The effect of combinations of the conventional chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (
CCNU) and
nitroimidazole radiation sensitizers was evaluated in female C3H mice. Tumour response to single-agent or combination
therapy was assessed in a tumour growth-delay assay. In the KHT
sarcoma the simultaneous addition of
misonidazole (MISO) was found to increase significantly the tumour growth delay resulting from
CCNU treatment. The observed enhancement ratios (ER) increased with MISO dose, and ranged from 1.3 to 1.9 for sensitizer doses of 0.25-1.0 mg/g. The combination of
CCNU and 1.0 or 0.5 mg/g MISO in the RIF-1 tumour or the MT-1 tumour produced ERs of approximately 2.0 and approximately 1.5 respectively. In the KHT
sarcoma a series of other
nitroimidazole sensitizers, including Ro-05-9963,
SR-2555,
SR-2508 and
metronidazole (METRO), were also evaluated at equimolar doses (5 mmol/kg) in combination with a 20mg/kg dose of
CCNU. Unlike MISO, these compounds in general failed to enhance the
CCNU cytotoxicity in this tumour model. However,
SR-2508 did enhance the response of the RIF-1 tumour to large single doses of
CCNU, though not as much as MISO. Normal-tissue toxicity was determined using peripheral white blood cell (WBC) counts 3 days
after treatment.
CCNU doses of 10-50 mg/kg given either alone or in simultaneous combination with 0.5 or 1.0 mg/g MISO were studied. WBC toxicity increased with
CCNU dose, but the addition of MISO at either dose did not significantly enhance this normal-tissue toxicity.