Targeted therapy with a cytotoxic somatostatin analog, AN-238, inhibits growth of human experimental endometrial carcinomas expressing multidrug resistance protein MDR-1.

Abstract

BACKGROUND:

Chemoresistance mediated by membrane transporters such as multidrug resistance (MDR-1) glycoprotein remains a challenge in the chemotherapy treatment of advanced or recurrent endometrial carcinoma. Targeted chemotherapy might overcome this resistance. The cytotoxic somatostatin (SST) analog, AN-238, consists of a superactive derivative of doxorubicin (DOX), 2-pyrrolino-DOX (AN-201), linked to the SST analog carrier, RC-121. This conjugate binds strongly to SST receptor subtypes (sst) 2a (sst2(a)) and 5 (sst(5)) and can be targeted to tumors that express these receptors.

METHODS:

The presence of sst2(a) and sst(5) was determined in 3 human endometrial carcinoma cell lines (HEC-1A, RL-95-2, and AN3CA). Nude mice bearing xenografts of these cancers were treated with AN-238 and its radical, AN-201. The antitumor effects and toxicity were compared. The authors studied the effects of AN-238 and AN-201 on the expression levels of MDR-1, multidrug resistance related protein (MRP-1), and breast carcinoma resistance protein (BCRP) by real-time polymerase chain reaction.

RESULTS:

The authors demonstrated the presence of mRNA and receptor protein for sst(2a) and sst(5) on HEC-1A, RL-95-2, and AN3CA tumors. AN-238 significantly (P < 0.05) inhibited the growth of these tumors, whereas AN-201 had no effect. Blockade of SST receptors nullified the effects of AN-238. In all 3 endometrial carcinoma lines, AN-238 caused a weaker induction of MDR-1 than AN-201. No major induction of MRP-1 and BCRP occurred after treatment with AN-238 or AN-201.

CONCLUSIONS:

Targeted chemotherapy with the cytotoxic SST analog, AN-238, inhibited powerfully the growth of endometrial carcinoma, which express SST receptors, regardless of their expression level of MDR-1.

• Authors: Jorg B Engel, Andrew V Schally, Gabor Halmos, Ben Baker, Attila Nagy, Gunhild Keller
• Journal: Cancer (Cancer) Vol. 104 Issue 6 Pg. 1312-21 (Sep 15 2005) ISSN: 0008-543X [Print] United States
• PMID: 16047355 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright 2005 American Cancer Society.

Chemical References

• ABCG2 protein, human
• AN 238
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• Pyrroles
• RNA, Messenger
• Receptors, Somatostatin
• Somatostatin
• Doxorubicin
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (genetics)
• Aged
• Animals
• Cell Line, Tumor
• Doxorubicin (adverse effects, analogs & derivatives, pharmacology, therapeutic use)
• Endometrial Neoplasms (drug therapy, metabolism, pathology)
• Female
• Humans
• Mice
• Multidrug Resistance-Associated Proteins (genetics)
• Neoplasm Proteins (genetics)
• Neoplasm Transplantation
• Pyrroles (adverse effects, pharmacology, therapeutic use)
• RNA, Messenger (analysis)
• Receptors, Somatostatin (analysis, genetics)
• Somatostatin (analysis, genetics)
• Transplantation, Heterologous