Targeted chemotherapy with cytotoxic bombesin analogue AN-215 inhibits growth of experimental human prostate cancers
Anton Stangelberger
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Search for more papers by this authorCorresponding Author
Andrew V. Schally
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Fax: +504-566-1625
Veterans Affairs Medical Center, 1601 Perdido Street, New Orleans, LA 70112-1262Search for more papers by this authorMarkus Letsch
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Search for more papers by this authorKaroly Szepeshazi
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Search for more papers by this authorAttila Nagy
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Search for more papers by this authorGabor Halmos
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Search for more papers by this authorCelia A. Kanashiro
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Search for more papers by this authorEva Corey
Department of Urology, University of Washington, Seattle, WA, USA
Search for more papers by this authorRobert Vessella
Department of Urology, University of Washington, Seattle, WA, USA
Search for more papers by this authorAnton Stangelberger
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Search for more papers by this authorCorresponding Author
Andrew V. Schally
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Fax: +504-566-1625
Veterans Affairs Medical Center, 1601 Perdido Street, New Orleans, LA 70112-1262Search for more papers by this authorMarkus Letsch
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Search for more papers by this authorKaroly Szepeshazi
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Search for more papers by this authorAttila Nagy
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Search for more papers by this authorGabor Halmos
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Search for more papers by this authorCelia A. Kanashiro
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
Search for more papers by this authorEva Corey
Department of Urology, University of Washington, Seattle, WA, USA
Search for more papers by this authorRobert Vessella
Department of Urology, University of Washington, Seattle, WA, USA
Search for more papers by this authorAbstract
We developed a powerful cytotoxic analogue of bombesin AN-215, in which the bombesin (BN)-like carrier peptide is conjugated to 2-pyrrolino doxorubicin (AN-201). Human prostate cancers express high levels of receptors for BN/gastrin releasing peptide (GRP) that can be used for targeted chemotherapy. The effects of targeted chemotherapy with cytotoxic BN analogue AN-215 were evaluated in nude mice bearing subcutaneous xenografts of DU-145, LuCaP-35, MDA-PCa-2b and intraosseous implants of C4-2 human prostate cancers. Intraosseous growth of C4-2 tumors was monitored by serum PSA. BN/GRP receptors were evaluated by 125I-[Tyr4]BN binding assays and RT-PCR. The effects of AN-215 on apoptosis and cell proliferation were followed by histology, and the expression of Bcl-2 and Bax protein was determined by Western blot analysis. Targeted analog AN-215 significantly inhibited growth of subcutaneously implanted DU-145, LuCaP-35 and MDA-PCa-2b prostate cancers by 81% to 91% compared to controls, while cytotoxic radical AN-201 was less effective and more toxic. Serum PSA levels of mice bearing intraosseous C4-2 prostate tumors were significantly reduced. In LuCaP-35 tumors administration of BN antagonist RC-3095 prior to AN-215 blocked the receptors for BN/GRP and inhibited the effects of AN-215. High affinity receptors for BN/GRP and their m-RNA were detected on membranes of all 4 tumor models. Therapy with AN-215, but not with AN-201, decreased the ratio of Bcl-2/Bax in DU-145 and the expression of antiapoptotic Bcl-2 in LuCaP-35 tumors. The presence of BN/GRP receptors on primary and metastatic prostate cancers makes possible targeted chemotherapy with AN-215 for the treatment of this malignancy. © 2005 Wiley-Liss, Inc.
References
- 1 Jemal A, Tiwari RC, Murray T, Ghafoor A, Ward E, Thun, MJ. Cancer statistics 2004. CA Cancer J Clin 2004; 8–29.
- 2 Schally, AV, Comaru-Schally AM. Hypothalamic and other peptide hormones. In: DW Kufe, RE Pollock, RR Weichselbaum, RC. Bast, TS Gansler, JF Holland, E Frei, eds. Cancer medicine, 6th ed., chap. 61. Hamilton, Ontario: B.C. Dekker Publishers, 2003. pp 911–26.
- 3
Oh WK.
Chemotherapy for patients with advanced carcinoma.
Cancer
2000;
88;
3015–21.
10.1002/1097-0142(20000615)88:12+<3015::AID-CNCR18>3.0.CO;2-M CAS PubMed Web of Science® Google Scholar
- 4 Rini BI, Small EJ. Prostate cancer update. Curr Opin Oncol 2002; 14: 286–91.
- 5 Giordano GG, Muto M, Sigalotti L, Maio M. Cancer therapies: basic and clinical perspectives in brain, prostate, and lung tumors. J Cell Physiol 2001; 188: 274–80.
- 6 Oh WK, Kantoff PW. Management of hormone refractory prostate cancer: current standards and future prospects. J Urol 1998; 160: 1220–9.
- 7 Schally AV, Nagy A. New approaches to treatment of various cancers based on cytotoxic analogs of LHRH, somatostatin and bombesin. Life Sci 2003; 72: 2305–20.
