Potentiation of combination chemotherapy by nitroheterocyclics.
The effect of including a nitroimidazole in a treatment regimen combining two alkylating chemotherapeutic agents was evaluated in a mouse tumor model. KHT sarcoma-bearing female C3H/HeJ mice were treated with a single dose of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) either alone or in combination with the radiosensitizer misonidazole (MISO) prior to a range of cyclophosphamide (CY) doses. CCNU (5 mg/kg) preceded CY treatment by 3 hr. MISO (1 mmol/kg) was given 1 hr after CCNU (2 hr prior to CY). Tumor response was assessed using either an in vitro to in vivo clonogenic cell survival assay 22-24 hr after treatment or an in situ delay of tumor regrowth assay. The results demonstrated that the inclusion of MISO at a dose of 1.0 mmol/kg increased tumor cell kill resulting from the combination of CCNU-CY by a factor of 1.4-1.5 compared to that seen in the absence of the nitroimidazole. Normal tissue toxicity resulting from the CCNU-CY or CCNU-MISO-CY combinations was determined by measuring bone marrow stem cell (CFU-S or CFU-GM) toxicity. Compared to CCNU-CY alone, the addition of MISO did not enhance this normal tissue toxicity. These findings indicate that the inclusion of MISO in a combination chemotherapy protocol may yield a significant therapeutic benefit.
Siemann
D W
DW
Experimental Therapeutics Division, University of Rochester Cancer Center, NY 14642.
Allalunis-Turner
M J
MJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004357:Drug Synergism; D005260:Female; D008130:Lomustine / Q000008:administration & dosage; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000008:administration & dosage*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D012513:Sarcoma, Experimental / Q000188:drug therapy*
D011838:Radiation-Sensitizing Agents; D008130:Lomustine; D008920:Misonidazole; D003520:Cyclophosphamide