Effect of administration schedules on the potentiation of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) by misonidazole in subcutaneous 9l tumors

Abstract

Our previous studies demonstrated that metabolism of misonidazole (MISO) by hypoxic cells is required to potentiate the cytotoxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in sc 9L tumors. To determine the influence of administration schedules on this chemosensitization, tumors were either clamped to produce a reversible hypoxia or left unclamped. MISO (2.5 mmoles kg −1) was administered to rats with unclamped tumors simultaneously with BCNU (9 or 12 mg kg −1), 20 min before BCNU, or 2.5 hr before BCNU, and the drug pharmacokinetics and BCNU cytotoxicity were measured. MISO administered 20 min or 2.5 hr before BCNU increased the plasma elimination half-time (t 1 2 of BCNU, but MISO administered simultaneously with BCNU did not change the plasma elimination t 1 2 of BCNU. In unclamped sc 9L tumors, all administration schedules decreased the peak BCNU concentration and increased the initial BCNU elimination t 1 2 ; however, the BCNU exposure dose (AUC0 0-∞) calculated from these data did not change significantly. In agreement with the AUC calculations, none of the administration schedules altered the BCNU cytotoxicity in unclamped tumors. If the tumors were clamped for 5–120 min after the peak MISO concentration was reached, BCNU-induced cell kill was increased by a constant factor of 3 over the first hour of the clamping period and by an additional factor of 7 over the second hour of the clamping period. If the tumors were clamped for 2 hr after the peak MISO concentration was reached and then BCNU administered 0–60 min after the clamp was released, this chemosensitization remained at a constant factor of ≈20 for the first 10 min, and then decreased rapidly to a factor of ≈3 by 20 min after the clamp was released. These data indicate that in sc 9L tumors, (1) at least two biochemical mechanisms are involved in this MISO-BCNU interaction, one of which depends on the duration and extent of the metabolism of MISO by hypoxic cells, and (2) reoxygenation does not immediately eliminate the potentiation of BCNU by MISO. These data also suggest that MISO should be given 2–4 hr before BCNU to achieve the maximum chemosensitization in clinical trials.