Vasoactive intestinal peptide inhibits human small-cell lung cancer proliferation in vitro and in vivo.

Small-cell lung carcinoma (SCLC) is an aggressive, rapidly growing and metastasizing, and highly fatal neoplasm. We report that vasoactive intestinal peptide inhibits the proliferation of SCLC cells in culture and dramatically suppresses the growth of SCLC tumor-cell implants in athymic nude mice. In both cases, the inhibition was mediated apparently by a cAMP-dependent mechanism, because the inhibition was enhanced by the adenylate cyclase activator forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine in proportion to increases in intracellular cAMP levels, and the inhibition was abolished by selective inhibition of cAMP-dependent protein kinase. If confirmed in clinical trials, this antiproliferative action of vasoactive intestinal peptide may offer a new and promising means of suppressing SCLC in human subjects, without the toxic side effects of chemotherapeutic agents.

Common bile duct stones: management strategies in the laparoscopic era.

We reviewed our experience with the treatment of common bile duct (CBD) stones in 70 patients by sequential endoscopic-laparoscopic management and single-stage laparoscopic treatment during the past 7 years. The advantages, disadvantages, and feasibility of the two procedures are discussed to elucidate therapeutic strategies for patients harboring gallbladder stones and associated choledocholithiasis. In 44 patients, sequential endoscopic-laparoscopic management was indicatedd, and was successful in 37 of them but, in seven patients endoscopic stone extraction could not be accomplished. Single-stage laparoscopic treatment was attempted in 26 patients. In practice, laparoscopic transcystic common duct exploration or choledochotomy may not always be feasible if the cystic duct or CBD are not dilated; there is a high risk of intraoperative CBD injury in such circumstances. Laparoscopic management was considered to be especially useful for the treatment of numerous, large or difficult stones, because stone removal could be succesfully performed without any injury to the papilla of Vater. This last issue is of particular importance in patients with dilated CBD, because insufficient opening of the ampulla of Vater made by endoscopic sphincterotomy (EST) may lead to stasis and reflux-related complications such as cholangitis and recurrent stones. We conclude that the most rational management of CBD stones should be decided according to the size of the CBD, which depends on the size, number, and location of stones. Patients with dilated CBD are indicated to under-go laparoscopic single-stage treatment and combined endoscopic-laparoscopic treatment may be best for patients with non-dilated CBD.

VIP inhibits basal and histamine-stimulated proliferation of human airway smooth muscle cells.

Airway smooth muscle (ASM) cell proliferation contributes to increased airway resistance in bronchial asthma. We have examined the modulation of ASM proliferation by vasoactive intestinal peptide (VIP), a cotransmitter of airway relaxation. Human ASM cells were grown in culture as a monolayer. VIP (1.0 nM-1.0 microM) inhibited proliferation in a dose-dependent manner by up to 82% on day 2, but the related peptide glucagon had no effect. Histamine (100 nM-100 microM) increased cell counts by 66%, but in the presence of VIP, cell counts and [3H]thymidine incorporation were reduced by up to 55%. Adenosine 3',5'-cyclic monophosphate (cAMP)-promoting agents, including 3-isobutyl-1-methylxanthine, forskolin, and 8-bromo-adenosine 3',5'-cyclic monophosphate, alone and especially combined with VIP, reduced cell counts and [3H]thymidine incorporation, in correlation with cAMP levels. KT-5720 (1.0 nM-1.0 microM), a selective inhibitor of cAMP-dependent protein kinase A (PKA), abolished the inhibitory effect of VIP. The results show that VIP selectively and potently inhibits human ASM cell growth and multiplication, and nullifies the mitogenic effect of histamine, by a PKA-mediated mechanism. A deficiency of VIP may lead to ASM hyperplasia due to unopposed stimulation by endogenous mitogens.

Small-cell lung carcinoma: inhibition of proliferation by vasoactive intestinal peptide and helodermin and enhancement of inhibition by anti-bombesin antibody.

Small-cell lung cancer (SCLC) is a common and highly fatal malignancy for which there is no satisfactory treatment. The amphibian peptide bombesin and its mammalian counterpart, gastrin-releasing peptide, serve as autocrine growth factors for the SCLC cells, but little is known about endogenous substances that inhibit the growth and proliferation of these tumor cells. We report that the neuropeptide vasoactive intestinal peptide (VIP) markedly inhibits the growth and multiplication of SCLC cell lines NCI-H345 and NCI-H69, and that the closely related peptide helodermin inhibits the proliferation of NCI-H345 cells with even higher efficacy. In the latter cells, the inhibition by VIP and isobutyl methyl xanthine paralleled their ability to stimulate cyclic adenosine monophosphate production within the cells. The peptide-induced suppression of SCLC proliferation is enhanced in the presence of an anti-bombesin monoclonal antibody. The antimitogenic activities of VIP and helodermin, and their enhancement by anti-bombesin antibody, offer the potential for a new approach to the pharmacologic control of SCLC.

