Modeling the Effects of Space Structure and Combination Therapies on Phenotypic Heterogeneity and Drug Resistance in Solid Tumors

Histopathological evidence supports the idea that the emergence of phenotypic heterogeneity and resistance to cytotoxic drugs can be considered as a process of selection in tumor cell populations. In this framework, can we explain intra-tumor heterogeneity in terms of selection driven by the local c...

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Bibliographic Details
Published in:Bulletin of mathematical biology 2015-01, Vol.77 (1), p.1-22
Main Authors: Lorz, Alexander, Lorenzi, Tommaso, Clairambault, Jean, Escargueil, Alexandre, Perthame, Benoît
Format: Article
Language:English
Subjects:
Analysis of PDEs
Antineoplastic Combined Chemotherapy Protocols
Cell Biology
Drug Resistance, Neoplasm
Humans
Life Sciences
Mathematical and Computational Biology
Mathematical Concepts
Mathematics
Mathematics and Statistics
Models, Biological
Neoplasms - drug therapy
Neoplasms - pathology
Original Article
Phenotype
Spheroids, Cellular - drug effects
Spheroids, Cellular - pathology
Tumor Microenvironment - drug effects
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Summary:Histopathological evidence supports the idea that the emergence of phenotypic heterogeneity and resistance to cytotoxic drugs can be considered as a process of selection in tumor cell populations. In this framework, can we explain intra-tumor heterogeneity in terms of selection driven by the local cell environment? Can we overcome the emergence of resistance and favor the eradication of cancer cells by using combination therapies? Bearing these questions in mind, we develop a model describing cell dynamics inside a tumor spheroid under the effects of cytotoxic and cytostatic drugs. Cancer cells are assumed to be structured as a population by two real variables standing for space position and the expression level of a phenotype of resistance to cytotoxic drugs. The model takes explicitly into account the dynamics of resources and anticancer drugs as well as their interactions with the cell population under treatment. We analyze the effects of space structure and combination therapies on phenotypic heterogeneity and chemotherapeutic resistance. Furthermore, we study the efficacy of combined therapy protocols based on constant infusion and bang–bang delivery of cytotoxic and cytostatic drugs.
ISSN:0092-8240
1522-9602
DOI:10.1007/s11538-014-0046-4