Combination of Hydroxyurea and Verapamil for Refractory Meningiomas

The investigators have demonstrated previously that the calcium channel antagonists (CCAs) verapamil, nifedipine, and diltiazem can block in vitro and in vivo meningioma growth at clinically relevant doses (Jensen, Lee et al. 1995; Jensen, Petr et al. 2000; Jensen and Wurster 2001). However, only modest growth inhibition was exhibited in the tumors in these studies with CCAs alone. Many authors have shown augmented growth inhibition by adding CCAs to traditional chemotherapies in other tumor types (Tsuruo, Iida et al. 1981; Tsuruo, Iida et al. 1983; Helson 1984; Robinson, Clutterbuck et al. 1985; Ince, Appleton et al. 1986; Merry, Fetherston et al. 1986; Cano-Gauci and Riordan 1987). For instance, the combination of verapamil and 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) is better than BCNU alone in inhibiting the growth of human gliomas in vitro and in vivo (Bowles, Pantazis et al. 1990). Calcium antagonists seem to exert the majority of their anti-tumor effects by inhibiting calcium dependent secondary messenger systems (Metcalfe, 1986 #74; Jensen, 2000 #15). Furthermore, the investigators have more recently demonstrated that the addition of a verapamil or diltiazem with HU enhances the growth inhibition seen with these drugs in vitro and in vivo.

Hydroxyurea inhibits DNA synthesis by inhibition of ribonucleotide diphosphate reductase and is a well-known drug used for the treatment of a number of tumor types including head and neck tumors and chronic myelogenous leukemia. It has also been used as an adjuvant for antiretroviral treatment for patients with HIV and as a treatment for polycythemia vera, essential thrombocythemia and sickle cell disease.

Hydroxyurea is well absorbed after oral administration with the peak serum concentration achieved in two hours. The drug is excreted primarily in the urine, either as urea or as the unchanged compound. The drug is supplied as 500 mg capsules in a white crystalline powder. It is stored at room temperature. Dosing is usually in the range of 20 mg/kg/day with adjustments necessary for patients with renal insufficiency. In the current study population patients would be usually treated with 500mg twice a day. It is contraindicated in patients with myelosuppression or severe anemia.

Verapamil is another commonly used medication. It is used for the treatment of angina, hypertension, supraventricular arrhythmias, and migraine prophylaxis. Dosing with standard verapamil is 80-120 mg pox three times a day but the sustained release form can be given 120-480mg once or twice each day. It is contraindicated in patients with left ventricular dysfunction, congestive hart failure, hypotension (systolic <90bpm) 2nd or 3rd degree atrioventricular block (except in patients with a functioning artificial pacemakers), or sick sinus syndrome and atrial flutter or atrial fibrillation and an accessory bypass tract (Wolff-Parkinson-White Syndrome, Lown-Ganong-Levine Syndrome). Serious adverse reactions associated with Verapamil use are congestive heart failure, hypotension, bradycardia, 2nd or 3rd degree AC block, angina, myocardial infarction, syncope and GI obstruction.

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