caa a22 4500 605491208 CHVBK 20210128100509.0 cr unu---uuuuu 210128e20150801xx s 000 0 eng 10.1007/s10147-014-0779-y doi (NATIONALLICENCE)springer-10.1007/s10147-014-0779-y Fibrates protect against vascular endothelial dysfunction induced by paclitaxel and carboplatin chemotherapy for cancer patients: a pilot study [Elektronische Daten] [Ayako Watanabe, Akiko Tanabe, Risa Maruoka, Kiyoko Nakamura, Koji Hatta, Yoshihiro Ono, Yoshito Terai, Masahide Ohmichi] Background: Although we previously demonstrated that paclitaxel and carboplatin chemotherapy (TCchem) is associated with vascular toxicities, the underlying mechanisms remain unclear. Cisplatin is known to inhibit PPARα following microvascular damage to the kidneys. The primary aim of this study was to evaluate whether TCchem induces vascular endothelial dysfunction via systemic PPARα deficiency. In addition, human umbilical vein endothelial cells (HUVECs) were used to elucidate the mechanisms responsible for TCchem-induced vascular toxicities. Methods: This study enrolled 45 gynecological cancer patients with normal lipid profiles who underwent surgical treatment followed by TCchem. The elevated triglyceride (TG) group included patients (n=19) who exhibited hypertriglyceridemia during TCchem, and the stable TG group (n=15) included patients with a normal TG level. Eleven patients exhibiting hypertriglyceridemia during TCchem were administered bezafibrate (fibrate group). Endothelial dysfunction was evaluated based on flow-mediated dilation (FMD) values and serum pentraxin-3 levels measured before TCchem and immediately after the final TCchem. HUVECs were used to elucidate the biological mechanisms underlying the endothelial dysfunction induced by TCchem. Results: The administration of TCchem induced hypertriglyceridemia in 66 percent of the participants, and bezafibrate reduced the serum TG levels. Meanwhile, the decrease in flow-mediated dilatation (%FMD) induced by TCchem improved following treatment with bezafibrate. The serum pentraxin-3 level increased rapidly after TCchem and decreased following bezafibrate treatment. An in vitro examination demonstrated TCchem attenuated nitric oxide production and PPARα activity in HUVECs, which was partially improved by treatment with bezafibrate. Conclusion: Bezafibrate prevents endothelial dysfunction induced by TCchem via TG-dependent and TG-independent mechanisms. Japan Society of Clinical Oncology, 2014 Bezafibrate nationallicence Platinum-based chemotherapy nationallicence Carboplatin nationallicence Paclitaxel nationallicence Gynecological cancer nationallicence Triglyceride nationallicence FMD nationallicence PtChem : Platinum-based chemotherapy nationallicence TG : Triglycerides nationallicence TCchem : Paclitaxel and carboplatin combination chemotherapy nationallicence FMD : Flow-mediated dilation nationallicence PPARα : Peroxisome proliferator-activated receptor-α nationallicence OC : Ovarian cancer nationallicence EC : Endometrial cancer nationallicence CVD : Cardiovascular disease nationallicence LDL : Low-density lipoprotein nationallicence HDL : High-density lipoprotein nationallicence hsCRP : High-sensitivity C-reactive protein nationallicence CDDP : Cisplatin nationallicence CBDCA : Carboplatin nationallicence PTX : Paclitaxel nationallicence Watanabe Ayako Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut Tanabe Akiko Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut Maruoka Risa Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut Nakamura Kiyoko Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut Hatta Koji Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut Ono Yoshihiro Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut Terai Yoshito Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut Ohmichi Masahide Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut International Journal of Clinical Oncology Springer Japan 20/4(2015-08-01), 829-838 1341-9625 20:4<829 2015 20 10147 https://doi.org/10.1007/s10147-014-0779-y text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10147-014-0779-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Watanabe Ayako Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut NATIONALLICENCE 700 1- Tanabe Akiko Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut NATIONALLICENCE 700 1- Maruoka Risa Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut NATIONALLICENCE 700 1- Nakamura Kiyoko Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut NATIONALLICENCE 700 1- Hatta Koji Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut NATIONALLICENCE 700 1- Ono Yoshihiro Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut NATIONALLICENCE 700 1- Terai Yoshito Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut NATIONALLICENCE 700 1- Ohmichi Masahide Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, 569-8686, Takatsuki, Osaka, Japan aut NATIONALLICENCE 773 0- International Journal of Clinical Oncology Springer Japan 20/4(2015-08-01), 829-838 1341-9625 20:4<829 2015 20 10147