in a lethal model of MTX-induced enterocolitis, possibly by maintaining gut mucosal structure. Administration of bombesin to patients receiving chemotherapy may be clinically useful in preventing the severe enterocolitis induced by various chemotherapeutic agents.     

Source of plasma chromogranin A elevation in gastrinoma patients

Chromogranin A (Cg A) is a protein that is coreleased with peptide hormones from gut endocrine cells and tumors. Plasma levels of Cg A, pepsinogen group I, and gastrin were measured in 31 patients with gastrinoma. Mean Cg A level in 10 patients with gastrinoma who were not operated on was 169 +/- 32 ng/mL, while in 9 control patients it was 28 +/- 5 ng/mL. In 18 patients with gastrinoma with residual tumor after total gastrectomy, the mean Cg A level was 45 +/- 6 ng/mL, and in 10 patients with normal gastrin levels after total gastrectomy and tumor excision, the mean Cg A level was 40 +/- 4 ng/mL. In 7 patients in whom pregastrectomy and postgastrectomy Cg A levels were measured, the mean reduction was 94 +/- 27 ng/mL, or 66%. There was no correlation between Cg A levels and amount of tumor, presence of metastases, or multiple endocrine neoplasia type I syndrome. There was a significant correlation between Cg A and pepsinogen I levels but no correlation between Cg A and gastrin levels. The results suggest that the elevated plasma Cg A levels in patients with gastrinoma are determined primarily by the trophic effects of gastrin on gastric enterochromaffinlike cells rather than by corelease from the gastrin-producing tumor itself.     

Somatostatin analog: effects on hypergastrinemia and hypercalcitoninemia

A somatostatin analog (SMS 201-995) was used to treat symptomatic patients with a residual tumor burden of gastrinoma or medullary thyroid carcinoma and pathologic elevations of circulating marker peptides associated with these neuroendocrine tumors. Possible inhibitory effects of the analog on marker peptides, patients' symptoms, or tumor progression were studied in a dose-response protocol and during several months of self-injection of SMS 201-995. Both patients reported remarkable relief of secretory diarrhea and other symptoms, and serum gastrin was successfully suppressed by increasing doses of the analog. However, no effect was seen in reduction of hypercalcitoninemia. Morphologic imaging of residual tumor showed no progression of medullary thyroid carcinoma during treatment and, in the case of hepatic gastrinoma metastases, remarkable tumor regression was confirmed. No toxicity or glucose intolerance was experienced. Somatostatin analog shows promise for palliative management of endocrinologic symptoms due to neuroendocrine tumors, and an inhibitory effect can be measured in some but not all peptide markers. Further evidence of its negative trophic effect on tumor blood flow may suggest an antineoplastic potential, as well as palliative use of this new treatment.     

Proglumide, a gastrin receptor antagonist, inhibits growth of colon cancer and enhances survival in mice.

Some tumors are responsive to hormone manipulation. Some gastric and colonic adenocarcinomas from both humans and animals have specific gastrin receptors. A transplantable mouse colon adenocarcinoma cell line (MC-26) contains gastrin receptors; growth of MC-26 colon cancer in vivo is stimulated by pentagastrin (PG). The purpose of this study was to determine whether a gastrin-receptor antagonist, proglumide (PGL), would inhibit growth of MC-26 colon cancer and prolong survival in tumor-bearing mice. Subcutaneous tumors were induced by injecting single-cell suspensions of MC-26 cells into 50 mice divided into 10/group. In Experiment 1, all mice received 1 X 10(5) tumor cells and treatment groups were divided as follows: Group A received intraperitoneal (IP) saline (0.2 ml tid beginning on day 1); B, IP, PGL (250 mg/kg tid) from day of tumor cell inoculation; and C, IP PGL (250 mg/kg tid) from day 7 after tumor implantation. In Experiment 2, mice were inoculated with half the number of tumor cells. Group I mice received saline and Group II received PGL in the same manner starting on day 1. Tumors were measured and all mice were sacrificed on day 23. In Experiment 1, mean tumor area in Group B (PGL-treated) was significantly smaller than Group A on days 11, 14, 17, and 21. Tumors of Group C were significantly smaller than controls on day 21. Survival of PGL-treated mice was significantly prolonged. In Experiment 2, mean tumor area, mean tumor weight, and tumor DNA and RNA content were significantly less in the PGL-treated group than control. It was concluded that growth of a gastrin-responsive colon cancer was inhibited and host survival was enhanced by treatment with a gastrin-receptor antagonist. Hormone manipulation may be a useful treatment for gastrointestinal cancers.     