- 8 Schally AV, Nagy A. Chemotherapy targeted to cancers through tumoral hormone receptors. Trends Endocrinol Metab 2004; 15: 300–10.
- 9 Reile H, Armatis PE, Schally AV. Characterization of high-affinity receptors for bombesin/gastrin-releasing peptide on the human prostate cancer cell lines PC-3 and DU-145: internalization of receptor bound 125I-(Tyr4) bombesin by tumor cells. Prostate 1994; 25: 29–38.
- 10 Aprikian AG, Han K, Chevalier S, Bazinet M, Viallet J. Bombesin specifically induces intracellular calcium mobilization via gastrin-releasing peptide receptors in human prostate cancer cells. J Mol Endocrinol 1996; 16: 297–306.
- 11
Bartholdi FM,
Wu JM,
Pu H,
Troncoso P,
Eden PA,
Feldman RI.,
In situ hybridization for gastrin-releasing peptide receptors (GRP receptor) expression in prostatic carcinoma.
Int J Cancer
1998;
79:
82–90.
10.1002/(SICI)1097-0215(19980220)79:1<82::AID-IJC16>3.0.CO;2-J CAS PubMed Web of Science® Google Scholar
- 12 Markwalder R, Reubi JC. Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer Res 1999; 59: 1152–9.
- 13
Sun B,
Halmos G,
Schally AV,
Wang X,
Martinez M.
Presence of receptors for bombesin/gastrin-releasing peptide and mRNA for three receptor subtypes in human prostate cancers.
Prostate
2000;
42:
295–303.
10.1002/(SICI)1097-0045(20000301)42:4<295::AID-PROS7>3.0.CO;2-B CAS PubMed Web of Science® Google Scholar
- 14 Kiaris H, Schally AV, Nagy A, Sun B, Armatis P, Szepeshazi K. 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 1999; 81: 966–71.
- 15 Szereday Z, Schally AV, Nagy A, Plonowski A, Bajo AM, Halmos G, Szepeshazi, K, Groot K. Effective treatment of experimental U-87MG human glioblastoma in nude mice with a targeted cytotoxic bombesin analogue, AN–215. Br J Cancer 2002; 86: 1322–7.
- 16 Szepeshazi K, Schally AV, Nagy A, Wagner BW, Bajo AM, Halmos G. Preclinical evaluation of therapeutic effects of targeted cytotoxic analogs of somatostatin and bombesin on human gastric carcinomas. Cancer 2003; 98: 1401–10.
- 17 Plonowski A, Nagy A, Schally AV, Sun B, Groot K, Halmos G. In vivo inhibition of PC-3 human androgen-independent prostate cancer by a targeted cytotoxic bombesin analogue, AN-215. Int J Cancer 2000; 88: 652–7.
- 18 Danila DC, Schally AV, Nagy A, Alexander JM. Selective induction of apoptosis by the cytotoxic analog AN-207 in cells expressing recombinant receptor for luteinizing hormone-releasing hormone. Proc Natl Acad Sci U S A 1999; 96: 669–73.
- 19 McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT, Tu SM, Campbell ML. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res 1992; 52: 6940–4.
- 20 Hamdy FC, Thomas BG. New therapeutic concepts in prostate cancer. BJU Int 2001; 88: 43–50.
- 21 Navone NM, Rodriquez-Vargas MC, Benedict WF, Troncoso P, McDonnell TJ, Zhou JH, Luthra R, Logothetis CJ. TabBO: a model reflecting common molecular features of androgen-independent prostate cancer. Clin Cancer Res 2000; 6: 1190–7.
- 22 Gjertsen BT, Logothetis CJ, McDonnell TJ. Molecular regulation of cell death and therapeutic strategies for cell death induction in prostate carcinoma. Cancer Metastasis Rev 1998; 17: 345–51.
- 23 Nagy A, Armatis P, Cai RZ, Szepeshazi K, Halmos G, Schally AV. 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 U S A 1997; 94: 652–6.
- 24 Nagy P, Armatis P, Schally AV. High yield conversion of doxorubicin to 2pyrrolinodoxorubicin, an analog 500–1000 times more potent; structure-activity relationship of daunosamine-modified derivatives of doxorubicin. Proc Natl Acad Sci U S A 1996; 93: 2464–9.
- 25 Radulovic S, Cai RZ, Serfozo P, Groot K, Redding TW, Pinski J, Schally AV. Biological effects and receptor binding affinities of new pseudononapeptide bombesin/GRP receptor antagonists with N-terminal D-Trp or D-Tpi. Int J Pept Protein Res 1991; 38: 593–600.
- 26 Corey E, Quinn JE, Buhler KR, Nelson PS, Macoska JA, True LD, Vessella RL. LuCaP 35: a new model of prostate cancer progression to androgen independence. Prostate 2003; 55: 239–46.
