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.
Highlights
An investigational form of therapy known as low-dose metronomic chemotherapy has been studied both preclinically and clinically for almost two decades [1,2,3,4,5]
231/LM2-4 human breast cancer variant cell line was orthotopically implanted in the mammary fat pad of female severe combined immunodeficient (SCID) mice
Our results provide a possible explanation for a previously reported paradoxical observation, namely, why a particular metronomic chemotherapy regimen, in this case that was used to treat a triple negative breast cancer xenograft–had only a very modest effect on delaying orthotopic primary tumor growth, but caused major inhibition of established metastatic disease in a postsurgical model
Summary
An investigational form of therapy known as low-dose metronomic chemotherapy has been studied both preclinically and clinically for almost two decades [1,2,3,4,5]. Most preclinical and metronomic clinical trial studies utilize oral drugs such as CTX, the 5-fluorouracil (5-FU) prodrugs capecitabine or UFT (uracil plus tegafur), methotrexate, topotecan, and vinorelbine [13,14,15,16,17,18,19,20], all of which can be taken on a convenient out-patient basis at home, and are usually associated with reduced serious acute toxic (adverse) events [4] These drugs, all being off-patent, mean that the cost of metronomic chemotherapies can be inexpensive [5]
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