Phase I and phase II trials of a laboratory-derived synergistic combination of cisplatin (cDDP) and 2'-deoxy-5-azacytidine (5-aza-CdR) were conducted. The maximum tolerated doses (MTDs) were 50 mg/m(2) of 5-aza-CdR and 75 mg/m(2) of cDDP. A response rate of 17% (90% confidence interval (CI) = 0%-37%) was observed in patients with metastatic carcinoma of unknown primary (UPC). The 5-aza-CdR/cDDP combination was safely administered at doses mirroring concentrations that significantly lessen cDDP resistance of human ovarian cancer cells in vitro. While the observed response rate did not warrant further study in UPC, evaluation of this regimen should be considered in patients with cDDP-resistant ovarian cancer.