Cediranib administration in rats induced hypertension (up to 35-50 mmHg increase at 3 mg/kg/d), which was effectively reversed by nifedipine without compromising antitumor activity.
Does concomitant antihypertensive therapy with captopril or nifedipine reduce cediranib-induced hypertension in rat models without affecting antitumor activity?
Cediranib-induced hypertension in rats can be effectively managed with nifedipine without compromising the drug's antitumor efficacy.
PURPOSE: Inhibition of vascular endothelial growth factor-A (VEGF) signaling is a key therapeutic approach in oncology given the role of VEGF in angiogenesis and vascular permeability in solid tumors. Clinical trials examining VEGF signaling inhibitors commonly report hypertension. We examined the effect of cediranib, a highly potent VEGF signaling inhibitor, on the blood pressure of rats and the ability of standard antihypertensive agents to modulate the consequences of VEGF signaling inhibition. EXPERIMENTAL DESIGN: The ability of cediranib to induce hypertensive changes and the effect of giving antihypertensive therapy were investigated in conscious, unrestrained telemetered rats. Two antihypertensive agents were studied: captopril, an angiotensin-converting enzyme inhibitor, and nifedipine, a dihydropyridine calcium channel blocker. The antitumor activity of cediranib, alone and in combination with nifedipine, was also evaluated in a LoVo human colorectal tumor xenograft model in nude rats. All treatments were given orally. RESULTS: Administration of 0.1 to 1.5 mg/kg/d of cediranib for 4 consecutive days induced a relatively mild hypertensive effect, elevating diastolic blood pressure by 10 to 14 mmHg. Dosing 3 mg/kg/d cediranib for 4 days induced a marked hypertension of 35 to 50 mmHg. Captopril (30 mg/kg, qd) was effective at lowering a 10 mmHg increase in blood pressure but not a 35 to 50 mmHg increase. However, the latter was rapidly reversed by administration of nifedipine (10 mg/kg, bd). Coadministration of nifedipine did not negatively affect the antitumor activity of cediranib (1.5 mg/kg/d). CONCLUSIONS: Hypertension is a direct consequence of inhibiting VEGF signaling but can be controlled with appropriately selected, standard antihypertensive medication.
Curwen et al. (2008) studied VEGF inhibitor-induced hypertension. Cediranib with or without captopril or nifedipine was evaluated on Blood pressure changes. Cediranib administration in rats induced hypertension (up to 35-50 mmHg increase at 3 mg/kg/d), which was effectively reversed by nifedipine without compromising antitumor activity.