Cargando…

Integration of Principles of Systems Biology and Radiation Biology: Toward Development of in silico Models to Optimize IUdR-Mediated Radiosensitization of DNA Mismatch Repair Deficient (Damage Tolerant) Human Cancers

Over the last 7 years, we have focused our experimental and computational research efforts on improving our understanding of the biochemical, molecular, and cellular processing of iododeoxyuridine (IUdR) and ionizing radiation (IR) induced DNA base damage by DNA mismatch repair (MMR). These coordina...

Descripción completa

Detalles Bibliográficos
Autores principales: Kinsella, Timothy J., Gurkan-Cavusoglu, Evren, Du, Weinan, Loparo, Kenneth A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Research Foundation 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355906/
https://www.ncbi.nlm.nih.gov/pubmed/22649757
http://dx.doi.org/10.3389/fonc.2011.00020
_version_ 1782233458203951104
author Kinsella, Timothy J.
Gurkan-Cavusoglu, Evren
Du, Weinan
Loparo, Kenneth A.
author_facet Kinsella, Timothy J.
Gurkan-Cavusoglu, Evren
Du, Weinan
Loparo, Kenneth A.
author_sort Kinsella, Timothy J.
collection PubMed
description Over the last 7 years, we have focused our experimental and computational research efforts on improving our understanding of the biochemical, molecular, and cellular processing of iododeoxyuridine (IUdR) and ionizing radiation (IR) induced DNA base damage by DNA mismatch repair (MMR). These coordinated research efforts, sponsored by the National Cancer Institute Integrative Cancer Biology Program (ICBP), brought together system scientists with expertise in engineering, mathematics, and complex systems theory and translational cancer researchers with expertise in radiation biology. Our overall goal was to begin to develop computational models of IUdR- and/or IR-induced base damage processing by MMR that may provide new clinical strategies to optimize IUdR-mediated radiosensitization in MMR deficient (MMR(−)) “damage tolerant” human cancers. Using multiple scales of experimental testing, ranging from purified protein systems to in vitro (cellular) and to in vivo (human tumor xenografts in athymic mice) models, we have begun to integrate and interpolate these experimental data with hybrid stochastic biochemical models of MMR damage processing and probabilistic cell cycle regulation models through a systems biology approach. In this article, we highlight the results and current status of our integration of radiation biology approaches and computational modeling to enhance IUdR-mediated radiosensitization in MMR(−) damage tolerant cancers.
format Online
Article
Text
id pubmed-3355906
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher Frontiers Research Foundation
record_format MEDLINE/PubMed
spelling pubmed-33559062012-05-30 Integration of Principles of Systems Biology and Radiation Biology: Toward Development of in silico Models to Optimize IUdR-Mediated Radiosensitization of DNA Mismatch Repair Deficient (Damage Tolerant) Human Cancers Kinsella, Timothy J. Gurkan-Cavusoglu, Evren Du, Weinan Loparo, Kenneth A. Front Oncol Oncology Over the last 7 years, we have focused our experimental and computational research efforts on improving our understanding of the biochemical, molecular, and cellular processing of iododeoxyuridine (IUdR) and ionizing radiation (IR) induced DNA base damage by DNA mismatch repair (MMR). These coordinated research efforts, sponsored by the National Cancer Institute Integrative Cancer Biology Program (ICBP), brought together system scientists with expertise in engineering, mathematics, and complex systems theory and translational cancer researchers with expertise in radiation biology. Our overall goal was to begin to develop computational models of IUdR- and/or IR-induced base damage processing by MMR that may provide new clinical strategies to optimize IUdR-mediated radiosensitization in MMR deficient (MMR(−)) “damage tolerant” human cancers. Using multiple scales of experimental testing, ranging from purified protein systems to in vitro (cellular) and to in vivo (human tumor xenografts in athymic mice) models, we have begun to integrate and interpolate these experimental data with hybrid stochastic biochemical models of MMR damage processing and probabilistic cell cycle regulation models through a systems biology approach. In this article, we highlight the results and current status of our integration of radiation biology approaches and computational modeling to enhance IUdR-mediated radiosensitization in MMR(−) damage tolerant cancers. Frontiers Research Foundation 2011-08-10 /pmc/articles/PMC3355906/ /pubmed/22649757 http://dx.doi.org/10.3389/fonc.2011.00020 Text en Copyright © 2011 Kinsella, Gurkan-Cavusoglu, Du and Loparo. http://www.frontiersin.org/licenseagreement This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.
spellingShingle Oncology
Kinsella, Timothy J.
Gurkan-Cavusoglu, Evren
Du, Weinan
Loparo, Kenneth A.
Integration of Principles of Systems Biology and Radiation Biology: Toward Development of in silico Models to Optimize IUdR-Mediated Radiosensitization of DNA Mismatch Repair Deficient (Damage Tolerant) Human Cancers
title Integration of Principles of Systems Biology and Radiation Biology: Toward Development of in silico Models to Optimize IUdR-Mediated Radiosensitization of DNA Mismatch Repair Deficient (Damage Tolerant) Human Cancers
title_full Integration of Principles of Systems Biology and Radiation Biology: Toward Development of in silico Models to Optimize IUdR-Mediated Radiosensitization of DNA Mismatch Repair Deficient (Damage Tolerant) Human Cancers
title_fullStr Integration of Principles of Systems Biology and Radiation Biology: Toward Development of in silico Models to Optimize IUdR-Mediated Radiosensitization of DNA Mismatch Repair Deficient (Damage Tolerant) Human Cancers
title_full_unstemmed Integration of Principles of Systems Biology and Radiation Biology: Toward Development of in silico Models to Optimize IUdR-Mediated Radiosensitization of DNA Mismatch Repair Deficient (Damage Tolerant) Human Cancers
title_short Integration of Principles of Systems Biology and Radiation Biology: Toward Development of in silico Models to Optimize IUdR-Mediated Radiosensitization of DNA Mismatch Repair Deficient (Damage Tolerant) Human Cancers
title_sort integration of principles of systems biology and radiation biology: toward development of in silico models to optimize iudr-mediated radiosensitization of dna mismatch repair deficient (damage tolerant) human cancers
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355906/
https://www.ncbi.nlm.nih.gov/pubmed/22649757
http://dx.doi.org/10.3389/fonc.2011.00020
work_keys_str_mv AT kinsellatimothyj integrationofprinciplesofsystemsbiologyandradiationbiologytowarddevelopmentofinsilicomodelstooptimizeiudrmediatedradiosensitizationofdnamismatchrepairdeficientdamagetoleranthumancancers
AT gurkancavusogluevren integrationofprinciplesofsystemsbiologyandradiationbiologytowarddevelopmentofinsilicomodelstooptimizeiudrmediatedradiosensitizationofdnamismatchrepairdeficientdamagetoleranthumancancers
AT duweinan integrationofprinciplesofsystemsbiologyandradiationbiologytowarddevelopmentofinsilicomodelstooptimizeiudrmediatedradiosensitizationofdnamismatchrepairdeficientdamagetoleranthumancancers
AT loparokennetha integrationofprinciplesofsystemsbiologyandradiationbiologytowarddevelopmentofinsilicomodelstooptimizeiudrmediatedradiosensitizationofdnamismatchrepairdeficientdamagetoleranthumancancers