Targeted chemotherapy with cytotoxic bombesin analogue AN-215 can overcome chemoresistance in experimental renal cell carcinomas

Authors

  • 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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  • Andrew V. Schally Ph.D., M.D.hc.mult.,

    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
    • Endocrine, Polypeptide and Cancer Institute Veterans Administration Medical Center, 1601 Perdido St., New Orleans, LA 70112-1262
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    • Fax: (504) 566-1625

    • This work is dedicated to the late Ana-Maria Comaru-Schally, M.D., who died recently from thyroid cancer, for her intellectual, spiritual, and personal contribution and for the inspiration she provided to this project.

  • 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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  • 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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  • Benjamin Baker M.B.,

    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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  • 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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Abstract

BACKGROUND

Multidrug resistance (MDR) mediated by membrane transporters, such as P-glycoprotein (MDR-1) and MDR-associated protein (MRP), remains a challenge in the therapy of renal cell carcinoma (RCC). Chemotherapy targeted to hormone receptors may provide a new approach to overcome chemoresistance. The cytotoxic analogue of bombesin/gastrin-releasing peptide (GRP), AN-215, consists of a superactive derivative of doxorubicin, AN-201, which is linked to a bombesin analogue carrier: RC-3094.

METHODS

The authors examined the expression of bombesin/GRP receptors in 3 human RCC cell lines (A-498, ACHN. and 786-0) by using reverse-transcriptase-polymerase chain reaction (RT-PCR) analysis and radioligand-binding assays. They also evaluated the effects of AN-215 and its cytotoxic radical AN-201 in the same RCC models in vivo, and they studied the effects of AN-215 and AN-201 on the expression levels of MDR-1 and subtype 1 of MRP (MRP-1) by using real-time PCR.

RESULTS

A N-215 significantly (P < 0.05) inhibited the growth of A-498, ACHN, and 786-0 RCC xenografted into nude mice by 59.2–67.6%, whereas the cytotoxic radical AN-201 alone had no significant antitumor effects. The efficacy of AN-215 was independent of the expression patterns of MDR-1 and MRP-1 in these RCC cell lines. The induction of MDR-1 by AN-215 was similar (Experiment 2) or weaker (Experiment 1) compared with AN-201. Both AN-215 and AN-201 caused only a minor induction of MRP-1.

CONCLUSIONS

The current findings indicated that targeted chemotherapy with cytotoxic bombesin/GRP analogue AN-215 can inhibit the growth of RCC, providing a new treatment modality for patients with advanced RCC. Cancer 2005. © 2005 American Cancer Society.

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