Fibrates Prevent Paclitaxel- and Carboplatin-Induced Vascular Endothelial Dysfunction

the Cancer Therapy Advisor take:

Paclitaxel and carboplatin (TCchem) are chemotherapy agents associated with vascular toxicities caused by unclear mechanisms. Cisplatin, a platinum-containing anti-cancer agent, is known to inhibit PPARα and damage the microvascular vessels in the kidneys.

Investigators conducted a pilot study to determine whether the systemic deficiency of PPARα, caused by TCchem, is the underlying mechanism for the vascular endothelial dysfunction.

In the study, there were 45 patients with gynecological cancer who were treated with TCchem and were grouped according to their triglyceride (TG) levels. Of the 30 patients exhibiting hypertriglyceridemia during TCchem, 11 patients were given bezafibrate; 15 patients exhibited stable TG levels. Endothelial dysfunction was evaluated by measuring the flow-mediated dilation (FMD) values and serum pentraxin-3 levels before and after the administration of TCchem. Human umbilical vein endothelial cells (HUVECs) were used to assess the biological mechanisms induced by TCchem via in vitro examinations.

The results showed that TCchem contributes to endothelial dysfunction by TG-dependent and TG-independent mechanisms. The administration of TCchem caused hypertriglyceridemia in 66% of patients, and in vitro examinations showed that TCchem reduced nitric oxide production and PPARα activity in HUVECs.

However, patients treated with TCchem followed by bezafibrate showed reduced TG levels, improved FMD%, and decreased serum pentraxin-3 levels. Overall, the findings indicate that bezafibrate, a PPARα agonist fibrate, can prevent endothelial dysfunction caused by TCchem.