PEPTIDE-LINKED 1,3-DIALKYL-3-ACYLTRIAZENES - GASTRIN RECEPTOR DIRECTED ANTINEOPLASTIC ALKYLATING-AGENTS

The gastrin receptor is expressed in various human cancers, such as th e adenocarcinoma of the colon. The peptide hormone gastrin and the C-t erminal peptides derived from it act as growth factors for these cance rs. The hypothesis for the present work was to use the gastrin recepto r as a target for appropriately constructed cytotoxic agents. We devel oped methods to link tetragastrin and pentagastrin by their N-termini to cytotoxic 1-(2-chloroethyl)-3-benzyl-3-succinoyltriazene. These com pounds, CBS-4 and CBS-5, respectively, whose complete structures were determined by multinuclear NMR and mass spectrometry, competed effecti vely with gastrin in an assay using either guinea pig stomach fundus o r the rat acinar tumor cell line AR42J as the source of the receptor. CBS-5 was cytotoxic to AR42J cells but was not toxic to A549 human lun g cancer cells, which do not express the receptor.