Document Detail

Evaluation of a reductively activated duocarmycin prodrug against murine and human solid cancers.
MedLine Citation:
PMID:  23760495     Owner:  NLM     Status:  MEDLINE    
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.
George A Vielhauer; Megan Swink; Nikhil K Parelkar; James P Lajiness; Amanda L Wolfe; Dale Boger
Related Documents :
23178255 - Synthesis and anti-tumor evaluation of novel 25-hydroxyprotopanaxadiol analogues incorp...
23029025 - Activating mutations in β-catenin in colon cancer cells alter their interaction with ma...
24297535 - Integrative analysis of two cell lines derived from a non-small-lung cancer patient - a...
8614855 - Tumoral calcinosis: radiologic-pathologic correlation.
21750865 - Expression of 4f2hc (cd98) in pulmonary neuroendocrine tumors.
21165225 - A case of primary cutaneous mucinous carcinoma with neuroendocrine differentiation.
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    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
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
Indoles / pharmacology*,  therapeutic use
Lung Neoplasms / drug therapy*
Mice, Nude
Prodrugs / pharmacology*,  therapeutic use
Xenograft Model Antitumor Assays
Reg. No./Substance:
0/Antineoplastic Agents; 0/Carbamates; 0/Indoles; 0/Prodrugs

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Dietary supplemented 2-mercaptoethanol prevents spontaneous and delays virally-induced murine mammar...
Next Document:  Comparative antiproliferative effects of iniparib and olaparib on a panel of triple-negative and non...