[Gastrin-releasing peptide as a specific tumor marker in patients with small cell lung carcinoma, compared with neuron-specific enolase].

A sensitive radioimmunoassay (RIA) system for plasma gastrin-releasing peptide (GRP) was developed using immune-affinity chromatography for plasma extraction. Plasma neuron-specific enolase (NSE) levels were determined by use of RIA without extraction. Plasma GRP levels in 12 control subjects were (mean +/- SD) 1.2 +/- 0.26pg/ml. Plasma GRP levels were elevated at frequencies of 79% in untreated patients with small cell lung carcinoma (SCLC). The levels in 21 patients with non-SCLC were not elevated. In nine of 10 patients with complete response (CR) or partial response (PR), plasma GRP levels decreased significantly when the patients were judged to have achieved CR or PR. In four patients with progressive disease (PD), the levels were elevated after treatment when compared with levels before treatment. In six of 10 patients with CR or PR, plasma NSE levels decreased significantly at the judgment of CR or PR. In two of four patients with PD, the levels were elevated after treatment. Furthermore, changes in plasma GRP level showed more excellent correlation with the therapeutic response than changes in plasma NSE level in the clinical courses of two patients with CR and a patient with PD. These results suggest that the plasma GRP level could be a useful tumor marker in SCLC patients.

Immunoreactive gastrin-releasing peptide as a specific tumor marker in patients with small cell lung carcinoma.

Gastrin-releasing peptide (GRP) is now known to be a very common product of small cell lung carcinoma (SCLC). With the aim of investigating the possible role of this peptide as a tumor marker of SCLC, we have developed a sensitive radioimmunoassay system for plasma immunoreactive GRP using immune-affinity chromatography for plasma extraction. Plasma immunoreactive GRP levels in control subjects were determined by using 15 ml of plasma as the starting material (minimum concentration detectable, 0.8 pg/ml). The levels in 10 control subjects were (mean +/- SD) 1.2 +/- 0.27 pg/ml; range, 0.86-1.7 pg/ml. This assay system was applied for the clinical use by using 3 ml of plasma as the starting material (minimum concentration detectable, 4.0 pg/ml). Plasma immunoreactive GRP levels were elevated in SCLC patients at frequencies of 71% in patients with limited disease and 80% in those with extensive disease. Furthermore, a change in the level showed excellent correlation with the therapeutic response. In six patients with complete response who had had elevated levels before treatment, the levels decreased to an undetectable range when the tumor disappeared, and they remained undetectable until 1 month later, when the patients were judged to have achieved complete response. In the partial response group, plasma immunoreactive GRP levels had decreased to an undetectable level in two of three patients, when the patients achieved partial response. In four patients with progressive disease, plasma immunoreactive GRP levels were elevated at the time of the progressive disease judgment, when compared with levels before treatment. The levels in 21 patients with non-SCLC (10 with adenocarcinoma, seven with squamous cell carcinoma and four with large cell carcinoma) were not elevated. These results indicate the plasma immunoreactive GRP level as a useful tumor marker in SCLC patients. It is now believed that GRP can function as an autocrine growth factor for SCLC. The present study suggests that the possible autocrine growth factor could serve as a reliable tumor marker for cancer patients.

Peptide hormone production in small cell lung carcinomas with particular reference to gastrin-releasing peptide.

Tissues of 50 small cell lung carcinomas were examined for production of 17 peptide hormones. Only when the concentration of a peptide detected in the tumor was 10 pmol or more per g wet weight, was the peptide considered to be produced by the tumor. The frequency of production of at least one of these peptide hormones was 84%, and that of two or more hormones was 50%. These results indicate that peptide hormone production is a very common phenomenon in small cell lung carcinoma. Of the peptide hormones examined, gastrin-releasing peptide is produced with the highest frequency, suggesting that this peptide could play an important role in small cell lung carcinoma.

Twenty-four-hour variations of plasma pancreatic polypeptide, insulin and glucagon in normal human subjects.

Twenty-four-hour variations of plasma hPP levels together with plasma glucose, IRI and GI levels were studied in four normal human subjects. Before examination, their food intakes were strictly controlled during two days' hospitalization. Plasma hPP values were assayed by a radioimmunoassay. They showed sharp peaks after each meal. Mean levels of hPP just prior to breakfast were 88 +/- 26 pg/ml (SEM), and the peak values of the plasma hPP one hour after each meal were 307 +/- 124 pg/ml, 398 +/- 77 pg/ml, and 544 +/- 118 pg/ml, respectively. During the nocturnal sleeping period the hPP levels were stable and returned to the fasting level of the previous morning. IRI increased significantly after each meal, but no significant change was found in plasma GI levels.