This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koppan, M. Articles by Halmos, G. Search for Related Content PubMed PubMed Citation Articles by Koppan, M. Articles by Halmos, G.

Targeted Cytotoxic Analogue of Somatostatin AN-238 Inhibits Growth of Androgen-independent Dunning R-3327-AT-1 Prostate Cancer in Rats at Nontoxic Doses¹

Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70146; and Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112

Receptors for somatostatin (SST) that are found on prostate cancers might be used for targeting of chemotherapeutic agents. Thus, doxorubicin derivative 2-pyrrolinodoxorubicin (AN-201) can be linked to SST analogue RC-121 to form targeted cytotoxic SST analogue AN-238. In this study, we evaluated the effects of AN-238 on the growth of SST receptor (SSTR)-positive androgen-independent Dunning R-3327-AT-1 prostate cancers in Copenhagen rats. The dose range and tumor growth-inhibitory effects of AN-238 and AN-201 were investigated in preliminary experiments. Administration of cytotoxic radical AN-201 at single i.v. doses of 110, 125, and 150 nmol/kg resulted in 0, 77.7, and 100% mortality, respectively, within 6–10 days. Four weeks after the injection of 110 nmol/kg AN-201, mean tumor volume was reduced by 35.1% (P < 0.05), as compared with controls. In contrast, a single i.v. injection of analogue AN-238 at a dose of 300 nmol/kg was nontoxic and remarkably potent in inhibiting the growth of Dunning AT-1 tumors, resulting in a 85.9% (P < 0.01) reduction in tumor volume after 4 weeks. Treatment with AN-238 extended the survival time of tumor-bearing rats from 52.0 ± 3.75 to 91.8 ± 3.70 days, corresponding to a 76.5% (P < 0.01) increase. In a comprehensive experiment, we compared the effects of radical AN-201 at 115 nmol/kg, analogue AN-238 at 115 and 300 nmol/kg, carrier SST analogue RC-121 at 300 nmol/kg, and a mixture of AN-201 and RC-121 at doses of 300 nmol/kg administered i.v. Administration of AN-201 at 115 nmol/kg led to 90.0% mortality in 12 days, but animals treated with 115 nmol/kg of AN-238 showed no signs of toxicity, their tumor volume was reduced by 40.0% (P < 0.05), and their tumor weight was reduced by 42.8% (P < 0.01) after 4 weeks, as compared with controls. The dose of 300 nmol/kg of AN-238 was also nontoxic and diminished tumor volume by 80.9% (P < 0.01) and tumor weight by 82.0% (P < 0.01). No reduction in tumor growth or toxic effects was observed with carrier RC-121, but after the injection of unconjugated mixture of AN-201 and RC-121 at doses of 300 nmol/kg, all rats died within 4 days. Specific high-affinity receptors for SST were found on Dunning R-3327-AT-1 tumor membranes by radioligand binding assay and were identified by reverse transcription-PCR as SSTR2. Our study indicates that cytotoxic SST analogue AN-238 can be targeted to SSTRs on tumors and produces a powerful inhibition of the growth of Dunning-AT-1 rat prostate cancer at doses that are nontoxic, whereas its cytotoxic component, 2-pyrrolinodoxorubicin, is toxic and ineffective.

¹ This work was supported by a grant from ASTA Medica AG (Frankfurt am Main, Germany) and CaPCURE to Tulane University School of Medicine and by the Medical Research Service of the Veterans Affairs Department (to A. V. S.).

² Present address: Department of Human Anatomy, University Medical School of Pécs, Pécs, H-7643 Hungary.

³ To whom requests for reprints should be addressed, at Veterans Affairs Medical Center, 1601 Perdido Street, New Orleans, LA 70146. Phone: (504) 589-5230; Fax: (504) 566-1625.

Received 4/17/98. Accepted 7/17/98.

