The therapeutic potential of combining radiation and CCNU with clinical levels of misonidazole

The effect of combining misonidazole (MISO) with CCNU or CCNU plus radiation was evaluated in a protocol where multiple low sensitizer doses were given to simulate human MISO pharmacokinetics. When CCNU was administered 4 hr into an 8 hr chronic MISO dosing schedule, increased tumor responses compared to CCNU alone were seen (ER 1.2-1.3). This enhanced treatment efficacy occurred in the absence of pharmacological alterations of the chemotherapeutic agent or increased normal tissue toxicities. Experiments also were performed to determine whether chronic MISO administration could improve the tumor control probability of a combination of CCNU and radiation. CCNU (20 mg/kg), with or without MISO, was adminstered 24 hr prior to locally irradiating the tumors with radiation doses of 0-35 Gy. Combining CCNU and radiation significantly enhanced the tumor response as compared to radiation alone. Cures, not achievable with radiation alone due to metastatic spread, could be realized with the combined treatment. Coupling chronic MISO administration with CCNU in this protocol further enhanced the tumor control probability by a factor of 1.5-1.7. This enhancement was a consequence of improved antitumor efficacy in both the primary and metastatic disease. Compared to CCNU plus radiation, the 3 agent combination did not increase the normal tissue reactions in the treatment field. Thus these studies demonstrate a significant therapeutic gain