A PHASE-II STUDY OF HIGH-DOSE HYDROXYUREA AND DACARBAZINE (DTIC) IN THE TREATMENT OF METASTATIC MALIGNANT-MELANOMA

Dacarbazine (DTIC) exerts its major biochemical effect through the for mation of methylated DNA adducts. Hydroxyurea (HU) is a ribonucleotide reductase inhibitor which blocks DNA excision-repair by the depletion of intracellular ribonucleotides. Combination of HU and DTIC was used to enhance the activity of DTIC by inhibiting DNA repair. 16 patients with metastatic malignant melanoma were treated with the combination. All patients had measurable disease and none had received prior syste mic therapy. Hydroxyurea was given as a continuous intravenous (i.v.) infusion of 1 g/h (total 36 g) and DTIC 1 g/m(2) i.v. over 1 h, 23 h f rom the start of hydroxyurea infusion. 4 patients achieved partial rem ission with an objective remission rate of 25% [95% confidence interva l (CI) 7-52%]. Median duration of response was 3.5 months. 3 of the re sponding patients had predominant visceral metastases. Disease was sta bilised in 5 patients with a median time to progression of 16 months. The predominant toxicity to this treatment was gastrointestinal, with 3 patients developing grade 3 nausea/vomiting. Only 1 patient develope d grade 3 leucopenia complicated by septicaemia. It is concluded that the combination of hydroxyurea and DTIC is a well-tolerated regimen wi th activity against visceral metastases from malignant melanoma but th e duration of response to this treatment is short.