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.
Sella
A
A
Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Aggarwal
B B
BB
Kilbourn
R G
RG
Bui
C A
CA
Zukiwski
A A
AA
Logothetis
C J
CJ
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