Inhibition of growth of PC-82 human prostate cancer line xenografts in nude mice by bombesin antagonist RC-3095 or combination of agonist [D-Trp6]-luteinizing hormone-releasing hormone and somatostatin analog RC-160.

The effects of treatment with a bombesin receptor antagonist [D-Tpi6, Leu13 psi (CH2NH) Leu14]BN(6-14)(RC-3095) and the combination of an agonist of luteinizing hormone-releasing hormone [D-Trp6]-LH-RH and somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val- Cys-Trp-NH2 (RC-160) were studied in nude mice bearing xenografts of the hormone-dependent human prostate tumor PC-82. During the 5 weeks of treatment, tumor growth was decreased in all treated groups compared with controls. Bombesin antagonist RC-3095 and the combination of [D-Trp6]-LH-RH and RC-160 caused a greater inhibition of tumor growth than [D-Trp6]-LH-RH or RC-160 alone as based on measurement of tumor volume and percentage change in tumor volume. The largest decrease in tumor weight was also seen in the groups treated with the bombesin antagonist and with the combination of RC-160 and [D-Trp6]-LH-RH. Serum prostatic-specific antigen levels were greatly decreased, and insulin-like growth factor I (IGF-I) as well as growth hormone levels were reduced in all treated groups. Specific binding sites for [D-Trp6]-LH-RH, epidermal growth factor (EGF), IGF-I, and somatostatin (SS-14) were found in the tumor membranes. Receptors for EGF were significantly down-regulated by treatment with the bombesin antagonist or RC-160. Combination of LH-RH agonists with somatostatin analog RC-160 might be considered for improvement of hormonal therapy for prostate cancer. The finding that bombesin antagonist RC-3095 inhibits the growth of PC-82 prostate cancer suggests the merit of further studies to evaluate the possible usefulness of antagonists of bombesin in the management of prostatic carcinoma.     

Somatostatin-like peptides alter calcium but not secretin sensitivity of gastrinoma cells

The provocation of gastrin release by calcium or secretin is accepted as a method to differentiate the hypergastrinemia of the Zollinger-Ellison syndrome from that of other causes. We have previously shown that calcium and secretin failed to provoke gastrin release from acutely dispersed gastrinoma cells. This disparity between the in vivo and in vitro effects of these two provocative agents suggests that intermediates may be necessary for calcium- or secretin-induced gastrin release. In an acute cell dispersion, serum-free model, two gastrinomas with low levels of endogenous somatostatin (SRIF) and other peptides failed to respond to calcium or secretin provocation. Conversely, a third tumor containing high levels of endogenous SRIF-like peptides and low levels of other gut peptides did respond to calcium, but not to secretin provocation in vitro. We suggest that in vivo, SRIF modulation of gastrin release is a prerequisite for calcium-simulated gastrin secretion.     

Bombesin: A vagally independent stimulator of gastrin release

In this study we demonstrate that bombesin is a potent stimulant of canine gastrin and gastric acid secretion. Bombesin was shown to release almost fourfold more gastrin than a meal by a mechanism which is independent of vagal integrity. An exogenously administered cholinomimetic agent released only minimal amounts of gastrin after vagotomy and virtually none in the intact canine model. The combination of bombesin and bethanechol caused a significant increase in acid secretion compared with bombesin alone and was associated with a marked inhibition of gastrin release both before and after vagotomy. Gastric acid secretion in response to bombesin was not significantly altered by vagotomy. We interpret these data to reflect the sensitivity of bombesin-stimulated gastrin release to gastric luminal pH, although they also suggest the existence of a cholinergic inhibitory mechanism for gastrin release.The data provided by this study are consistent with the hypothesis that bombesin might function as a paracrine neuromodulator of gastrin release. In view of its presence in the nerves and mucosa of human stomach and its potent actions on gastrin release and gastric acid secretion, bombesin may play a role in gastric physiology.     

