Oncotarget

Research Papers:

Integrated experimental and simulation study of the response to sequential treatment with erlotinib and gemcitabine in pancreatic cancer

Paolo Ubezio, Francesca Falcetta, Laura Carrassa and Monica Lupi _

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Oncotarget. 2016; 7:15492-15506. https://doi.org/10.18632/oncotarget.7491

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Abstract

Paolo Ubezio1, Francesca Falcetta1, Laura Carrassa1, Monica Lupi1

1Department of Oncology, IRCCS – Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, Italy

Correspondence to:

Monica Lupi, e-mail: monica.lupi@marionegri.it

Keywords: erlotinib, gemcitabine, pancreatic cancer, mathematical model, cell cycle

Received: September 03, 2015     Accepted: January 29, 2016     Published: February 19, 2016

ABSTRACT

The combination of erlotinib with gemcitabine is one of the most promising therapies for advanced pancreatic cancer. Aiming at optimizing this combination, we analyzed in detail the response to sequential treatments with erlotinib → gemcitabine and gemcitabine → erlotinib with an 18 h interval, adopting a previously established experimental/computational approach to quantify the cytostatic and cytotoxic effects at G1, S and G2M checkpoints. This assessment was achieved by contemporary fits of flow cytometric and time-lapse experiments in two human pancreatic cancer cell lines (BxPC-3 and Capan-1) with a mathematical model reproducing the fluxes of cells through the cycle during and after treatment.

The S-phase checkpoint contributes in the response to erlotinib, suggesting that the G1 arrest may hamper S-phase cytotoxicity. The response to gemcitabine was driven by the dynamics of the progressive resumption from the S-phase arrest after drug washout. The effects induced by single drugs were used to simulate combined treatments, introducing changes when required. Gemcitabine → erlotinib was more than additive in both cell lines, strengthening the cytostatic effects on cells recovering from the arrest induced by gemcitabine. The interval in the erlotinib → gemcitabine sequence enabled to overcome the antagonist effect of G1 block on gemcitabine efficacy and improved the outcome in Capan-1 cells.


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