title: Fibrates protect against vascular endothelial dysfunction induced by paclitaxel and carboplatin chemotherapy for cancer patients: a pilot study.
abstract: 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.
  
  
  CONCLUSIONS
  Bezafibrate prevents endothelial dysfunction induced by TCchem via TG-dependent and TG-independent mechanisms.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka, 569-8686, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Watanabe
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanabe
authors.forename: Risa
authors.initials: R
authors.lastname: Maruoka
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Nakamura
authors.forename: Koji
authors.initials: K
authors.lastname: Hatta
authors.forename: Yoshihiro J
authors.initials: YJ
authors.lastname: Ono
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Terai
authors.forename: Masahide
authors.initials: M
authors.lastname: Ohmichi
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D001629:Bezafibrate / Q000494:pharmacology / Q000627:therapeutic use*; D016190:Carboplatin / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy; D006801:Humans; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D017239:Paclitaxel / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D010865:Pilot Projects; D014280:Triglycerides / Q000097:blood; D014471:Umbilical Veins / Q000187:drug effects; D014652:Vascular Diseases / Q000139:chemically induced / Q000517:prevention & control*; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047493:PPAR alpha; D014280:Triglycerides; D014665:Vasodilator Agents; D009569:Nitric Oxide; D016190:Carboplatin; D017239:Paclitaxel; D001629:Bezafibrate