Summary
Recently, we developed a powerful cytotoxic analogue of bombesin AN-215, in which the bombesin-like carrier peptide Gln–Trp–Ala–Val–Gly–His–Leu–Ψ(CH2-NH)–Leu–NH2 (RC-3094) is conjugated to a potent derivative of doxorubicin, 2-pyrrolinodoxorubicin (AN-201). Small-cell lung carcinomas (SCLCs) are known to express high levels of bombesin receptors. We evaluated whether these receptors could be used for targeting cytotoxic bombesin analogue to H-69 SCLC cells. H-69 cells were xenografted into male nude mice, which then received an intravenous injection of AN-215, cytotoxic radical AN-201, the carrier peptide RC-3094 alone or unconjugated mixture of RC-3094 and AN-201. The levels of mRNA for bombesin receptor subtypes were evaluated by reverse transcription-polymerase chain reaction. In vitro, both the analogue AN-215 and the radical AN-201 showed strong antiproliferative effects on H-69 cells, AN-215 requiring more time to exert its action at 10–8M concentration than AN-201. In vivo, the growth of H-69 SCLC tumours was significantly inhibited by the treatment with 200 nmol kg–1 of AN-215, while equimolar doses of the cytotoxic radical AN-201 or the mixture of AN-201 and the carrier peptide were toxic and produced only a minor tumour inhibition as compared with control groups. mRNA for bombesin receptor subtypes 2 (BRS-2) and 3 (BRS-3) was detected in H-69 tumours. The mRNA levels for BRS-3, but not for BRS-2, were lower in the AN-215-treated tumours as compared with controls. Our results demonstrate that the cytotoxic bombesin analogue AN-215 could be considered for targeted therapy of tumours, such as SCLC, that express bombesin receptors.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Cuttitta, F, Carney, DN, Mulshine, J, Moody, TW, Fedorko, J, Fischler, A & Minna, JD (1985). Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer. Nature (London) 316: 823–826.
Draoui, M, Chung, P, Park, M, Birrer, M, Jakowlew, S & Moody, TW (1995). Bombesin stimulates c-fos and c-jun mRNAs in small cell lung cancer cells. Peptides 16: 289–292.
Fathi, Z, Corjay, MH, Shapira, J, Wada, E, Benya, R, Jenesen, R, Viallet, J, Sausville, EA & Battey, JF (1993). BRS-3: a novel bombesin receptor subtype selectively expressed in testis and lung carcinoma cells. J Biol Chem 268: 5979–5984.
Ihde, DC (1995). Small cell lung cancer. Chest 107: 243–248.
Koppán, M, Halmos, G, Arencibia, JM, Lamharzi, N & Schally, AV (1998). Bombesin/gastrin-releasing peptide antagonists RC-3095 and RC-3940-II inhibit tumor growth and decrease the levels and mRNA expression of epidermal growth factor receptors in H-69 small cell lung cancer. Cancer 83: 1335–1343.
Mantey, SA, Weber, HC, Sainz, E, Akeson, M, Ryan, RR, Prahdan, TK, Searles, RP, Spindel, ER, Battey, JF, Coy, DH & Jensen, RT (1997). Discovery of a high affinity radioligand for the human orphan receptor, bombesin receptor subtype 3, which demonstrates that it has a unique pharmacology compared with other mammalian bombesin receptors. J Biol Chem 272: 26062–26071.
Moody, TW & Cuttitta, F (1993). Growth factor and peptide receptors in small cell lung cancer. Life Sci 52: 1161–1173.
Moody, TW, Carney, DN, Cuttitta, F, Quattrocchi, K & Minna, JD (1985). High affinity receptors for bombesin/GRP-like peptides on human small cell lung cancer. Life Sci 37: 105–113.
Nagalla, SR, Barry, BJ, Creswick, KC, Eden, P, Taylor, JT & Spindel, E (1995). Cloning of a receptor for amphibian [Phe13]bombesin distinct for the receptor for gastrin-releasing peptide: identification of a forth bombesin receptor subtype (BB4). Proc Natl Acad Sci USA 92: 6205–6209.
