In vivo chemosensitization by misonidazole in sensitive and resistant tumor lines

In an attempt to evaluate whether the radiation sensitizer misonidazole (MISO) could enhance the responsiveness of chemoresistant tumors, MISO was combined with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) for the treatment of BALB/c X DBA/2 F1 (hereafter called CD2F1) and C3H/HeJ mice bearing nitrosourea-resistant L1210/BCNU or KHT/CCR tumors, respectively. To determine whether comparable degrees of enhancement could be achieved in sensitive and resistant tumor lines, the magnitude of chemosensitization produced by treating the resistant tumors with the MISO-nitrosourea combinations was compared to the chemopotentiation produced in similarly treated nitrosourea-sensitive tumor lines from which the resistant lines had been derived. As evidenced by increased cure probabilities, the addition of MISO [5.0 mmol/kg (1.0 mg/g)] significantly potentiated the response of the parental nitrosourea-sensitive L1210/0 tumor to a 20-mg/kg dose of CCNU. When combined with doses of CCNU lower than 20 mg/kg or with BCNU, MISO failed to significantly modify the response of the L1210/0 tumor. Significant chemosensitization also was evident when 2.5- and 1.25-mmol/kg doses of MISO were used in combination with CCNU at 20 mg/kg. The effectiveness of BCNU and CCNU against the nitrosourea-resistant L1210/BCNU tumor was not significantly improved by MISO (5.0 mmol/kg), even when the sensitizer was combined with doses of nitrosoureas approaching 10% lethal dose (60 days) concentrations. In contrast, the effectiveness of CCNU against the parental KHT and resistant KHT/CCR tumors, assessed using a tumor regrowth assay, was equally enhanced by simultaneous MISO treatment. Therefore, one cannot safely predict the extent of enhancement which might result from the addition of MISO to a chemotherapeutic regimen based solely on the responsiveness of the tumor to the chemotherapy drug(s) alone.