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

Authors

  • Jorg B. Engel M.D.,

    1. Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana
    2. Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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  • Andrew V. Schally Ph.D., M.D.,

    Corresponding author
    1. Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana
    2. Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
    • VA Medical Center, 1601 Perdido Street, New Orleans, LA 70112-1262
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    • Fax: (504) 566-1625

  • Gabor Halmos Ph.D.,

    1. Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana
    2. Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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  • Ben Baker B.S.,

    1. Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana
    2. Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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  • Attila Nagy Ph.D.,

    1. Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana
    2. Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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  • Gunhild Keller M.D.

    1. Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana
    2. Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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  • The current study is dedicated to the late Ana-Maria Comaru-Schally, M.D., who died recently of thyroid carcinoma, for her intellectual, spiritual and personal contribution and for the inspiration she provided to this project.

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 sst2a 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. Cancer 2005. © 2005 American Cancer Society.

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