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Somatostatin Analogues and Bombesin/Gastrin-Releasing Peptide Antagonist RC-3095 Inhibit the Growth of Human Glioblastomas in Vitro and in Vivo1

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Somatostatin Analogues and Bombesin/Gastrin-Releasing Peptide Antagonist RC-3095 Inhibit the Growth of Human Glioblastomas in Vitro and in Vivo1 [CANCERRESEARCH54, 5895-5901, November 15, 19941 Somatostatin Analogues and Bombesin/Gastrin-releasing Peptide Antagonist RC-3095 Inhibit the Growth of Human Glioblastomas in Vitro and in Vivo1 Jacek Pliiski, Andrew V. Schally,2 Gabor Halmos, Karoly Szepeshazi, and Kate Groot Endocrine,Polypeptideand Cancerinstitute, VeteransAffairsMedical Center,New Orleans,Louisiana70146and Sectionof ExperimentalMedicine,TulaneUniversitySchoolof MedIcine. New Orleans, Louisiana 70112 ABSTRACT The expression of receptors for EGFS1 and IGF-I and IGF-II in human brain tumors, including malignant gliomas, is also well established (4, We Investigated the effects of somatostatin analogues and a synthetic 8—15).Itthusappearsthat sex steroidsand growth factorsmight be bombethilgastrln-releasing peptide (GRP) antagonist on the growth of the involved in the proliferation of brain tumors. Some types of brain human m@Ilgnantgiloma cell lines U-87MG and U-373MG transplanted tumors, such as astrocytomas and meningiomas, contain significant to nude mice or cultured in vitro. Nude mice bearing s.c. Implanted U-87MG or U-373MG tumors were treated for 4 and 6 weeks, respec levels of high-affinity receptors for bombesin/GRP or somatostatin lively, with various somatostatin analogues or bombesin/GRP antagonist (16—23).Thesefindingssuggestthe needfor investigationstodeter RC-3095. Soniatostatin analogues RC-160, RC-160-ll, and RC-101-I, mine the effects of somatostatin analogues and bombesin/GRP given s.c@Indoses of 100 pg/@nlmal/day,Inhibited the growth of U-S7MG antagonists on the growth of brain tumors. xenografts as shown by more than 60% reduction In tumor volumes and Potent octapeptide analogues of somatostatin and pseudononapep 45%reductIonIntumorweightscomparedwiththecontrolgroup.Bomb tide antagonists of bombesin/GRP have been synthesized in our esIn@RP antagonist RC-3095, given s.c. at a dose of 20 pg@an1maltwice laboratory (24—26).Somatostatin analogues RC-160, RC-160-II, and daily, had the greatest inhibitory effect and decreased tumor volumes and RC-101-I are about 100 times more potent than somatostatin in tests weights by approximately 79% and 72%, respectively. The growth of for inhibition of GH release in rats, and possess a prolonged duration U-373MG xenografts was also significantly Inhibited by treatment with of action (25). [D-Tpi6,Leu13uI@CH2NH)'4]bombesin(6-14)(RC-3095)is analogue RC-160 or antagonist RC-3095. The mean survival time of nude mice, Inoculated orthotopically with U-S7MG cells Into the brain, was a short-chain pseudononapeptide bombesin antagonist (26). This asia significantly prolonged by 4.9 days by treatment with antagonist RC-3095. logue blocks GRP-stimulated amylase release from rat pancreatic acini, @ Serum levels In nnhnals bearing U-S7MG tumors, treated with binds to Swiss 3D fibroblasts and H-345 small-cell lung carcinoma cells, antagonist RC-3095 or somatostatin analogues, were decreased compared and inhibits GRP-stimulated growth of these cells in vitro (26). Various with controls. All three somatostatin analogues also reduced serum findings suggest that somatostatin analogues as well as bombesin/GRP growth hormone levels. Receptor analyses demonstrated high-aMnity antagonists may inhibit the growth of several cancers by interfering with binding sites for bombesin, somatostatin, and epidermal growth factor on the action, secretion, signal transmission, or receptors of endogenous membranes of U-87MG and U-373MG tumors. The concentration of growth factors (24—31).Previously, we have shown that both types of bindingites for epidermal growth factor on both tumors was significantly these peptide analogues can significantly inhibit the growth of gastric, deciaiiid after in vivo treatment with antagonist RC-3095 or the soma tostatin analogues. In studies in vitro, RC-3095, added to the culture pancreatic, mammary, prostatic, and lung cancers in vivo (27—31).This medium, significantly IHifihited the proliferation of U-S7MG and antitumor effect ofbombesin/GRP antagonist and somatostatin analogues U-373MG cells In the presence of GRP(14-27), as measured by cell nuns was associated with a significant down-regulation of EGF receptors on ber, but only a moderate suppression of growth of both cell lines was membranes of these tumors. observed with somatostatin analogue RC-160. These results demonstrate In this study, we have evaluated the effects of somatostatin ana that bosnbeslnlGRP antagonist RC-3095 and somatostatin analogues such logues RC-160, RC-160-II, and RC-101-I and bombesinlGRP antag as RC-160 can Inhibit the growth