A PHASE-I PILOT-STUDY OF BCNU PLUS THYMIDINE IN PATIENTS WITH REFRACTORY CANCER

Thymidine (dThd) has been shown to increase the activity of BCNU in mi ce, possibly due to its ability to inhibit poly(ADP-ribose)polymerase (PADPRP), an enzyme thought to be active in DNA repair. The present ph ase I study characterized the pharmacokinetics and toxicity of dThd co mbined with BCNU. Sixty patients with refractory malignancies were inf used with escalating doses of dThd from 7.5 g/m(2)/day to 105.5 g/m(2) /day for 48 hr, along with 100 mg/m(2)/day of BCNU for 2 doses. Furthe r dose escalation of dThd was limited by large fluid volumes required; therefore, the BCNU dose was escalated to a maximum of 160 mg/m(2)/da y for 2 days. Plasma dThd concentrations were determined using high-pe rformance liquid chromatography. At doses above 37.5 g/m(2)/day, stead y-state concentrations of dThd approached or exceeded 1 mM, a concentr ation that nearly completely abolished BCNU-induced PADPRP activity in preclinical studies. Myelosuppression was consistent with BCNU dose b ut was not apparently increased by the coadministration of dThd. One p atient had a partial response to therapy. Both the lack of effect of i ncreasing dThd doses on BCNU-induced myelosuppression and the low resp onse rate suggest that the schedule of drug administration was not opt imal to inhibit PADPRP, or that PADPRP may not be essential in repairi ng BCNU-mediated DNA damage in humans.