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Peptide-linked 1,3-dialkyl-3-acyltriazenes: gastrin receptor directed antineoplastic alkylating agents
B F Schmidt1, L Hernandez, C Rouzer
1Molecular Aspects of Drug Design Section, MSL, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702.
Abstract:
The gastrin receptor is expressed in various human cancers, such as the adenocarcinoma of the colon. The peptide hormone gastrin and the C-terminal peptides derived from it act as growth factors for these cancers. The hypothesis for the present work was to use the gastrin receptor as a target for appropriately constructed cytotoxic agents. We developed methods to link tetragastrin and pentagastrin by their N-termini to cytotoxic 1-(2-chloroethyl)-3-benzyl-3-succinoyltriazene. These compounds, CBS-4 and CBS-5, respectively, whose complete structures were determined by multinuclear NMR and mass spectrometry, competed effectively with gastrin in an assay using either guinea pig stomach fundus or 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 lung cancer cells, which do not express the receptor.
Insights
Researchers targeted the gastrin receptor in cancers using novel cytotoxic agents. Tetragastrin and pentagastrin conjugates (CBS-4, CBS-5) effectively targeted the receptor, with CBS-5 showing cancer cell cytotoxicity.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- The gastrin receptor is implicated in the growth of various human cancers, including colon adenocarcinoma.
- Gastrin and its derived peptides function as growth factors for these specific cancer types.
- Targeting the gastrin receptor presents a potential therapeutic strategy for cancer treatment.
Purpose of the Study:
- To develop and evaluate cytotoxic agents that specifically target the gastrin receptor.
- To investigate the efficacy of novel gastrin-receptor-targeted compounds in cancer models.
Main Methods:
- Synthesis of tetragastrin and pentagastrin conjugates (CBS-4, CBS-5) linked to a cytotoxic triazene.
- Structural elucidation of CBS-4 and CBS-5 using multinuclear NMR and mass spectrometry.
- In vitro assays using guinea pig stomach fundus and rat AR42J tumor cells to assess receptor binding and cytotoxicity.
Main Results:
- CBS-4 and CBS-5 effectively competed with gastrin for receptor binding.
- CBS-5 demonstrated significant cytotoxicity against AR42J cells expressing the gastrin receptor.
- CBS-5 exhibited no toxicity towards A549 human lung cancer cells lacking gastrin receptor expression.
Conclusions:
- Gastrin receptor-targeted cytotoxic agents, CBS-4 and CBS-5, were successfully developed.
- CBS-5 shows promise as a selective cytotoxic agent for gastrin receptor-positive cancers.
- This approach validates the gastrin receptor as a viable target for novel cancer therapeutics.