Setting environmental agendas: the search for common ground.

Temozolomide (CCRG 81045: M&B 39831: NSC 362856) is an analogue of mitozolomide displaying similar broad spectrum activity in mouse tumours, but showing considerably less myelosuppression in the toxicology screen. Temozolomide was initially studied intravenously at doses between 50-200 mg m2 and subsequently was given orally up to 1,200 mg m-2. A total of 51 patients were entered on the single dose schedule. Temozolomide exhibits linear pharmacokinetics with increasing dose. Myelotoxicity was dose limiting. Experimentally, temozolomide activity was schedule dependent and therefore oral administration was studied as a daily x 5 schedule between total doses of 750 and 1,200 mg m'2 in 42 patients. Myelosuppression was again dose limiting. The recommended dose for Phase II trials is 150mgm-2 po for 5 days (total dose 750 mg m-2) for the first course, and if no major myelosuppression is detected on day 22 of the 4 week cycle, the subsequent courses can be given at 200 mg m-2 for 5 days (total dose 1 g m-2) on a 4 week cycle. Mild to moderate nausea and vomiting was dose related but readily controlled with antiemetics. Clinical activity was detected using the 5 day schedule in four (2CR, 2PR; 17%) out of 23 patients with melanoma and in one patient with mycosis fungoides (CR lasting 7 months). Two patients with recurrent high grade gliomas have also had partial responses. Temozolomide is easy to use clinically and generally well tolerated. In the extended Phase I trial temozolomide only occasionally exhibited the unpredictable myelosuppression seen with mitozo-lomide. Stevens and colleagues (1984) synthesised a series of imid-azotetrazine derivatives which exhibited broad-spectrum anti-tumour activity against murine tumours. The lead compound in this series, mitozolomide, has been extensively studied and is considered to exert its effect by crosslinking DNA (Gibson et al., 1984 and 1985). Mitozolomide is a pro-drug of the cytotoxic triazene MCTIC (Stevens et al., 1984). The major site of alkylation by MCTIC is thought to be the O6-position of guanine (Gibson et al., 1985) with additional alkylation also occurring at the N7 position (Hartley et al., 1986). Structurally temozolomide lacks the chloroethyl side chain present in mitozolomide and has been developed as a potential alternative to dacarbazine (Stevens et al., 1987). Bull and Tisdale (1987) showed that there were differences in the ability of mitozolomide and temozolomide to alkylate DNA. At physiological pH temozolomide undergoes chemical degradation to MTIC without the requirement of metabolic activation as …