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 nitrohetercyclic agent RB 6145 and its R enantiomer PD 144872 were determined in rodent tumor cells grown in tissue culture or as solid tumors. Using a clonogenic cell survival assay the degree of selective cytotoxicity of these bioreductive drugs was first determined in KHT/iv cells. Cells treated under hypoxic conditions were observed to be approximately 50-80-fold more susceptible to the action of RB 6145 or PD 144872 than were cells exposed under air. To assess the in vitro chemosensitizing potential of RB 6145 and PD 144872, doses of these agents which led to survival values between 0.5 and 1.0 under hypoxic conditions were administered, and were then combined concomitantly with variable doses of the nitrosourea CCNU. Exposure to the nitrosourea was for 1 h. The results showed that inclusion of either sensitizer enhanced the cell killing of the chemotherapeutic agent 2.4-2.6-fold. Subsequent experiments evaluated the therapeutic benefit of combining these bioreductive agents with CCNU in KHT sarcoma-bearing C3H/HeJ mice. When given at times ranging from 90 min before to 60 min after CCNU exposure, these bioreductive drugs increased the tumoricidal activity of the chemotherapeutic agent. Complete dose response curves combining RB 6145 and PD 144872 and a range of CCNU doses also were evaluated. The sensitizers (0.75 mmol/kg) were administered 30 min prior to the chemotherapeutic agent and survival of clonogenic tumor cells 22-24 h after treatment was used to assay tumor response.(ABSTRACT TRUNCATED AT 250 WORDS)
Siemann
D W
DW
Tumor Biology Division, University of Rochester Cancer Center, NY 14642, USA.
D000818:Animals; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008130:Lomustine / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D009593:Nitroimidazoles / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000473:pathology; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D009593:Nitroimidazoles; D011355:Prodrugs; C067834:RB 6145; D008130:Lomustine