This article has been cited by other articles:

				L. J. Hofland, A. Capello, E. P. Krenning, M. de Jong, and M. P. van Hagen Induction of Apoptosis with Hybrids of Arg-Gly-Asp Molecules and Peptides and Antimitotic Effects of Hybrids of Cytostatic Drugs and Peptides J. Nucl. Med., January 1, 2005; 46(1_suppl): 191S - 198S. [Abstract] [Full Text] [PDF]

				L. J. Hofland and S. W. J. Lamberts The Pathophysiological Consequences of Somatostatin Receptor Internalization and Resistance Endocr. Rev., February 1, 2003; 24(1): 28 - 47. [Abstract] [Full Text] [PDF]

				P. D. Zapata, R. M. Ropero, A. M. Valencia, L. Buscail, J. I. Lopez, R. M. Martin-Orozco, J. C. Prieto, J. Angulo, C. Susini, P. Lopez-Ruiz, et al. Autocrine Regulation of Human Prostate Carcinoma Cell Proliferation by Somatostatin through the Modulation of the SH2 Domain Containing Protein Tyrosine Phosphatase (SHP)-1 J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 915 - 926. [Abstract] [Full Text] [PDF]

				M. Koutsilieris, C. Mitsiades, T. Dimopoulos, A. Ioannidis, A. Ntounis, and T. Lambou A Combination Therapy of Dexamethasone and Somatostatin Analog Reintroduces Objective Clinical Responses to LHRH Analog in Androgen Ablation-Refractory Prostate Cancer Patients J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5729 - 5736. [Abstract] [Full Text] [PDF]

				K. Szepeshazi, A. V. Schally, G. Halmos, B. Sun, F. Hebert, B. Csernus, and A. Nagy Targeting of Cytotoxic Somatostatin Analog AN-238 to Somatostatin Receptor Subtypes 5 and/or 3 in Experimental Pancreatic Cancers Clin. Cancer Res., September 1, 2001; 7(9): 2854 - 2861. [Abstract] [Full Text] [PDF]

				G. Halmos, A. V. Schally, B. Sun, R. Davis, D. G. Bostwick, and A. Plonowski High Expression of Somatostatin Receptors and Messenger Ribonucleic Acid for Its Receptor Subtypes in Organ-Confined and Locally Advanced Human Prostate Cancers J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2564 - 2571. [Abstract] [Full Text]

				A. Plonowski, A. V. Schally, A. Nagy, H. Kiaris, F. Hebert, and G. Halmos Inhibition of Metastatic Renal Cell Carcinomas Expressing Somatostatin Receptors by a Targeted Cytotoxic Analogue of Somatostatin AN-238 Cancer Res., June 1, 2000; 60(11): 2996 - 3001. [Abstract] [Full Text] [PDF]

				S. Schulz, S. U. Pauli, S. Schulz, M. Händel, K. Dietzmann, R. Firsching, and V. Höllt Immunohistochemical Determination of Five Somatostatin Receptors in Meningioma Reveals Frequent Overexpression of Somatostatin Receptor Subtype sst2A Clin. Cancer Res., May 1, 2000; 6(5): 1865 - 1874. [Abstract] [Full Text]

				H. Kiaris, A. V. Schally, A. Nagy, B. Sun, K. Szepeshazi, and G. Halmos Regression of U-87 MG Human Glioblastomas in Nude Mice after Treatment with a Cytotoxic Somatostatin Analog AN-238 Clin. Cancer Res., February 1, 2000; 6(2): 709 - 717. [Abstract] [Full Text]

				A. Nagy, A. Plonowski, and A. V. Schally 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 PNAS, January 18, 2000; 97(2): 829 - 834. [Abstract] [Full Text] [PDF]

				A. Plonowski, A. V. Schally, A. Nagy, B. Sun, and K. Szepeshazi Inhibition of PC-3 Human Androgen-independent Prostate Cancer and Its Metastases by Cytotoxic Somatostatin Analogue AN-238 Cancer Res., April 1, 1999; 59(8): 1947 - 1953. [Abstract] [Full Text] [PDF]

				N. Benali, P. Cordelier, D. Calise, P. Pages, P. Rochaix, A. Nagy, J.-P. Esteve, P. M. Pour, A. V. Schally, N. Vaysse, et al. Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238 PNAS, August 1, 2000; 97(16): 9180 - 9185. [Abstract] [Full Text] [PDF]