A phase II study of high-dose hydroxyurea and dacarbazine (DTIC) in the treatment of metastatic malignant melanoma.
Philip PA., Carmichael J., Tonkin K., Ganesan TA., Harris AL.
Dacarbazine (DTIC) exerts its major biochemical effect through the formation 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 systemic therapy. Hydroxyurea was given as a continuous intravenous (i.v.) infusion of 1 g/h (total 36 g) and DTIC 1 g/m2 i.v. over 1 h, 23 h from the start of hydroxyurea infusion. 4 patients achieved partial remission with an objective remission rate of 25% [95% confidence interval (CI) 7-52%]. Median duration of response was 3.5 months. 3 of the responding patients had predominant visceral metastases. Disease was stabilised 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 developed grade 3 leucopenia complicated by septicaemia. It is concluded that the combination of hydroxyurea and DTIC is a well-tolerated regimen with activity against visceral metastases from malignant melanoma but the duration of response to this treatment is short.