Targeted cytotoxic analogue of somatostatin AN-238 inhibits growth of androgen-independent Dunning R-3327-AT-1 prostate cancer in rats at nontoxic doses.

Abstract

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 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2) 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.

• Authors: M Koppan, A Nagy, A V Schally, J M Arencibia, A Plonowski, G Halmos
• Journal: Cancer research (Cancer Res) Vol. 58 Issue 18 Pg. 4132-7 (Sep 15 1998) ISSN: 0008-5472 [Print] United States
• PMID: 9751625 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• AN 238
• Pyrroles
• Receptors, Somatostatin
• Doxorubicin
• RC 121
• Octreotide

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, metabolism, therapeutic use)
• Doxorubicin (administration & dosage, adverse effects, analogs & derivatives, metabolism)
• Drug Screening Assays, Antitumor
• Male
• Octreotide (administration & dosage, adverse effects, analogs & derivatives, metabolism)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Pyrroles (administration & dosage, adverse effects, metabolism)
• Rats
• Receptors, Somatostatin (metabolism)
• Tumor Cells, Cultured