The aim of the study was to evaluate the effects and the related pharmacological mechanisms of switched schedules of antiangiogenic and chemotherapeutic drugs beyond progression after a first line treatment in a colorectal cancer preclinical model. In vivo studies were performed in nude mice subcutaneously transplanted with colon cancer cells. The treatments included drug combinations with a switch between chemotherapeutic (i.e., irinotecan and 5-fluoruracil) and/or antiangiogenic drugs (i.e., anti-VEGF antibodies and sunitinib) at the time of tumor progression. Proliferation assays were also achieved in vitro on different colon cancer cell lines exposed to SN-38 and sunitinib alone or in combination. ABCG2 gene expression were performed with real-time PCR and SN-38 intracellular concentrations were measured. The switch in the combined treatments, at the time of tumor progression, of the chemotherapeutic (from irinotecan to 5-fluoruracil), or the antiangiogenic drug (from anti-VEGF antibodies to sunitinib) or of both drugs induced a new response. Immunohistochemistry of stromal PDGF-C, PlGF, SD1-α, Tie-2, and VEGFR-2 showed statistical differences between tumors at the time of relapse and after the switched therapy. Moreover, the combination of SN-38 and sunitinib caused synergism on colon cancer cells, with a significant inhibition of the ABCG2 gene expression and an increase of SN-38 intracellular concentrations. Our observations may be of clinical relevance, suggesting the switch of single chemotherapeutic or antiangiogenic drugs beyond progression of disease to obtain a new tumor response due to a modulation of angiogenic factors and a direct effect on tumor cells with possible variation of intracellular drug concentrations.
DI DESIDERO, TERESA (Primo)
BOCCI, GUIDO (Ultimo)
|Autori:||Di Desidero, Teresa; Orlandi, Paola; Fioravanti, Anna; Alì, Greta; Cremolini, Chiara; Loupakis, Fotios; Gentile, Daniela; Banchi, Marta; Cucchiara, Federico; Antoniotti, Carlotta; Masi, Gianluca; Fontanini, Gabriella; Falcone, Alfredo; Bocci, Guido|
|Titolo:||Chemotherapeutic and antiangiogenic drugs beyond tumor progression in colon cancer: evaluation of the effects of switched schedules and related pharmacodynamics|
|Anno del prodotto:||2019|
|Digital Object Identifier (DOI):||10.1016/j.bcp.2019.04.001|
|Appare nelle tipologie:||1.1 Articolo in rivista|