Abstract
Cancers have been revealed to be extremely heterogenous in terms of the frequency and types of mutations present in cells from different malignant tumors. Thus, it is likely that uniform clinical treatment is not optimal for all patients, and that the development of individualized therapeutic regimens may be beneficial. We describe the generation of multiple, unique small peptides nine to thirty-four amino acids in length which, when labeled with the radioisotope 32P, bind with vastly differing efficiencies to cell lines derived from different colon adenocarcinomas. In addition, the most effective of these peptides permanently transfers the 32P radioisotope to colorectal cancer cellular proteins within two hours at a rate that is more than 150 times higher than in cell lines derived from other cancers or from the normal tissues tested. Currently, the only two FDA-approved radioimmunotherapeutic agents in use both employ antibodies directed against the B cell marker CD20 for the treatment of non-Hodgkin's lymphoma. By using the method described herein, large numbers of different 32P-labeled peptides can be readily produced and assayed against a broad spectrum of cancer types. This report proposes the development and use of 32P-labeled peptides as potential individualized peptide-binding therapies for the treatment of colon adenocarcinoma patients.
Highlights
Recent landmark discoveries have convincingly documented the extensive genetic heterogeneity among human cancers, colorectal tumors, by establishing the existence of a small number of frequently mutated gene ‘‘mountains’’ and a much higher number of gene ‘‘hills’’ mutated at much lower frequencies [1,2]
We recently reported a set of nine different decapeptides, each varying from the others by only one to three amino acids, which when labeled with the beta-emitter 32P, bound to and permanently delivered, to varying degrees, this radioisotope to cell lines derived from a panel of different colorectal adenocarcinomas [13]
32P-Labeled Peptides to three amino acids, that exhibited widely disparate abilities to bind to and transfer radioisotope permanently to proteins in cell lines established from a panel of colon adenocarcinomas
Summary
Recent landmark discoveries have convincingly documented the extensive genetic heterogeneity among human cancers, colorectal tumors, by establishing the existence of a small number of frequently mutated gene ‘‘mountains’’ and a much higher number of gene ‘‘hills’’ mutated at much lower frequencies [1,2]. Several anticancer immunotherapies are currently in use, including Herceptin, Rituxin, and Avastin, a monoclonal antibody directed against VEGF (vascular endothelial growth factor) that is approved for colorectal cancer treatment [3,4,5,6,7,8,9]. Each protocol utilizes a monoclonal antibody directed against the CD20 B-cell marker and can deliver 90Y (Zevalin) or 131I (Bexxar), each of which generates electrons (beta particles) that damage DNA, resulting in cell death [10,11]. No RIT has yet been approved for the treatment of colorectal cancer [12]
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