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

Jörg B Engel; Andrew V Schally; Gabor Halmos; Benjamin Baker; Attila Nagy; Gunhild Keller

doi:10.1677/erc.1.01022

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

Endocr Relat Cancer. 2005 Dec;12(4):999-1009. doi: 10.1677/erc.1.01022.

Authors

Jörg B Engel¹, Andrew V Schally, Gabor Halmos, Benjamin Baker, Attila Nagy, Gunhild Keller

Affiliation

¹ Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center and Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.

PMID: 16322338
DOI: 10.1677/erc.1.01022

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters / genetics
ATP-Binding Cassette Transporters / metabolism*
Animals
Antineoplastic Agents / adverse effects
Antineoplastic Agents / therapeutic use*
Bombesin / adverse effects
Bombesin / analogs & derivatives*
Bombesin / therapeutic use
Breast Neoplasms / chemistry
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Doxorubicin / adverse effects
Doxorubicin / analogs & derivatives*
Doxorubicin / therapeutic use
Drug Resistance, Multiple
Female
Humans
Mice
Mice, Nude
Multidrug Resistance-Associated Proteins / genetics
Multidrug Resistance-Associated Proteins / metabolism
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
RNA, Messenger / analysis
RNA, Messenger / metabolism
Receptors, Bombesin / analysis
Receptors, Bombesin / antagonists & inhibitors
Receptors, Bombesin / metabolism
Up-Regulation
Xenograft Model Antitumor Assays

Substances

ABCG2 protein, human
AN 215
ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
Antineoplastic Agents
Multidrug Resistance-Associated Proteins
Neoplasm Proteins
RNA, Messenger
Receptors, Bombesin
Doxorubicin
Bombesin
multidrug resistance-associated protein 1