PHASE-I STUDY OF TUMOR NECROSIS ACTINOMYCIN-D IN PATIENTS WITH INDEPENDENT PROSTATE-CANCER

Based on preclinical studies which reveal enhanced antitumor activity of tumor necrosis factor (TNF) when combined with actinomycin D in hum an prostate cancer cell lines, we performed a phase I clinical study c ombining TNF and actinomycin D. All patients had metastatic prostatic carcinoma exhibiting androgen-independent growth. Patients were treate d with a combination of a short infusion of actinomycin D followed by a TNF infusion daily for five consecutive days. Soluble TNF receptor p 60 was not modulated by treatment but p80 receptor increased significa ntly following treatment with a combination of TNF and actinomycin D ( baseline median 3.4 ng/ml) range 2.5-6.6 ng/ml follow up (9.3 ng/ml) r ange 6-24 ng/ml. We concluded that the maximum tolerated dose of conti nuous infusion TNF and short infusion actinomycin D is 400 mu g/m(2) o f actinomycin D and 400 mu g/m(2) of TNF. The increased soluble recept or isoform (p80) may account for the lack of clinical activity seen in this trial. Should these results be confirmed, a strategy focused on overcoming the upregulation of the TNF soluble receptor will be requir ed before further study of TNF should be considered.