PTG, a new antineoplastic epipodyphyllotoxin

The pharmacology of 4'-demethylepipodophyllotoxin 9-(4,6-0-thenylidene-beta-D-glucopyranoside) PTG, a new anticancer drug, is reported. Six patients with advanced cancer were treated with PTG (67 mg/m2 of body surface area intravenously) specifically labeled with tritium as the first dose of a weekly x 6 course. Recovery of drug in the urine was 44.49 +/- 8.2% of the administered dose in 72 hr, of which 78.7 +/- 5.1% was metabolite. Recovery in the feces was 0 to 10.05% in 4 patients. Plasma decay fitted the equation Cp = Ae(-alphat) + Be(-betat) + Ce(-gammat) by nonlinear least-squares regression. Mean values for the parameters (after infusion) were A 14.3 +/- 5.5, B 9.66 +/- 3.98, C 2.44 +/- 1.33 mug/ml; alpha 2.05 +/- 1.25, beta 0.26 +/- 0.15, gamma 0.038 +/- 0.016 hr(-1). Levels of drug in the cerebrospinal fluid (CSF) were less than 1% of plasma levels in 3 patients at 24 hr after treatment and 27% in 1 patient who had had brain surgery and brain radiotherapy. Four of 4 patients considered evaluable for toxicity (greater than 2 consecutive weekly doses) developed leukopenia (WBC les than 5,000/mm3). Mean nadir of WBC was 3,600/mm3. The most marked leukopenia (WBC, 2,300/mm3) was seen in the patient with the longest terminal phase plasma half-life (38.5 hr). Two of 5 patients evaluable for response received clinical benefit (1 laryngeal carcinoma, 1 histiocytic lymphoma). It is concluded that PTG has a long terminal phase half-life (11-38.5 hr), is largely metabolized, and does not penetrate the normal blood-brain barrier.