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

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

Research output: Contribution to journalArticle

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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 n 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.

Original languageEnglish
Pages (from-to)2266-2274
Number of pages9
JournalCancer
Volume104
Issue number10
DOIs
StatePublished - Nov 15 2005
Externally publishedYes

Fingerprint

Bombesin
Renal Cell Carcinoma
Drug Therapy
Multiple Drug Resistance
Gastrin-Releasing Peptide
Bombesin Receptors
Cell Line
Radioligand Assay
Proteins
Membrane Transport Proteins
P-Glycoprotein
Growth
AN 215
Reverse Transcriptase Polymerase Chain Reaction
Nude Mice
Doxorubicin
AN 204
Real-Time Polymerase Chain Reaction
Hormones
Therapeutics

Keywords

  • Bombesin/gastrin-releasing peptide receptor
  • Cytotoxic bombesin analogue AN-215
  • MDR-1
  • Multidrug resistance-associated protein subtype 1
  • Multiple drug resistance
  • Renal cell carcinoma
  • Targeted chemotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Targeted chemotherapy with cytotoxic bombesin analogue AN-215 can overcome chemoresistance in experimental renal cell carcinomas. / Keller, Gunhild; Schally, Andrew V; Nagy, Attila; Halmos, Gabor; Baker, Benjamin; Engel, Jorg B.

In: Cancer, Vol. 104, No. 10, 15.11.2005, p. 2266-2274.

Research output: Contribution to journalArticle

Keller, Gunhild ; Schally, Andrew V ; Nagy, Attila ; Halmos, Gabor ; Baker, Benjamin ; Engel, Jorg B. / Targeted chemotherapy with cytotoxic bombesin analogue AN-215 can overcome chemoresistance in experimental renal cell carcinomas. In: Cancer. 2005 ; Vol. 104, No. 10. pp. 2266-2274.
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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 n 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.",
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T1 - Targeted chemotherapy with cytotoxic bombesin analogue AN-215 can overcome chemoresistance in experimental renal cell carcinomas

AU - Keller, Gunhild

AU - Schally, Andrew V

AU - Nagy, Attila

AU - Halmos, Gabor

AU - Baker, Benjamin

AU - Engel, Jorg B.

PY - 2005/11/15

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N2 - 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 n 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.

AB - 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 n 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.

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KW - Cytotoxic bombesin analogue AN-215

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KW - Multiple drug resistance

KW - Renal cell carcinoma

KW - Targeted chemotherapy

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