Nagy, A, Armatis, P & Schally, AV (1996). High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500–1000 times more potent: structure– activity relationship of daunosamine-modified derivatives of doxorubicin. Proc Natl Acad Sci USA 93: 2464–2469.
Nagy, A, Armatis, P, Cai, R-Z, Szepeshazi, K, Halmos, G & Schally, AV (1997). Design, synthesis, and in vitro evaluation of cytotoxic analogs of bombesin-like peptides containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin. Proc Natl Acad Sci USA 94: 652–656.
Orosz, A, Schrett, J, Nagy, J, Bartha, L, Schon, I & Nyeki, O (1995). New short-chain analogs of a substance-P antagonist inhibit proliferation of human small-cell lung-cancer cells in vitro and in vivo. Int J Cancer 60: 82–877.
Pastan, I & FitzGerald, D (1991). Recombinant toxins for cancer treatment. Science 254: 1173–1177.
Pinski, J, Schally, AV, Halmos, G, Szepeshazi, K, Groot, K, O’Byrne, K & Cai, R-Z (1994). Effects of somatostatin analogue RC-160 and bombesin/gastrin releasing peptide antagonists on the growth of human small-cell and non-small-cell lung carcinomas in nude mice. Br J Cancer 70: 886–892.
Plonowski, A, Schally, AV, Nagy, A, Sun, B & Szepeshazi, K (1999). Inhibition of PC-3 human androgen-independent prostate cancer and its metastases by cytotoxic somatostatin analog AN-238. Cancer Res. 59: 1947–1953.
Plumb, JA, Milroy, R & Kaye, SB (1989). Effects of the pH dependence of 3-(4,5-Dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide-formazan absorption on chemosensitivity determined by a novel tetrazolium-based assay. Cancer Res 49: 4435–4440.
Schally, AV & Nagy, A (1999). Chemotherapy targeted to hormone receptors on tumors. Eur J Endocrinol 141: 1–14.
Spindel, ER, Giladi, E, Segerson, TP & Nagalla, S (1993). Bombesin-like peptides: of ligands and receptors. Recent Prog Horm Res 48: 365–391.
Szepeshazi, K, Milovanovic, S, Lapis, K, Groot, K & Schally, AV (1992). Growth inhibition of estrogen independent MXT mouse mammary carcinomas in mice treated with an agonist or antagonist of LHRH, an analog of somatostatin or a combination. Breast Cancer Res Treat 21: 181–192.
Toi-Scott, M, Jones, CL & Kane, MA (1996). Clinical correlates of bombesin-like peptide receptor subtype expression in human lung cancer cells. Lung Cancer 15: 341–354.
UKCCCR, (1998). United Kingdom Coordinating Committee on Cancer Research (UKCCCR) guidelines for the welfare of animals in experimental neoplasia, 2nd edn. Br J Cancer 77: 1–10.
Von Schrenck, T, Heinz-Erian, P, Moran, T, Mantey, SA, Gardner, JD & Jenson, RT (1989). Neuromedin B receptor in esophagus: evidence for subtypes of bombesin receptors. Am J Physiol 256: 747–758.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Kiaris, H., Schally, A., Nagy, A. et al. Targeted cytotoxic analogue of bombesin/ gastrin-releasing peptide inhibits the growth of H-69 human small-cell lung carcinoma in nude mice. Br J Cancer 81, 966–971 (1999). https://doi.org/10.1038/sj.bjc.6690794
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690794
Keywords
This article is cited by
-
Conjugates of Anthracycline Antibiotics with Macromolecules
Pharmaceutical Chemistry Journal (2015)
-
Targeting GRPR in urological cancers—from basic research to clinical application
Nature Reviews Urology (2013)
-
Immunohistochemical detection of bombesin receptor subtypes GRP-R and BRS-3 in human tumors using novel antipeptide antibodies
Virchows Archiv (2006)
-
Effective treatment of experimental U-87MG human glioblastoma in nude mice with a targeted cytotoxic bombesin analogue, AN-215
British Journal of Cancer (2002)