Targeted cytotoxic bombesin analog AN-215 effectively inhibits experimental human breast cancers with a low induction of multi-drug resistance proteins

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Abstract

The cytotoxic analog of bombesin (BN)/gastrin releasing peptide (GRP) AN-215 consisting of 2-pyrrolinodoxorubicin (AN-201), a superactive derivative of doxorubicin linked to a bombesin analog carrier, displays a high affinity to BN/GRP receptors and can be targeted to tumors that express these receptors. We evaluated the antitumor effect and the toxicity of AN-215 in 5 human breast cancer cell lines xenografted into nude mice. In addition, we measured the mRNA expression of multi drug resistance protein 1 (MDR-1), multi drug resistance related protein 1 (MRP-1) and breast cancer resistance protein (BCRP) by real-time PCR analysis after treatment with AN-215. All five cell lines expressed BN/GRP receptors, and AN-215 significantly (P<0.05) inhibited tumor growth in all models, while its cytotoxic radical AN-201 had no significant effect in four models. In MX-1 tumors, AN-201 had a significantly weaker antitumor effect than AN-215. The effect of AN-215 was nullified by a blockade of BN/GRP receptors with a bombesin antagonist. Low or no induction of MDR-1, MRP-1 and BCRP occurred after treatment with AN-215. In conclusion, targeted chemotherapy with the cytotoxic BN/GRP analog AN-215 strongly inhibits breast cancers that express BN/GRP receptors and might provide a new treatment modality for mammary carcinoma. © 2005 Society for Endocrinology Printed in Great Britain.

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Engel, J. B., Schally, A. V., Halmos, G., Baker, B., Nagy, A., & Keller, G. (2005). Targeted cytotoxic bombesin analog AN-215 effectively inhibits experimental human breast cancers with a low induction of multi-drug resistance proteins. Endocrine-Related Cancer, 12(4), 999–1009. https://doi.org/10.1677/erc.1.01022

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