Elemental diet-induced bacterial translocation can be hormonally modulated.

BACKGROUND: The authors have previously documented that feeding mice an elemental diet resulted in bacterial translocation (BT) that could be prevented by the provision of dietary fiber. To test whether the protective effect of fiber was related to the stimulation of trophic gut hormones, the effects of sandostatin and bombesin were tested. METHODS: Mice fed either chow or the elemental diet were stratified into several groups and the ability of bombesin (10 micrograms/kg, tid) or sandostatin (100 micrograms/kg bid) to modulate BT was examined. After 14 days, mice were sacrificed and BT, cecal bacterial population levels, mucosal protein, and small bowel weight was measured. Segments of the ileum and jejunum were examined histologically. RESULTS: Incidence of elemental diet-induced BT (75%) was reduced by fiber (9%) or the administration of bombesin (13%) (p < 0.01). Although sandostatin did not promote BT in chow-fed mice, it reversed the protective effect of fiber on BT (75%) (p < 0.01). CONCLUSION: Elemental diet-induced bacterial translocation can be modulated hormonally and the beneficial effects of fiber on diet-induced BT appears to be hormonally mediated.     

Effect of bombesin on plasma cholecystokinin in normal persons and gastrectomized patients measured by sequence-specific radioimmunoassays

Since bombesin is known to stimulate pancreatic enzyme secretion and gallbladder contraction, we have measured plasma cholecystokinin (CCK) concentrations during bombesin infusion using sequence-specific radioimmunoassays. Antibody 1703 binds to COOH terminal CCK peptides containing at least 14 amino acid residues, while antibody T204 is specific for the sulfated tyrosine region of CCK. In nine normal persons infusion of increasing doses of bombesin (2.4, 6, 18, and 60 pmol/kg X 20 min) induced dose-related integrated plasma CCK responses (58.5 +/- 9.7, 70.5 +/- 12.2, 79.5 +/- 11.1, and 101.4 +/- 15.4 pmol/L X 20 min [antibody 1703] and 50.4 +/- 11.9, 62.0 +/- 13.4, 74.7 +/- 9.2, and 116.1 +/- 11.3 pmol/L X 20 min [antibody T204]). Infusion of 60 pmol bombesin/kg X 20 min in eight patients with partial gastrectomy resulted in similar increases in plasma CCK (8.1 +/- 1.8 pmol/L, antibody 1703; 9.5 +/- 2.0 pmol/L, antibody T204) as in eight normal control subjects (6.5 +/- 0.9 pmol/L, antibody 1703; 8.8 +/- 1.0 pmol/L, antibody T204). During infusion of bombesin, plasma gastrin levels increased from 16.7 +/- 1.4 to 49.6 +/- 8.1 pmol/L (P less than 0.005) in the normal persons, while there was no significant change in plasma gastrin levels in gastrectomized patients. Bombesin did not significantly influence gastric acid secretion in three patients with partial gastrectomy studied. It is concluded that infusion of bombesin releases CCK in humans by a gastrin-independent mechanism.     

Gastrinomas demonstrate amplification of the HER-2/neu proto-oncogene.

