NDLI: Cytotoxic agents directed to peptide hormone receptors: Defining the requirements for a successful drug

Content Provider	PubMed Central
Author	Czerwinski, Grzegorz Tarasova, Nadya I. Michejda, Christopher J.
Copyright Year	1998
Abstract	In principle, cell surface receptors that are overexpressed intumor tissue could serve as targets for anticancer drugs attached toreceptor ligands. The purpose of this paper is to identify thenecessary elements for a successful receptor-targeted drug. We used thegastrin/cholecystokinin type B receptor as a model delivery system,and we report on the synthesis, trafficking, and invitro and in vivo evaluation of heptagastrin,the C-terminal heptapeptide of gastrin, linked via an appropriatelinker to a potently cytotoxic ellipticine derivative,1-[3-[N-(3-aminopropyl)-N-methylamino]propyl]amino-9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole.These data, and previous work from our laboratory, show that thedrug-complexed ligand is sorted to lysosomes whereas the receptor isrecycled to the plasma membrane. The lysosomal processing of theligand/drug construct depends on the linker between the ligandsequence and the cytotoxic moiety. We show that heptagastrin linked toellipticine via a succinoyl-substituted pentapeptide, AlaLeuAlaLeuAla,is at least 103 more toxic to cholecystokinin type Breceptor-positive NIH/3T3 cells than to isogenic NIH/3T3 cellslacking the receptor. The conjugated drug eradicated allreceptor-positive tumor cells in vivo without producingany general toxicity. The data indicate that the density of the cellsurface receptor, the properties of the cytotoxic moiety, and thecorrect processing of the drug-conjugated ligand in lysosomes arecrucial to the effectiveness of a receptor-targeted drug.
Starting Page	11520
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	20
Volume Number	95
Language	English
Publisher	National Academy of Sciences
Publisher Date	1998-09-29
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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Antagonistic actions of analogs related to growth hormone-releasing hormone (GHRH) on receptors for GHRH and vasoactive intestinal peptide on rat pituitary and pineal cells in vitro

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Cytotoxic agents directed to peptide hormone receptors: Defining the requirements for a successful drug

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