Trimodality therapy (drug/hyperthermia/radiation) with BCNU or mitomycin C

Abstract

To develop multimodality treatment combinations with high curative potential in advanced local disease, BCNU (N,N′- bis(2-chloroethyl)-N-nitro-sourea) And mitomycin C were tested with hyperthermia And radiation in the FSaIIC fibrosarcoma system. Growth delay experiments demonstrated that, while neither BCNU nor mitomycin C produced dose modification of the radiation response, And hyperthermia (43°C, 30 min) produced only a moderate dose modification (1.4 ± 0.2), the combination of BCNU plus hyperthermia resulted in A radiation dose modifying factor (DMF) of 1.9 ± 0.3, And mitomycin C plus hyperthermia A dose modifying factor of 2.1 ± 0.4. Tumor cell survival over A range of BCNU doses Administered i.p. immediately before hyperthermia resulted in A dose modifying factor of 1.8 ± 0.2 versus drug Alone. With mitomycin C however, giving the drug immediately prior to heating produced A dose modifying factor due to hyperthermia of only 1.2 ± 0.10. Hoechst 33342 diffusion was used to separate tumor cells into predominately oxic And hypoxic subpopulations. Administration of the single, double And trimodality therapies showed that BCNU was 3.1-fold more toxic to the oxic versus the hypoxic cells whereas mitomycin C was 3.5-fold more toxic to the hypoxic compared to the oxic cells. Hyperthermia was 1.4-fold more toxic to the hypoxic versus the oxic cells whereas 10 Gy of radiation was 2.0-fold more toxic to the oxic compared to the hypoxic cells. The combination of hyperthermia plus radiation increased killing in both Hoechst dye defined subpopulations but relatively more in the hypoxic cells in which killing was 1.8-fold greater than in the oxic cells. When heat was delivered immediately After i.p. administration of the anticancer drugs, hyperthermia increased BCNU killing in the oxic cells by 17.2-fold versus 4.4-fold in the hypoxic cells And increased mitomycin-killing by 2.6-fold in the oxic cells versus 17-fold in the hypoxic cells. Use of the full trimodality treatment, given in the sequence drug (BCNU, 50 mg/kg or mitomycin-C 5 mg/kg) → heat (43°C, 30 min) → radiation (10 Gy) produced a 3 log kill in the oxic cells versus A 2 log kill in the hypoxic cells with BCNU And A 2 log kill in the oxic cells versus A 3 log kill in the hypoxic cells with mitomycin C. These results indicate that the use of selected anticancer drugs with hyperthermia And radiation can produce highly cytotoxic interactions which markedly modify the effect of radiation. Proper choice of the anticancer drug can shift the maximum cytotoxicity to either the oxic, presumably oxic or to the hypoxic, presumably hypoxic, cell populations.