OBJECTIVE: This study determined whether genomic amplification of HER-2/neu or mutations of the p53 and ras genes were present in gastrinomas. SUMMARY BACKGROUND DATA: Amplification of HER-2/neu, a proto-oncogene related to the epidermal growth factor receptor, and mutation of the ras proto-oncogene and p53 tumor suppressor gene appear to play a role in the pathogenesis of some human cancers. Little is known about possible molecular alterations in gastrinomas, tumors that may be particularly virulent because of gastrin overproduction, resulting in the severe ulcer diathesis, the Zollinger-Ellison syndrome. METHODS: The differential polymerase chain reaction (PCR) procedure was used to detect amplification of the HER-2/neu gene in DNA samples from the novel human gastrinoma cell line (PT) and from paraffin-embedded samples of gastrinomas. Sequencing techniques were used to determine whether mutations of the p53 or ras (Ha-ras, N-ras, Ki-ras) genes were present. RESULTS: Amplification (> twofold) occurred in all gastrinoma tumor samples. Compared with normal pancreas or ileum, a 4- to 12-fold amplification of HER-2/neu was found in 3 gastrinomas, 3 to 3.3-fold in four samples and 2.1- to 2.4-fold in the remaining five tumors. A heterozygous point mutation in the p53 gene (codon 273) was found in a single sample; none of the gastrinomas contained a mutation of the ras genes. CONCLUSIONS: Amplification of the HER-2/neu gene, but not alterations of either p53 or ras, may be involved in the pathogenesis of gastrinomas. The unique PT cell line will be a useful model to further elucidate the molecular mechanisms that contribute to gastrinoma formation and growth.     

Regression of Type II Gastric Carcinoids in Multiple Endocrine Neoplasia Type 1 Patients with Zollinger-Ellison Syndrome after Surgical Excision of All Gastrinomas

Enterochromaffin-like (ECL) tumors are documented in patients with hypergastrinemia secondary to chronic atrophic gastritis or with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1 (ZES-MEN-1). In patients with ECL tumors and atrophic gastritis, normogastrinemia after antrectomy has resulted in resolution, regression, or stabilization of ECL tumors. The natural history of ECL tumors associated with ZES-MEN-1 following normalization of gastrin levels after gastrinoma resection has not been previously reported. The purpose of this study was to determine the course of ECL tumors in patients with ZES-MEN-1 following normalization of serum gastrin levels after gastrinoma resection. Two patients with ZES-MEN-1 had biopsy-proven ECL tumors on endoscopic evaluation. They then underwent surgical exploration that included distal pancreatectomy, enucleation of pancreatic head tumors, duodenotomy with excision of submucosal tumors, and peripancreatic lymphadenectomy. Gastric ECL tumors larger than 1.0 cm were locally excised. Patients underwent long-term follow-up with biochemical and endoscopic surveillance. Normogastrinemia was achieved and sustained following gastrinoma resection in two patients with ZES-MEN-1. Periodic endoscopic surveillance over a 6-year period showed complete resolution of the ECL tumors. The development of ECL tumors associated with ZES-MEN-1 is multifactorial. Studies identified a genetic influence on tumor growth with loss of heterozygosity at the MEN-1 gene locus in ECL tumors. The resolution of ECL tumors in ZES-MEN-1 patients who are normogastrinemic indicates that an elevated gastrin level is a primary initiator for development of these tumors. Therefore both genetic defects and hypergastrinemia are causative agents. Normalization of serum gastrin levels is critical for the prevention of aggressive forms of ECL tumors.     

TNP-470对裸鼠体内人结肠癌细胞增殖和凋亡的影响

目的 研究TNP-470对裸鼠体内人结肠癌细胞增殖和凋亡的影响。方法 将16只人结肠癌皮下移植瘤裸鼠随机分成实验组和对照组，实验组隔日予以TNP-47030mg/kg，皮下注射，对照组予以相同体积的生理盐水，4周后处死，应用免疫组织化学法（免疫组化）和图象分析技术检测肿瘤细胞中增殖细胞核抗原（PCNA）的表达，TdT介导的dUTP缺口末端标记（TUNEL）法检测肿瘤细胞的凋亡，透射电镜观察凋亡细胞的超微结构。结果 TNP-470明显抑制了肿瘤的生长，抑瘤率为45.53%。实验组肿瘤中PCNA的表达显低于对照组，凋亡指数上升，电镜下可见典型的细胞凋亡形态学变化。结论 TNP-470除了通过抗血管生成作用抑制肿瘤生长外，还可通过抑制LOVO细胞本身的增殖和诱导凋亡发挥抗肿瘤作用。