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

Jorg B. Engel, Andrew V. Schally, Gabor Halmos, Ben Baker, Attila Nagy, Gunhild Keller

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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 (sst2a) and 5 (SSt5) and can be targeted to tumors that express these receptors. METHODS. The presence of sst2a and SSt5 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 sst5 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.

Original languageEnglish (US)
Pages (from-to)1312-1321
Number of pages10
JournalCancer
Volume104
Issue number6
DOIs
StatePublished - Sep 15 2005
Externally publishedYes

Keywords

  • Cytotoxic conjugate AN-238
  • Endometrial carcinoma
  • Multidrug resistance
  • Somatostatin receptor
  • Targeted chemotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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