title: Integrated experimental and simulation study of the response to sequential treatment with erlotinib and gemcitabine in pancreatic cancer.
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.
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ubezio
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Falcetta
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Carrassa
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Lupi
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage*; D006801:Humans; D008962:Models, Theoretical; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D000093542:Gemcitabine
keywords: cell cycle; erlotinib; gemcitabine; mathematical model; pancreatic cancer