Effect of clinical levels of misonidazole on the response of tumour and normal tissues in the mouse to alkylating agents

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Abstract
Experiments were carried out to determine whether the enhancement of alkylating-agent cytotoxicity seen after large single doses of misonidazole (MISO) in mouse tumours can also be achieved by prolonged exposure to low MISO levels similar to those which can be tolerated clinically. The level in mouse blood plasma could be maintained at about 100 micrograms/ml for 7 h by injecting small doses of MISO every 1/2 h. The effect of this treatment in combination with cyclophosphamide (CY) or melphalan (L-PAM) was studied in the RIF-1 tumour, using regrowth delay and cell-survival cloning assays. In each case, prolonged exposure to low levels of MISO gave enhancement ratios very close to those obtained with a large single dose. ERs of 1.6-2.0 were obtained with CY and 1.8-2.2 with L-PAM over the range of alkylating-agent doses used. In experiments with CY the response of 2 normal-tissue systems, marrow and WBC count, was also studied. No significant enhancement of CY damage occurred in either case. In the L-PAM experiments the LD50/30 and WBC counts were determined as normal-tissue end points. Multiple MISO had no effect. Our results show that levels of MISO which can be achieved safely in man yield good enhancement of the tumour cytotoxicity of 2 widely used chemotherapeutic agents without increasing the damage to normal tissues.