Continuous administration of bevacizumab plus capecitabine, even after acquired resistance to bevacizumab, restored anti-angiogenic and antitumor effect in a human colorectal cancer xenograft model
| Autor: | Keigo Yorozu, Kaname Yamamoto, Suguru Harada, Mitsue Kurasawa, Toshiki Iwai, Masamichi Sugimoto |
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| Rok vydání: | 2016 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A 0301 basic medicine Oncology Cancer Research Colorectal cancer Angiogenesis medicine.medical_treatment Angiogenesis Inhibitors Mice angiogenesis chemistry.chemical_compound 0302 clinical medicine Antineoplastic Combined Chemotherapy Protocols Mice Inbred BALB C galectin Neovascularization Pathologic Articles General Medicine Vascular endothelial growth factor 030220 oncology & carcinogenesis Heterografts Colorectal Neoplasms HT29 Cells medicine.drug Antimetabolites Antineoplastic medicine.medical_specialty Bevacizumab Combination therapy Mice Nude Antineoplastic Agents bevacizumab lung resistance Capecitabine 03 medical and health sciences Cell Line Tumor Internal medicine medicine Animals Humans breast combination Chemotherapy colon business.industry Cancer HCT116 Cells medicine.disease 030104 developmental biology chemistry Drug Resistance Neoplasm business |
| Zdroj: | Oncology Reports |
| ISSN: | 1791-2431 1021-335X |
| DOI: | 10.3892/or.2016.4902 |
| Popis: | Vascular endothelial growth factor (VEGF)-neutralizing therapy with bevacizumab has become increasingly important for treating colorectal cancer. It was demonstrated that second-line chemotherapy together with bevacizumab after disease progression (PD) on first-line therapy including bevacizumab showed clinical benefits in metastatic colorectal and breast cancers (ML18147 trial, TANIA trial). One of the rationales for these trials was that the refractoriness to first-line therapy is caused by resistance to not so much bevacizumab as to the chemotherapeutic agents. Nevertheless, resistance to bevacizumab cannot be ruled out because VEGF-independent angiogenesis has been reported to be a mechanism of resistance to anti-VEGF therapy. In this study, we used a xenograft model with the human colon cancer HT-29 cells to investigate the mechanisms underlying the effect of continued administration of bevacizumab plus capecitabine even after resistance to bevacizumab was acquired. The combination of capecitabine plus bevacizumab exhibited significantly stronger antitumor and anti-angiogenic activities than did monotherapy with either agent. Capecitabine treatment significantly increased the intratumoral VEGF level compared with the control group; however, the combination with bevacizumab neutralized the VEGF. Among angiogenic factors other than VEGF, intratumoral galectin-3, which reportedly promotes angiogenesis both dependent on, and independently of VEGF, was significantly decreased in the capecitabine group and the combination group compared with the control group. In an in vitro experiment, 5-fluorouracil (5-FU), an active metabolite of capecitabine, inhibited galectin-3 production by HT-29 cells. These results suggested that capecitabine has a dual mode of action: namely, inhibition of tumor cell growth and inhibition of galectin-3 production by tumor cells. Thus, capecitabine and bevacizumab may work in a mutually complementary manner in tumor angiogenesis inhibition to overcome the resistance caused by angiogenic factors other than VEGF. These results suggest the clinical relevance and the mechanism of action of treatment with bevacizumab in combination therapy beyond PD. |
| Databáze: | OpenAIRE |
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