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

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.

• Authors: Gunhild Keller, Andrew V Schally, Attila Nagy, Gabor Halmos, Benjamin Baker, Jorg B Engel
• Journal: Cancer (Cancer) Vol. 104 Issue 10 Pg. 2266-74 (Nov 15 2005) ISSN: 0008-543X [Print] United States
• PMID: 16211544 (Publication Type: Comparative Study, 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

• AN 215
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Chemokines, CC
• Pyrroles
• RNA, Messenger
• Receptors, Bombesin
• Ccl6 protein, mouse
• AN 204
• Doxorubicin
• Bombesin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (biosynthesis, drug effects)
• Animals
• Antineoplastic Agents (pharmacology)
• Bombesin (analogs & derivatives, pharmacology)
• Carcinoma, Renal Cell (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Transplantation
• Chemokines, CC (biosynthesis)
• Disease Models, Animal
• Doxorubicin (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm (physiology)
• Humans
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Pyrroles (pharmacology)
• RNA, Messenger (analysis)
• Receptors, Bombesin (biosynthesis)
• Reverse Transcriptase Polymerase Chain Reaction