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PLoS Biol. 2017 Feb 9;15(2):e2001110. doi: 10.1371/journal.pbio.2001110. eCollection 2017 Feb.

How to Use a Chemotherapeutic Agent When Resistance to It Threatens the Patient.

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Center for Infectious Disease Dynamics, Departments of Biology and Entomology, Pennsylvania State University, Pennsylvania, United States of America.
Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.


When resistance to anticancer or antimicrobial drugs evolves in a patient, highly effective chemotherapy can fail, threatening patient health and lifespan. Standard practice is to treat aggressively, effectively eliminating drug-sensitive target cells as quickly as possible. This prevents sensitive cells from acquiring resistance de novo but also eliminates populations that can competitively suppress resistant populations. Here we analyse that evolutionary trade-off and consider recent suggestions that treatment regimens aimed at containing rather than eliminating tumours or infections might more effectively delay the emergence of resistance. Our general mathematical analysis shows that there are situations in which regimens aimed at containment will outperform standard practice even if there is no fitness cost of resistance, and, in those cases, the time to treatment failure can be more than doubled. But, there are also situations in which containment will make a bad prognosis worse. Our analysis identifies thresholds that define these situations and thus can guide treatment decisions. The analysis also suggests a variety of interventions that could be used in conjunction with cytotoxic drugs to inhibit the emergence of resistance. Fundamental principles determine, across a wide range of disease settings, the circumstances under which standard practice best delays resistance emergence-and when it can be bettered.

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