Inhibition of the UCI-107 human ovarian carcinoma cell line by a targeted cytotoxic analog of somatostatin, AN-238

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

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

BACKGROUND. Cytotoxic analogs of somatostatin (SST), such as AN-238, which consists of 2-pyrrolinodoxorubicin (AN-201) linked to the SST carrier RC-121, can be targeted to tumors that express SST receptors. Because SST receptors are present in ovarian carcinoma cells, the authors evaluated the effect of AN-238 on the UCI-107 ovarian carcinoma cell line. METHODS. An analysis of microsatellite alleles in cocultured SST receptor positive and receptor negative cells was used for the demonstration of in vitro targeting. The toxicity and antitumor effects of AN-238 in nude mice bearing UCI-107 human ovarian tumors were investigated with or without pharmacologic inhibition of serum carboxylesterases (CE). The expression of SST receptor subtypes was determined by reverse transcriptase-polymerase chain reaction analysis, and the binding affinity of AN-238 to SST receptors was determined by radioligand assays. RESULTS. The proliferation of SST receptor positive UCI-107 cells in vitro was inhibited preferentially by AN-238. AN-238 showed high-affinity binding to UCI-107 tumor membranes at a 50% inhibition concentration of 3.39 nM ± 0.74 nM. In vivo, the volume and weights of UCI-107 tumors treated with AN-238 were decreased by more than 60% (P < 0.05) compared with controls. Cytotoxic radical AN-201 or the unconjugated mixture of AN-201 with carrier RC-121 had no significant effects on tumors and were toxic. In mice with inhibited serum CE activity, AN-201 at 400 nmol/kg was lethal, whereas AN-238 at a total dose of 800 nmol/kg caused only 22% mortality and reduced tumor weight by 69% and volume by 70% (P < 0.05 vs. control). CONCLUSIONS. Targeted chemotherapy with the SST conjugate AN-238 inhibits SST receptor positive experimental ovarian tumors. AN-238 may provide a new treatment modality for patients with advanced ovarian carcinoma.

Original languageEnglish (US)
Pages (from-to)1168-1176
Number of pages9
JournalCancer
Volume92
Issue number5
DOIs
StatePublished - Sep 1 2001
Externally publishedYes

Keywords

  • Cytotoxic
  • Ovarian carcinoma
  • Somatostatin receptors
  • Targeted chemotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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