Effect of route of administration, dose, and schedule on the anti-tumor activity of Panzem® NCD in a murine orthotopic lung cancer model

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2-Methoxyestradiol (2ME2), an endogenous metabolite of estradiol, is an inhibitor of both tumor and endothelial cell proliferation. 2ME2 is currently in oncology clinical trials under the name of Panzem®. A new formulation, Panzem® NCD, has recently been developed to increase its absorption in vivo. The aim of these preclinical studies was to assess the effect of route of administration, schedule, and dose on the anti-tumor activity of Panzem® NCD in an orthotopic model of murine lung cancer. Three days following the intravenous injection of Lewis lung carcinoma, groups of ten mice were treated with Panzem® NCD (200 mg/kg) once every 24 hours (q.d.) by either oral gavage (p.o.) or intraperitoneal (i.p.) injection. Inhibition of pulmonary metastases was observed whether Panzem® NCD was administered p.o. or by i.p. injection (T/C = 0.28 and 0.17, respectively, p<0.05 compared to control). An improvement in anti-tumor activity was observed when the frequency of administration of a specific dose level was increased from q.d. (2 mg/injection, 100 mg/kg/day) to q.i.d. (2 mg/injection, 400 mg/kg/day), supporting a clinical trial strategy employing multiple daily dosing. To investigate the effect of dose schedule on the anti-tumor activity of Panzem® NCD we compared an equivalent daily dose (100 mg/kg) delivered i.p. as either a single bolus injection or administered continuously using a mini-osmotic pump. Enhanced inhibition of tumor growth was observed when Panzem® NCD was delivered by continuous infusion as compared to a single daily bolus injection. Fractionating the single bolus q.d. injection (2 mg/injection, 100 mg/kg/day) into 4 smaller, equal doses (q.i.d., 0.5 mg/injection, 100 mg/kg/day) injected every 6 hours did not improve upon the therapeutic response observed with the single bolus injection at this dose level. Additional studies investigated whether therapy with Panzem® NCD requires daily dosing over the entire treatment period (low daily dose, long treatment period), or if an equivalent total dose of Panzem® NCD could be administered in an abbreviated period of time using a dose-intensification strategy (high daily dose, short treatment period). Tumor-bearing animals treated with daily i.p. injections of Panzem® NCD (4mg/injection, 200 mg/kg/day, 56 mg total, 14 days of therapy) had a similar therapeutic response as mice treated with Panzem® NCD using a dose-intensification schedule (14 mg/injection, 700 mg/kg/day, 56 mg total dose, 4 consecutive days of therapy). Taken together these data suggest that the schedule of Panzem® NCD administration is a key determinant of the anti-tumor activity in this orthotopic model of murine lung cancer. The effect that scheduling has on the pharmacokinetics of Panzem® NCD is currently under investigation and will be used to further develop a pharmacodynamic model that defines optimal anti-tumor effects of Panzem® NCD.