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

Miklos Koppan, Attila Nagy, Andrew V. Schally, Jose M. Arencibia, Artur Plonowski, Gabor Halmos

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Abstract

Receptors for somatostatin (SST) that are found on prostate cancers might be used for targeting of chemotherapeutic agents. Thus, doxorubitin 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.

Original languageEnglish (US)
Pages (from-to)4132-4137
Number of pages6
JournalCancer Research
Volume58
Issue number18
StatePublished - Sep 15 1998
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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