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Effects of Bombesin on Growth of Human Small Cell Lung Carcinoma in Vivo1

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Effects of Bombesin on Growth of Human Small Cell Lung Carcinoma in Vivo1 (CANCER RESEARCH 48, 1439-1441, March 15, 1988] Effects of Bombesin on Growth of Human Small Cell Lung Carcinoma in Vivo1 Robert W. Alexander, James R. Upp, Jr., Graeme J. Poston,2 Vicram Gupta, Courtney M. Townsend, Jr.,3 and James C. Thompson Department of Surgery [R. W. A., J. R. V., G. J. P., C. M. T., J. C. T.] and Department of Internal Medicine [V. G.J, The University of Texas Medical Branch, Galveston, Texas 77550 ABSTRACT léñate(30HM)],HITES supplemented with bombesin or argi nine vasopressin, as well as in serum-supplemented media, Bombesin-like peptides are found in many different human tumors and suggesting that SCLC secrete an autocrine growth factor (15). are thought to function as an autocrine growth factor for small cell lung cancer in humans. In this study, a human small cell lung carcinoma (NCI- Cuttitta and colleagues (16) developed a monoclonal antibody H69) was s.c. implanted bilaterally into the flanks of 12 nude mice. The against a synthetic analogue of amphibian bombesin. This mice were randomized and divided into two groups and given either antibody inhibited the growth of a xenografted SCLC (NCI- bombesin (20 Mg/kg) or saline i.p. 3 times a day. Tumor areas were N592) in nude mice and inhibited cloning of SCLC cell lines measured twice weekly for 6 wk. At sacrifice, the tumors and normal in soft agarose in vitro. Analysis of membrane preparations of pancreas were excised, weighed, and assayed for DNA, KN'A,and protein both rat brain and SCLC revealed the antibody blocked a content. Significant stimulation of rumor growth was observed at weeks specific bombesin receptor. 4, 5, and 6. Tumor weight at sacrifice was significantly elevated (77%) Specific receptors for bombesin have been demonstrated on above the control, as was DNA content (78%). Bombesin significantly the Swiss 3T3 fibroblasts (17) as well as in the rat brain (18), increased the weight (42%), DNA (48%), and protein (61%) contents of guinea pig pancreatic acini (19), rat pituitary (20), and human the normal mouse pancreas. We conclude that bombesin may act as an small cell tumors and cell lines (5, 16, 21). autocrine growth factor, or indirectly through the release of other growth factors, on human small cell lung carcinoma. The purpose of our study was to determine whether exoge nous administration of bombesin would affect the growth of a human SCLC growing in nude mice. INTRODUCTION It is estimated that lung cancer will cause approximately 136,000 deaths in the United States in 1987 (1). SCLC4 or oat MATERIALS AND METHODS cell carcinoma accounts for approximately 20% of the classified Animals. Male athymic nude BALB/c mice (21-24 g) were purchased lung tumors (2). Many SCLC have been found to contain from Life Sciences, St. Petersburg, FL. The mice were housed in a bombesin-like immunoreactivity (3-10). Bombesin is a 14- specific pathogen-free, temperature-controlled isolation compound and amino acid peptide initially isolated from two European frogs, were exposed to a light-controled day (lights on, 0700-1900 h). Diet Bombina bombino and Bombina veriegata veriegata (10). Bom was composed of standard chow (Autoclavable Rodent Chow No. 5010; besin-like immunoreactivity is not specific for SCLC; other Ralston Purina, St. Louis, MO) and water given ad libitum. tumors of neuroendocrine (bronchial and gastrointestinal car- Tumor. A human SCLC (NCI-H69) (American Type Culture Collec tion, Rockville, MD), which contains bombesin-like immunoreactivity cinoids) and nonneuroendocrine origin (squamous, large cell, (3, 4), was xenografted as 2-mm2 pieces s.c. through an interscapular and adenocarcinoma of the lung) have been found to contain bombesin-like immunoreactivity (7-10). However, bombesin- incision bilaterally into the flanks (two tumors per mouse) of 12 anesthetized mice. Mice were weighed weekly, tumors were measured like immunoreactivity has been found in elevated concentra twice weekly with calipers, and tumor surface areas were calculated tions in SCLC when compared with other tumors (3-6, 9). using the product of the two greatest perpendicular tumor diameters. Bombesin stimulates in vitro proliferation of 3T3 mouse Tumor doubling times were calculated from semilogarithmic graphs of fibroblasts (11) and of epithelial cells from the normal human tumor area versus day from implantation. At termination of the exper bronchus (12). GRP, the mammalian counterpart of bombesin, iment, mice were sacrificed by cervical dislocation followed by excision has recently been shown to serve as a mitogen for SCLC cell of tumors and pancreas. Tissues were frozen in liquid nitrogen and lines in vitro (13). The carboxyterminal fragment (GRPI4~27), stored at —70°Cuntilassay. which exhibits