Utilizing temporal variations in chemotherapeutic response to improve breast cancer treatment efficacy

Daniel J. McGrail; Krishan S. Patel; Niti N. Khambhati; Kishan Pithadia; Michelle R. Dawson; Daniel J. McGrail; Krishan S. Patel; Niti N. Khambhati; Kishan Pithadia; Michelle R. Dawson

doi:10.3934/bioeng.2015.4.310

AIMS Bioengineering

2015, Volume 2, Issue 4: 310-323. doi: 10.3934/bioeng.2015.4.310

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Research article

Utilizing temporal variations in chemotherapeutic response to improve breast cancer treatment efficacy

1.
School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332-0100;
2.
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA;
3.
School of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA;
4.
The Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA

Received: 25 June 2015 Accepted: 26 August 2015 Published: 06 September 2015

Though survival rates for women with stage I breast cancer have radically improved, treatment options remain poor for the 40% of women diagnosed with later-stage disease. For these patients, improved chemotherapeutic treatment strategies are critical to eradicate any disseminated tumor cells. Despite many promising new drugs in vitro, most ultimately fail in the clinic. One aspect often lost during testing is in vivo circulation half-lives rarely exceed 24 hours, whereas in vitro studies involve drug exposure for 2-3 days. Here, we show how mimicking these exposure times alters efficacy. Next, using this model we show how drug response is highly time-dependent by extending analysis of cell viability out to two weeks. Variations in response both with feeding and time were dependent on drug mechanism of action. Finally, we show that by implementing this temporal knowledge of drug effects to optimize scheduling of drug administration we are able to regain chemosensitivity in a Carboplatin-resistant cell line.
- high-throughput screening,
- drug discovery,
- pharmacodynamics,
- pharmacokinetics,
- breast cancer,
- chemotherapy
Citation: Daniel J. McGrail, Krishan S. Patel, Niti N. Khambhati, Kishan Pithadia, Michelle R. Dawson. Utilizing temporal variations in chemotherapeutic response to improve breast cancer treatment efficacy[J]. AIMS Bioengineering, 2015, 2(4): 310-323. doi: 10.3934/bioeng.2015.4.310

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Abstract

Though survival rates for women with stage I breast cancer have radically improved, treatment options remain poor for the 40% of women diagnosed with later-stage disease. For these patients, improved chemotherapeutic treatment strategies are critical to eradicate any disseminated tumor cells. Despite many promising new drugs in vitro, most ultimately fail in the clinic. One aspect often lost during testing is in vivo circulation half-lives rarely exceed 24 hours, whereas in vitro studies involve drug exposure for 2-3 days. Here, we show how mimicking these exposure times alters efficacy. Next, using this model we show how drug response is highly time-dependent by extending analysis of cell viability out to two weeks. Variations in response both with feeding and time were dependent on drug mechanism of action. Finally, we show that by implementing this temporal knowledge of drug effects to optimize scheduling of drug administration we are able to regain chemosensitivity in a Carboplatin-resistant cell line.

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