- 27
Wu TT,
Sikes RA,
Cui Q,
Thalmann GN,
Kao C,
Murphy CF,
Yang H,
Zhau HE,
Balian G,
Chung LW.
Establishing human prostate cancer cell xenografts in bone: induction of osteoblastic reaction by prostate-specific antigen-producing tumors in athymic and SCID/bg mice using LNCaP and lineage-derived metastatic sublines.
Int J Cancer
1998;
77:
887–94.
10.1002/(SICI)1097-0215(19980911)77:6<887::AID-IJC15>3.0.CO;2-Z CAS PubMed Web of Science® Google Scholar
- 28 Thalmann GN, Anezinis PE, Chang SM, Zhau HE, Kim EE, Hopwood VL, Pathak S, von Eschenbach AC, Chung LW. Androgen-independent cancer progression and bone metastasis in the LNCaP modelof human prostate cancer. Cancer Res 1994; 54: 2577–81.
- 29 Lamharzi N, Schally AV, Koppan M, Groot K. Growth hormone-releasing hormone antagonist MZ-5-156 inhibits growth of DU-145 human androgen-independent prostate carcinoma in nude mice and suppresses the levels and mRNA expression of insulin-like growth factor II in tumors. Proc Natl Acad Sci U S A 1998; 95: 8864–8.
- 30 Navone NM, Olive M, Ozen M, Davis R, Troncoso P, Tu SM, Johnston D, Pollak A, Pathak S, von Eschenbach AC, Logothetis CJ. Establishment of two human prostate cancer cell lines derived from a single bone metastasis. Clin Cancer Res 1997; 3: 2493–500.
- 31 Letsch M, Schally AV, Busto R, Bajo AM, Varga JL. Growth hormone-releasing hormone (GHRH) antagonists inhibit the proliferation of androgen-dependent and -independent prostate cancers. Proc Natl Acad Sci U S A 2003; 100: 1250–5.
- 32 Halmos G, Wittliff JL, Schally AV. Characterization of bombesin/gastrin releasing pepetide receptors in human breast cancer and their relationship to steroid receptor expression. Cancer Res 1995; 55: 280–7.
- 33 Halmos G, Schally AV. Reduction in receptors for bombesin and epidermal growth factor in xenografts of human small-cell lung cancer after treatment with bombesin antagonist RC-3095. Proc Natl Acad Sci U S A 1997; 94: 956–60.
- 34 Szepeshazi K, Schally AV, Nagy A. Effective treatment of advanced estrogen-independent MXT mouse mammary cancers with targeted cytotoxic LH-RH analogs. Breast Cancer Res Treat 1999; 56: 267–76.
- 35 Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev 2003; 24: 389–427.
- 36 Xiao D, Qu X, Weber HC. GRP receptor-mediated immediate early gene expression and transcription factor Elk-1 activation in prostate cancer cells. Regul Pept 2002; 109: 141–8.
- 37 Jungwirth A, Pinski J, Galvan G, Halmos G, Szepeshazi K, Cai RZ, Groot K, Vadillo-Buenfil M, Schally AV. Inhibition of growth of androgen-independent DU-145 prostate cancer in vivo by luteinizing hormone-releasing hormone antagonist Cetrorelix and bombesin antagonists RC-3940-II and RC-3950-II. Eur J Cancer 1997; 33: 1141–8.
- 38 Kaliste-Korhonen E, Tuovinen K, Hanninen O. Interspecies differences in enzymes reacting with organophosphates and their inhibition by paraoxon in vitro. Hum Exp Toxicol 1996; 15: 972–8.
- 39 Nagy A, Plonowski A, Schally AV. Stability of cytotoxic luteinizing hormone-releasing hormone conjugate (AN-152) containing doxorubicin-14-O-hemiglutarate in mouse and human serum in vitro; implications for the design of preclinical studies. Proc Natl Acad Sci U S A 2000; 97: 829–34.
- 40 Denmeade SR, Isaacs JT. A history of prostate cancer treatment. Nat Rev Cancer 2002; 2: 389–96.
- 41 Shi C, Yu L, Yang F, Yan J, Zeng H. A novel organoselenium compound induces cell cycle arrest and apoptosis in prostate cancer cell lines. Biochem Biophys Res Commun 2003; 309: 578–83.
- 42 Xu K, Wang X, Ling PM, Tsao SW, Wong YC. The alpha1-adrenoceptor antagonist terazosin induces prostate cancer cell death through a p53 and Rb independent pathway. Oncol Rep 2003; 10: 1555–60.
- 43 Ng AY, Bales W, Veltri RW. Phenylbutyrate-induced apoptosis and differential expression of Bcl-2, Bax, p53 and Fas in human prostate cancer cell lines. Anal Quant Cytol Histol 2000; 22: 45–54.
Citing Literature