significant homology to bombesin, appears to Drugs. Mice with implanted tumors were randomized and divided be the active site, since GRP1"16 does not act as a mitogen (13). into two groups, each receiving 0.1 ml i.p. injections 3 times per day. The control mice received saline with 0.1% bovine serum albumin Bombesin, when added to cultures of SCLC, stimulates colony (Calbiochem, La Jolla, CA), and the mice in the treatment group formation in soft agarose (14). Media taken from established received bombesin tetradecapeptide in 0.1% bovine serum albumin (20 cultures of SCLC stimulated the soft agarose cloning of SCLC Mg/kg) (Sigma Chemical Co., St. Louis, MO). in serum-free HITES medium [RPMI Medium 1640 supple Biochemical Assays. Tissues were extracted for measurement of mented with hydrocortisone (10 nM), bovine insulin (5 fig/ml), DNA, RNA, and protein (22). DNA was measured by the Burton transferrin (10 ^g/rnl), 17/î-estradiol(10 nM), and sodium se- modification of the diphenylamine procedure, with calf thymus DNA as a standard (23). RNA was measured using the orcinol procedure and Received 8/31/87; revised 11/30/87; accepted 12/11/87. yeast RNA as a standard (24). Protein was determined by the method The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in of Lowry and colleagues (25). accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Statistical Analysis. Statistical significance was determined by the 1Supported by grants from N1H (ROÕDK 15241, POI DK 35608, and RCDA Kruskal-Wallis analysis of variance. A value of P< 0.05 was considered CA 00854), from the American Cancer Society (PDT-220), and from the National to be significant. Cancer Institute (CA 17701). 'Visiting Scientist from the Department of Surgery, Royal Postgraduate Medical School, University of London, London, United Kingdom. Supported by the Wellcome Foundation, Ethicon Foundation, and British Digestive Founda RESULTS tion. 3To whom requests for reprints should be addressed. 4 The abbreviations used are: SCLC, small cell lung cancers; GRP, gastrin- The body weights in both groups increased by approximately releasing peptide. 87% over the 6-wk study period and were not significantly 1439 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1988 American Association for Cancer Research. BOMBESIN AND HUMAN SMALL CELL LUNG CANCER different from each other. Tumor growth was seen in 8 of 12 DISCUSSION tumors implanted in each group. Bombesin reduced the tumor cell doubling time by 24% from We found that bombesin produced significant stimulation of 7.5 days in the control to 5.75 days in the treated group. growth of a human SCLC and the normal mouse pancreas. The Bombesin produced significant stimulation of tumor growth; tumor cell line that we studied has been reported to contain the areas increased from weeks 4-6 (Fig. 1). At sacrifice, both bombesin-like immunoreactivity (3, 4). The importance of our tumor weight (77%) (Fig. 2) and tumor DNA content (78%) study is that, to our knowledge, this is the first demonstration (Fig. 3) were significantly stimulated above the control group. that exogenous bombesin stimulates growth of human SCLC in vivo. Our findings support and extend the work of Cuttitta Tumor RNA and protein content were also increased (67 and and colleagues (16) who suggested that bombesin-like peptides 32%), although they were not significantly different from con trol (Table 1). may act as autocrine growth factors in SCLC. Bombesin significantly increased the weight (42%), protein We and others have previously shown that bombesin stimu lates growth of the normal rat pancreas (26-29). In the present (61%), and DNA content (48%) of the normal mouse pancreas study, bombesin (20 ¿tg/kgi-p-3 times a day) produced hyper- (Table 1). plasia of the normal mouse pancreas which was characterized 150^120¿ by significant increases in weight, DNA, and protein content. The mechanism by which exogenous bombesin induces growth may involve both a direct effect of bombesin and an indirect :< effect through bombesin-mediated release of cholecystokinin 90K (27, 29). Although we have demonstrated stimulation of human SCLC CO§\1 «0¡ growth In vivo, we have not used a bombesin receptor antagonist to show inhibition of bombesin stimulated growth. The syn 30*rira thetic peptide, spantide [(o-Arg1, o-Pro2, o-Trp7-9, Leu") sub reulu1234WEEKS.Li*I_ä8iÈ¡LU stance P], inhibits the in vitro effects of bombesin (17, 30, 31); however, the nonspecificity of action and lack of potency limit the use of spantide in vivo (32). We have found that bombesin Fig. 1. Tumor area in relation to time from implantation. Values, mean ± does not stimulate the growth of a human colon cancer growing SEM (n = 8 in each group; *, P < 0.05). in nude mice,5 suggesting it may be specific for tumors with bombesin receptors. Bombesin has been implicated as a mitogen or as an autocrine growth factor for normal and malignant cells (11-17).
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