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Volume 5 Toxicology: Open Access Toxicology Congress 2019
May 06-07, 2019
May 06-07, 2019 Tokyo, Japan
20th World Congress on
Toxicology and Pharmacology
Ben C Valdez et al., Toxicol Open Access 2019, Volume 5
DOI: 10.4172/2476-2067-C1-008
Pharmacological optimization of the conditioning regimen for hematopoietic stem cell transplantation
Ben C Valdez and Borje S Andersson
The University of Texas MD Anderson Cancer Center, USA
Hematopoietic stem cell transplantation is an effective treatment for a variety of hematological disorders. Its success partly
depends on the optimization of the pre-transplant conditioning regimen. To identify an efficacious regimen, we exposed
cells to different drug combinations, analyzed their cytotoxicity and identified their molecular mechanisms of interaction
using various techniques. We have shown the synergistic cytotoxicity of DNA Alkylating Agents (AA) and Nucleoside Analogs
(NA) in leukemia and lymphoma cells and proposed a mechanistic model called the loop of death. Exposure of cells to a
nucleoside analog initiates DNA damage resulting in chromatin remodeling and makes genomic DNA more susceptible to
DNA alkylation. DNA damage response is then activated and the loop of DNA damage, chromatin remodeling and DNA
alkylation continues until the tumor cells commit to apoptosis. Using this model and the [AA+NA] combination as a backbone
to identify drugs that may further enhance its anti-tumor activity, we hypothesized that epigenetic modifiers would amplify the
loop of death. Indeed, inhibitors of Histone Deacetylases (HDACi) and DNA Methyl Transferases (DNMTi), which facilitate
relaxation of chromatin, were found to be synergistic with [AA+NA]. Since active DNA repair may contribute to decreased
efficacy of these drug combinations, we also examined the inclusion of DNA repair inhibitors such as olaparib. Addition of
olaparib to [AA+NA] caused significant apoptosis by activation of the DNA, damage response, inhibition of PARP activity
and DNA repair, production of reactive oxygen species and depolarization of the mitochondrial membranes. Overall, our pre-
clinical and clinical results suggest that the conditioning regimen for HSCT may be optimized by combining drugs that provide
synergistic cytotoxicity based on their molecular mechanisms of action.
Biography
Ben C Valdez has completed his PhD in Biochemistry at Louisiana State University. He has completed his Post-doctoral training at Baylor College of Medicine
in Houston, Texas. His current research focuses on the identification of safe and efficacious conditioning regimen for hematopoietic stem cell transplantation for
patients with hematological disorders.