CHEMOSENSITIZATION OF CCNU IN KHT MURINE TUMOR-CELLS IN-VIVO AND IN-VITRO BY THE AGENT RB-6145 AND ITS ISOMER PD-144872

The cytotoxicity and chemosensitizing potential of the nitrohetercycli c agent RE 6145 and its R enantiomer PD 144872 were determined in rode nt tumor cells grown in tissue culture or as solid tumors. Using a clo nogenic cell survival assay the degree of selective cytotoxicity of th ese bioreductive drugs was first determined in KHT/iv cells. Cells tre ated under hypoxic conditions were observed to be similar to 50-80-fol d more susceptible to the action of RB 6145 or PD 144872 than were cel ls exposed under air. To assess the in vitro chemosensitizing potentia l of RB 6145 and PD 144872, doses of these agents which led to surviva l values between 0.5 and 1.0 under hypoxic conditions were administere d, and were then combined concomitantly with variable doses of the nit rosourea CCNU. Exposure to the nitrosourea was for 1 h. The results sh owed that inclusion of either sensitizer enhanced the cell killing of the chemotherapeutic agent 2.4-2.6-fold. Subsequent experiments evalua ted the therapeutic benefit of combining these bioreductive agents wit h CCNU in KHT sarcoma-bearing C3H/HeJ mice. When given at times rangin g from 90 min before to 60 min after CCNU exposure, these bioreductive drugs increased the tumoricidal activity of the chemotherapeutic agen t. Complete dose response curves combining RE 6145 and PD 144872 and a range of CCNU doses also were evaluated. The sensitizers (0.75 mmol/k g) were administered 30 min prior to the chemotherapeutic agent and su rvival of clonogenic tumor cells 22-24 h after treatment was used to a ssay tumor response. Normal tissue toxicity under similar treatment co nditions was assessed using a bone marrow stem cell (CFU-GM) assay. Wh en combined with CCNU, the bioreductive agents increased tumor cell ki ll by a factor of similar to 1.7. Bone marrow toxicity was not, howeve r, enhanced by the addition of either agent to the CCNU treatment. The se data suggest that further consideration should be given to the clin ical application of these bioreductive agents.