Suppressive impact of metronomic chemotherapy using UFT and/or cyclophosphamide on mediators of breast cancer dissemination and invasion
Autoři:
Raquel Muñoz aff001; Denise Hileeto aff002; William Cruz-Muñoz aff001; Geoffrey A. Wood aff003; Ping Xu aff001; Shan Man aff001; Alicia Viloria-Petit aff004; Robert S. Kerbel aff001
Působiště autorů:
Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada
aff001; School of Optometry & Vision Science, University of Waterloo, Waterloo, Ontario, Canada
aff002; Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
aff003; Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
aff004; Department of Medical Biophysics, University of Toronto, Toronto, Canada
aff005
Vyšlo v časopise:
PLoS ONE 14(9)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0222580
Souhrn
Metronomic chemotherapy using the 5-FU prodrug uracil-tegafur (UFT) and cyclophosphamide (CTX) was previously shown to only modestly delay primary tumor growth, but nevertheless markedly suppressed the development of micro-metastasis in an orthotopic breast cancer xenograft model, using the metastatic variant of the MDA-MB-231 cell line, 231/LM2-4. Furthermore, a remarkable prolongation of survival, with no toxicity, was observed in a model of postsurgical advanced metastatic disease. A question that has remained unanswered is the seemingly selective anti-metastatic mechanisms of action responsible for this treatment. We assessed the in vivo effect of metronomic UFT, CTX or their combination, on vascular density, collagen deposition and c-Met (cell mediators or modulators of tumor cell invasion or dissemination) via histochemistry/immunohistochemistry of primary tumor sections. We also assessed the effect of continuous exposure to low and non-toxic doses of active drug metabolites 5-fluorouracil (5-FU), 4-hydroperoxycyclophosphamide (4-HC) or their combination, on 231/LM2-4 cell invasiveness in vitro. In the in vivo studies, a significant reduction in vascular density and p-Met[Y1003] levels was associated with UFT+CTX treatment. All treatments reduced intratumoral collagen deposition. In the in vitro studies, a significant reduction of collagen IV invasion by all treatments was observed. The 3D structures formed by 231/LM2-4 on Matrigel showed a predominantly Mass phenotype under treated conditions and Stellate phenotype in untreated cultures. Taken together, the results suggest the low-dose metronomic chemotherapy regimens tested can suppress several mediators of tumor invasiveness highlighting a new perspective for the anti-metastatic efficacy of metronomic chemotherapy.
Klíčová slova:
Medicine and health sciences – Oncology – Cancer treatment – Cancer chemotherapy – Clinical oncology – Cancers and neoplasms – Breast tumors – Breast cancer – Invasive tumors – Pharmaceutics – Drug therapy – Chemotherapy – Clinical medicine – Diagnostic medicine – Signs and symptoms – Pathology and laboratory medicine – Necrosis – Biology and life sciences – Biochemistry – Proteins – Collagens – Research and analysis methods – Specimen preparation and treatment – Staining – Cytoplasmic staining – Nuclear staining
Zdroje
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