Response of murine tumours to combinations of CCNU with misonidazole and other radiation sensitizers.

D W Siemann

doi:10.1038/bjc.1982.43

Abstract

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.

Highlights

Summary.-The effect of combinations of the conventional chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) and nitroimidazole radiation sensitizers was evaluated in female C3H mice
Even at the lower doses of MISO (0.5 or 0-25 mg/g) there was a considerable improvement in tumour response to CCNU
The resultant enhancement ratios (ERs), defined as the dose of CCNU alone divided by the dose of CCNU + MISO to cause a given tumour effect, were determined for a CCNU dose of 30 mg/kg, and were found to be -1-9, 1-7 and 1-3 for MISO doses of 1-0, 0-5 and 0-25 mg/g respectively

Summary

OF CCNU WITH MISONIDAZOLE AND OTHER RADIATION SENSITIZERS

Others have reported that the addition of a radiation sensitizer such as misonidazole (MISO) may enhance the tumour-cell cytotoxicity of some chemotherapeutic agents (Sutherland et al, 1980; Rose et al, 1980; Clement et al, 1980; Tannock, 1980a,b; Mulcahy et al, 1981; Siemann, 1981; Law et al, 1981; Twentyman, 1981).

MATERIALS AND METHODS

RESULTS

Peripheral WBC

DISCUSSION