Phase I study of tumor necrosis factor plus actinomycin D in patients with androgen-independent prostate cancer.
Based on preclinical studies which reveal enhanced antitumor activity of tumor necrosis factor (TNF) when combined with actinomycin D in human prostate cancer cell lines, we performed a phase I clinical study combining TNF and actinomycin D. All patients had metastatic prostatic carcinoma exhibiting androgen-independent growth. Patients were treated with a combination of a short infusion of actinomycin D followed by a TNF infusion daily for five consecutive days. Soluble TNF receptor p60 was not modulated by treatment but p80 receptor increased significantly 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) range 6-24 ng/ml. We concluded that the maximum tolerated dose of continuous infusion TNF and short infusion actinomycin D is 400 micrograms/m2 of actinomycin D and 400 micrograms/m2 of TNF. The increased soluble receptor 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 required before further study of TNF should be considered.
Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
A
A
Sella
B B
BB
Aggarwal
R G
RG
Kilbourn
C A
CA
Bui
A A
AA
Zukiwski
C J
CJ
Logothetis
D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D003609:Dactinomycin / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000627:therapeutic use*
D000903:Antibiotics, Antineoplastic; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin