A Phase I Pilot Study of BCNU plus Thymidine in Patients with Refractory Cancer

Abstract

Thymidine (dThd) has been shown to increase the activity of BCNU in mice, possibly due to its ability to inhibit poly(ADP-ribose)polymerase (PADPRP), an enzyme thought to be active in DNA repair. The present phase I study characterized the pharmacokinetics and toxicity of dThd combined with BCNU. Sixty patients with refractory malignancies were infused with escalating doses of dThd from 7.5g/m²/day to 105.5 g/m²/day for 48 hr, along with 100 mg/m²/day of BCNU for 2 doses. Further dose escalation of dThd was limited by large fluid volumes required; therefore, the BCNU dose was escalated to a maximum of 160 mg/m²/day for 2 days. Plasma dThd concentrations were determined using high-performance liquid chromatography. At doses above 37.5 g/m /day, steady-state concentrations of dThd approached or exceeded 1 mM, a concentration that nearly completely abolished BCNU-induced PADPRP activity in preclinical studies. Myelosuppression was consistent with BCNU dose but was not apparently increased by the coadministration of dThd. One patient had a partial response to therapy. Both the lack of effect of increasing dThd doses on BCNU-induced myelosuppression and the low response rate suggest that the schedule of drug administration was not optimal to inhibit PADPRP, or that PADPRP may not be essential in repairing BCNU-mediated DNA damage in humans.