of human glioblastoma ecU lines omst RC-3095 on the growth of xenografts of the human malignant U-87MG and U-373MG in vim, as well as in vivo. Our work suggests the glioma cell lines U-87MG and U-373MG in athymic nude mice. To merit of fUrther Investigations of these analogues for the possible devel clarify the mechanisms of antitumor action of these agents, detailed opment of new approaches for treatments of patients with malignont receptor status and histological examinations were performed. We also examined the effects of RC-160 and RC-3095 on serum GH and gastrmnlevels because the growth of brain tumors may be promoted by INTRODUCTION GH through stimulation of IGF-I (32), as well as by gastrin, since Malignant astrocytomas or glioblastomas represent the most com evidence exists for the presence of gastrmn and gastrin receptors in mon type ofprimary braintumorin adults(1, 2). Morethanhalfof the human brain (33, 34). In addition, possible direct effects of RC-3095 glial tumors of adults are malignant astrocytomas (1, 2). Surgery, and RC-160 on proliferation of U-87MG and U-373MG cells in vitro radiation, and chemotherapy are of limited effectiveness in the treat were evaluatedin tissue cultures. ment of malignantgliomas and othertherapeuticapproachesmust be explored. That glioblastomas and other brain tumors are hormone MATERIALS AND METHODS sensitive is supported by epidemiological, clinical, and laboratory evidence (3—7).The presence of receptors for glucocorticoid, andro Peptides gen, and progesteronein glioblastomas has been documented(4—7). Somatostatin analogues D-Phe--C)@s-Tyr--D-Trp-Lys-Val-Cys--Trp-NH2 Received 6/20/94; accepted 9/27/94. (RC-160), N-acetyl-D-Phe-C@s-Tyr-D-Trp-Lys-Val--Cy@--Trp-NH2(RC Thecostsofpublicationofthisarticleweredefrayedinpartby thepaymentofpage 160-I! correspondingtoacetylatedRC-160),and N-acetyl-Phe-C@s-Phe-D charges.Thisarticlemustthereforebeherebymarkedadvertisementinaccordancewith 18 U.S.C Section 1734 solely to indicatethis fact. Trp—Lys—Thr--C@rs-Thr-NH2(RC-101-I),originally synthesized by us (35), 1 This work was supported by the Medical Research Service of the Veterans Affairs were made by classical synthesisby Novabiochem(Laufingen,Switzerland) [A. V. S.] and NIH GrantCA 40077.The contentsof this manuscriptaresolelythe responsibilityofthe authorsand do not necessarilyrepresenttheofficialviewsof the NatiOnal Cancer Institute. 3 The abbreviations used are: EOF, epidermal growth factor; CIRP, gastrin-releasing 2 To whom requests for reprints should be addressed, at VA Medical Center, 1601 peptide;IGF-I,insulin-likegrowthfactorl; OH,growthhormone;Tpi,2,3,4,9-tetrahydro PerdidoStreet,NewOrleans,LA70146. 1H-pyrido[3,4-b]indol-3-carboxylic acid; CNS, central nervous system. 5895 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1994 American Association for Cancer Research. PEPTIDEANALOGUESIN GUOBLASTOMAS and supplied by Debiopharm S. A. (Lausanne, Switzerland). For the injections, RC-3095, injected s.c. twice daily at a dose of 20 p@g/animal;and(c) RC-160, the somatostatin analogues were dissolved in 0.1 Macetic acid and diluted with injected s.c. at a dose of 100 p@g/day/animal. saline containing 0.1—0.5%bovine serum albumin. Histological Procedures. The histological procedures were the same as Bombesin/GRP antagonist RC-3095 [D-Tpi6, Leu'3 L1,(CH2NH) described previously (28). The number of mitotic and apoptotic cells per 1000 Leu'4]bombesin(6—14),originally synthesized in our laboratory (26), was cellswasdetermined,andthepercentageareaofnecrosisintumorsectionswas madeby Asta Medica(Frankfurt/Main,Germany).Tpi is a conformationally examinedusingthepoint-coustingmethod(28),inwhichthecrossingpointsof an constrained secondary amine derivate of tryptophan. GRP(14-27) was synthe ocular net that hide or coincide with necrosis in various sections are counted. sized using solid-phase methods in our laboratory. RC-3095 and GRP(14-27) Radioimmunoassays. Serum levels of OH were determined by double were dissolved in 0.1% dimethylsulfoxide in saline. antibody radioimmunoassay using materials supplied by the National Hormone and Pituitary Program of the National Institute of Diabetes and Digestive and Animals Kidney Diseases. Interassay and intraassay coefficients of variation were less than 15% and 10%, respectively. Serum gastrin levels were measured by Athymic male NCrnzilnu nude mice, approximately 6 weeks old on arrival, double-antibody radioimmunoassay with a kit provided by Becton Dickinson were obtained from the National Cancer Institute (Bethesda, MD) and (Orangeburg, NY). The interassay variation was less than 7.5%, and the maintained under pathogen-limited conditions. intraassay variation was less than 4.0%. Receptor Assays. Receptorsforbombesin,somatostatin,andEGFon the Cell Lines membranes of U-87M0 and U-373-MG tumors were measured as described previously (28, 29, 35). The UGAND PC computerized curve-fitting program
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