Predictive Modeling of Drug Response in Non-Hodgkin's Lymphoma. Academic Article uri icon

Overview

abstract

  • We combine mathematical modeling with experiments in living mice to quantify the relative roles of intrinsic cellular vs. tissue-scale physiological contributors to chemotherapy drug resistance, which are difficult to understand solely through experimentation. Experiments in cell culture and in mice with drug-sensitive (Eµ-myc/Arf-/-) and drug-resistant (Eµ-myc/p53-/-) lymphoma cell lines were conducted to calibrate and validate a mechanistic mathematical model. Inputs to inform the model include tumor drug transport characteristics, such as blood volume fraction, average geometric mean blood vessel radius, drug diffusion penetration distance, and drug response in cell culture. Model results show that the drug response in mice, represented by the fraction of dead tumor volume, can be reliably predicted from these inputs. Hence, a proof-of-principle for predictive quantification of lymphoma drug therapy was established based on both cellular and tissue-scale physiological contributions. We further demonstrate that, if the in vitro cytotoxic response of a specific cancer cell line under chemotherapy is known, the model is then able to predict the treatment efficacy in vivo. Lastly, tissue blood volume fraction was determined to be the most sensitive model parameter and a primary contributor to drug resistance.

publication date

  • June 10, 2015

Research

keywords

  • Antibiotics, Antineoplastic
  • Doxorubicin
  • Lymphoma, Non-Hodgkin
  • Models, Theoretical

Identity

PubMed Central ID

  • PMC4464754

Scopus Document Identifier

  • 84936803077

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0129433

PubMed ID

  • 26061425

Additional Document Info

volume

  • 10

issue

  • 6