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

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.

• Authors: A Plonowski, A V Schally, M Koppan, A Nagy, J M Arencibia, B Csernus, G Halmos
• Journal: Cancer (Cancer) Vol. 92 Issue 5 Pg. 1168-76 (Sep 01 2001) ISSN: 0008-543X [Print] United States
• PMID: 11571730 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright 2001 American Cancer Society.

Chemical References

• AN 238
• Antibiotics, Antineoplastic
• Pyrroles
• Receptors, Somatostatin
• Doxorubicin
• Carboxylic Ester Hydrolases

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Carboxylic Ester Hydrolases (antagonists & inhibitors)
• Doxorubicin (analogs & derivatives, pharmacology)
• Drug Screening Assays, Antitumor
• Female
• Humans
• Mice
• Mice, Nude
• Microsatellite Repeats
• Ovarian Neoplasms (drug therapy)
• Pyrroles (pharmacology)
• Radioligand Assay
• Receptors, Somatostatin (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays