Document Detail


Evaluation of a reductively activated duocarmycin prodrug against murine and human solid cancers.
MedLine Citation:
PMID:  23760495     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In treating cancer with clinically approved chemotherapies, the high systemic toxicity and lack of selectivity for malignant cells often result in an overall poor response rate. One pharmacological approach to improve patient response is to design targeted therapies that exploit the cancer milieu by reductively activating prodrugs, which results in the selective release of the free drug in the tumor tissue. Previously, we characterized prodrugs of seco-CBI-indole 2 (CBI-indole 2) designed to be activated in hypoxic tumor microenvironments, wherein the tumor maintains higher concentrations of "reducing" nucleophiles capable of preferentially releasing the free drug by nucleophilic attack on a weak N-O bond. Of these prodrugs, BocNHO-CBI-indole 2 (BocNHO) surpassed the efficacy of the free drug, CBI-indole 2, when examined in vivo in the murine L1210 leukemia model and demonstrated reduced toxicity suggesting a targeted or sustained release in vivo. Herein, we further examine the biological activity of the BocNHO prodrug in murine breast cancer, as well as human prostate and lung cancer cell lines, in vitro. Notably, BocNHO manifests potent antiproliferative and cytotoxic activity in all three tumor cell lines. However, in comparison to the activity observed in the murine cancer cell line, the human cancer cell lines were less sensitive, especially at early timepoints for cytotoxicity. Based on these findings, BocNHO was tested in a more clinically relevant orthotopic lung tumor model, revealing significant efficacy and reduced toxicity compared with the free drug. The data suggests that this pharmacological approach to designing targeted therapies is amenable to human solid tumors.
Authors:
George A Vielhauer; Megan Swink; Nikhil K Parelkar; James P Lajiness; Amanda L Wolfe; Dale Boger
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer biology & therapy     Volume:  14     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-06-13     Completed Date:  2014-01-14     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  527-36     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology*,  therapeutic use
Apoptosis / drug effects
Carbamates / pharmacology*,  therapeutic use
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Humans
Indoles / pharmacology*,  therapeutic use
Lung Neoplasms / drug therapy*
Mice
Mice, Nude
Oxidation-Reduction
Prodrugs / pharmacology*,  therapeutic use
Xenograft Model Antitumor Assays
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Carbamates; 0/Indoles; 0/Prodrugs
Comments/Corrections

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