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J. Biol. Chem., Vol. 279, Issue 22, 23580-23589, May 28, 2004

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Development of High Affinity Camptothecin-Bombesin Conjugates That Have Targeted Cytotoxicity for Bombesin Receptor-containing Tumor Cells^*

Terry W. Moody, Samuel A. Mantey, Tapas K. Pradhan, Michael Schumann, Tomoo Nakagawa, Alfredo Martinez¶, Joseph Fuselier||, David H. Coy||, and Robert T. Jensen**

From the Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892,Digestive Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892,^¶Cell and Cancer Biology Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892, and the^||Department of Medicine, Peptide Research Laboratories, Tulane University Health Sciences Center, New Orleans, Louisiana 70112

Mammalian bombesin (BN) receptors are among those most frequently overexpressed by a number of common tumors including prostate, breast, lung, and colon cancers. The aim of this study was to develop a camptothecin-bombesin (CPT-BN) conjugate that interacts with all classes of BN receptors and possibly functions as a prodrug via a labile linker with site-specific cytotoxicity for cancer cells bearing these receptors. CPT was coupled to analogs of [D-Tyr⁶,-Ala¹¹,Phe¹³,Nle¹⁴]BN-(6-14) (BA0) using carbamate linkers (L1 and L2) with built-in nucleophile-assisted releasing groups for intracellular cleavage of free cytotoxic agents. One conjugate, CPT-L2-BA3, bound to all three BN receptor classes with high affinity and functioned as a full agonist at each. ¹²⁵ICPT-L2-BA3 was rapidly internalized by cells expressing each BN receptor class and, using fluorescent imaging, was found to co-localize with BN receptors initially and later to be internalized in cytoplasmic compartments. HPLC analysis of internalized ligand showed that 40% was intact, 25% was metabolized by releasing free CPT, and 35% was metabolized to other breakdown products. CPT-L2-BA3 inhibited the growth of NCI-H1299 non-small cell lung cancer cells in 3-(4,5-dimethylthiazol-2-yl)-2.5-diphenyl-2H-tetrazolium bromide (MTT) and clonal growth assays. CPT-L2-BA3 was cytotoxic in an MTT assay for cells transfected with each class of BN receptor; however, it had significantly less effect in cells lacking BN receptors. These results indicate that CTP-L2-BA3 is a potent agonist that is cytotoxic for cells overexpressing any of the three BN receptor classes and functions as a prodrug for receptor-mediated cytoxicity. It therefore should be a useful prototype to explore the effectiveness of tumor-specific cytotoxicity delivery using a receptor-mediated mechanism.

Received for publication, February 22, 2004 , and in revised form, March 10, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: NIDDK, National Institutes of Health, DDB, Bldg. 10, Rm. 9C203, 10 Center Dr. MSC 1804, Bethesda, MD 20892-1804. Tel.: 301-496-4201; Fax: 301-402-0600; E-mail: robertj{at}intra.niddk.nih.gov.

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