The combination of 5-fluorouracil with misonidazole in patients with advanced colorectal cancer.

Misonidazole (MISO) has produced differential enhancement of tumor cell killing with a range of cytotoxic drugs including 5-fluorouracil (FU) in experimental mouse tumors and human xenografts. Since concomitant enhancement of normal tissue damage has been observed, a Phase I study of MISO and FU has been undertaken in patients with advanced colorectal cancer. Mild nausea and vomiting occurred more frequently after MISO and FU compared with FU alone; however, the incidence of leucopenia was similar with both treatment. No patients receiving the MISO/FU combination developed central nervous system toxicity or peripheral neuropathy. Twenty-four hour plasma nitroimidazole kinetics were analyzed and were not modified by the concomitant administration of the cytotoxic drug. Thus, in this preliminary study FU has been safely combined with MISO without significant modification of plasma nitroimidazole pharmacokinetics. Tumor regression was documented in 2/9 (22%) patients receiving more than 2 courses of MISO/FU. A Phase II study is proposed to investigate tumor response.

The penetration of misonidazole into a mature structural cartilage.

Mature cartilage may be expected to contain populations of hypoxic cells as a result of the tissues lack of direct vascularization and structure; it may therefore be at risk from possible radiosensitization. The hypoxic-cell radiosensitizing drug misonidazole Ro-07-0582 (MISO) was administered i.v. to mature New Zealand White rabbits at a dose of 100 mg/kg, and the resulting drug concentrations in both blood and ear-cartilage samples measured by HPLC. Samples were taken at regular intervals up to 4 h after administration of MISO. Blood concentrations of MISO rose rapidly to 240 microgram/ml within 5 min of administration, before falling steadily, with a t1/2 of 45 min. Cartilage levels reached a peak of 70% of the blood levels approximately 30 min after administration. The levels of MISO then fell, with a t1/2 of 44 min.

Distribution of misonidazole in human tumours and normal tissues.

Levels of misonidazole in human tumours, normal tissues and blood have been measured in patients given a 1g oral dose of drug before surgery or biopsy. The results show that 50--70% of the blood level was found in a wide range of tumours and that similar levels were found in adjacent normal tissues. Good penetration of drug was achieved within tumours, and up to 90--100% of the blood level was found in the necrotic cyst fluid at the centre of some tumours. CSF studies showed free diffusion into the CNS, which was confirmed by finding 50--70% of the blood level within brain tumours. A delay of passage of drugs into the CSF was noted, which was not found for drug diffusion into bile and saliva.

Distribution and tumour cytotoxicity of the radiosensitizer misonidazole (Ro-07-0582) in C57 mice.

The distribution and clearance of misonidazole (MIS = Ro-07-0582) were studied in C57 mouse tissues and in transplants of Lewis lung tumour. The half life of the drug in blood after a dose of 1 mg/g i.p. was 3 h. Some tissues, such as liver, were found to have consistently low MIS levels, and this was found to be due to degradation of the drug after removal of the tissues from the host. The in vivo cytotoxicity of MIS to Lewis lung tumour cells was studied using an in-vitro colony assay. After half of the tumours had been irradiated with 10 Gy to kill most of the oxic cells, the mice received i.p. injections of MIS. To simulate the longer drug exposure of human tumour cells (due to the longer half life in man) a repeated injection regime was used in some mice. There was no significant cell kill after a single dose, but with a prolonged exposure to the drug in the multiply injected animals, cell survival was reduced to 50% of control in both the irradiated and unirradiated tumours. Since the hypoxic fraction of the unirradiated tumour is probably not more than 30%, it would appear that MIS is not selectively cytotoxic to hypoxic cells. However, MIS had a much greater cytotoxic effect upon hypoxic Lewis lung tumour cells in vitro, with very little or no effect on cells grown in air. This would support the theory that the presence of hypoxic cells is essential for the expression of MIS cytotoxicity.