Suppressive impact of metronomic chemotherapy using UFT and/or cyclophosphamide on mediators of breast cancer dissemination and invasion

Abstract

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.

Efficacy of Cold Atmospheric Plasma vs. Chemotherapy in Triple-Negative Breast Cancer: A Systematic Review

“…To obtain animal models, the strains CB-17 of severe combined immunodeficiency mice [ 56 , 61 , 70 ] and Balb/c were used [ 79 , 84 ] and were inoculated with the TNBC cell line MDA-MB-231.…”

Co-targeting triple-negative breast cancer cells and endothelial cells by metronomic chemotherapy inhibits cell regrowth and migration via downregulation of the FAK/VEGFR2/VEGF axis and autophagy/apoptosis activation

“…Accordingly, in the tube formation assay, the mCHT administration resulted in ~50% of the total tube length, the total mesh area and the numbers of branching points compared to ~20% observed after STD administration ( Figure 8 ; Supplementary Figure 2 ). Several studies reported an anti-migratory effect of some antitumoral agents when given metronomically, such as ceramide analogs, docetaxel, the 5-FU prodrug UFT (uracil plus tegafur) plus cyclophosphamide ( 54 – 56 ).…”

Daphnoretin Arrests the Cell Cycle and Induces Apoptosis in Human Breast Cancer Cells

“…The incidence rate, mortality, and recurrence rate remain unsatisfactory for breast cancer patients. − In chemotherapy, which is an important clinical treatment for breast cancer, paclitaxel, docetaxel, doxorubicin, trastuzumab, and cyclophosphamide are the first-line drugs. − However, the adverse effects of drugs and the drug resistance in cancer often lead to a poor outcome of chemotherapy . Therefore, it is urgent to find novel and effective candidates to enhance the therapeutic effect of breast cancer.…”