Suppressive impact of metronomic chemotherapy using UFT and/or cyclophosphamide on mediators of breast cancer dissemination and invasion.
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 metastat...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0222580 |
| _version_ | 1818726910538022912 |
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| author | Raquel Muñoz Denise Hileeto William Cruz-Muñoz Geoffrey A Wood Ping Xu Shan Man Alicia Viloria-Petit Robert S Kerbel |
| author_facet | Raquel Muñoz Denise Hileeto William Cruz-Muñoz Geoffrey A Wood Ping Xu Shan Man Alicia Viloria-Petit Robert S Kerbel |
| author_sort | Raquel Muñoz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T22:05:43Z |
| format | Article |
| id | doaj.art-887d9a76c7014cc09b1151516c978166 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-17T22:05:43Z |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-887d9a76c7014cc09b1151516c9781662022-12-21T21:30:52ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01149e022258010.1371/journal.pone.0222580Suppressive impact of metronomic chemotherapy using UFT and/or cyclophosphamide on mediators of breast cancer dissemination and invasion.Raquel MuñozDenise HileetoWilliam Cruz-MuñozGeoffrey A WoodPing XuShan ManAlicia Viloria-PetitRobert S KerbelMetronomic 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.https://doi.org/10.1371/journal.pone.0222580 |
| spellingShingle | Raquel Muñoz Denise Hileeto William Cruz-Muñoz Geoffrey A Wood Ping Xu Shan Man Alicia Viloria-Petit Robert S Kerbel Suppressive impact of metronomic chemotherapy using UFT and/or cyclophosphamide on mediators of breast cancer dissemination and invasion. PLoS ONE |
| title | Suppressive impact of metronomic chemotherapy using UFT and/or cyclophosphamide on mediators of breast cancer dissemination and invasion. |
| title_full | Suppressive impact of metronomic chemotherapy using UFT and/or cyclophosphamide on mediators of breast cancer dissemination and invasion. |
| title_fullStr | Suppressive impact of metronomic chemotherapy using UFT and/or cyclophosphamide on mediators of breast cancer dissemination and invasion. |
| title_full_unstemmed | Suppressive impact of metronomic chemotherapy using UFT and/or cyclophosphamide on mediators of breast cancer dissemination and invasion. |
| title_short | Suppressive impact of metronomic chemotherapy using UFT and/or cyclophosphamide on mediators of breast cancer dissemination and invasion. |
| title_sort | suppressive impact of metronomic chemotherapy using uft and or cyclophosphamide on mediators of breast cancer dissemination and invasion |
| url | https://doi.org/10.1371/journal.pone.0222580 |
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