Iterative Design and in Vivo Evaluation of an Oncolytic Antilymphoma Peptide

Oncolytic peptides represent a promising new strategy within the field of cancer immunotherapy. Here we describe the systematic design and evaluation of short antilymphoma peptides within this paradigm. The peptides were tested in vitro and in vivo to identify a lead compound for further evaluation...

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Published inJournal of medicinal chemistry Vol. 60; no. 1; pp. 146 - 156
Main Authors Eksteen, J. Johannes, Ausbacher, Dominik, Simon-Santamaria, Jaione, Stiberg, Trine, Cavalcanti-Jacobsen, Cristiane, Wushur, Imin, Svendsen, John S, Rekdal, Øystein
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 12.01.2017
Amer Chemical Soc
Subjects
Animals
Cell Line, Tumor
Chemistry, Medicinal
Drug Design
Drug Evaluation, Preclinical
Humans
Life Sciences & Biomedicine
Membrane Potential, Mitochondrial
Mice
Peptides - chemistry
Peptides - pharmacology
Pharmacology & Pharmacy
Science & Technology
ANTICANCER MECHANISMS
CELLULAR-UPTAKE
KILLS CANCER-CELLS
CATIONIC ANTIBACTERIAL PEPTIDES
AMINO-ACIDS
ENHANCED ANTITUMOR-ACTIVITY
LTX-315
ANTIMICROBIAL PEPTIDES
ARGININE-RICH PEPTIDES
PENETRATING PEPTIDES
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Summary:Oncolytic peptides represent a promising new strategy within the field of cancer immunotherapy. Here we describe the systematic design and evaluation of short antilymphoma peptides within this paradigm. The peptides were tested in vitro and in vivo to identify a lead compound for further evaluation as novel oncolytic immunotherapeutic. In vitro tests revealed peptides with high activity against several lymphoma types and low cytotoxicity toward normal cells. Treated lymphoma cells exhibited a reduced mitochondrial membrane potential that resulted in an irreversible disintegration of their plasma membranes. No caspase activation or ultrastructural features of apoptotic cell death were observed. One of these peptides, 11, was shown to induce complete tumor regression and protective immunity following intralesional treatment of murine A20 B-lymphomas. Due to its selectivity for lymphoma cells and its ability to induce tumor-specific immune responses, 11 has the potential to be used in intralesional treatment of accessible lymphoma tumors.
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ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b00839