Phase II trial of copper depletion with tetrathiomolybdate as an antiangiogenesis strategy in patients with hormone-refractory prostate cancer.
OBJECTIVE
Preclinical studies suggest antiangiogenesis strategies may be effective in the treatment of prostate cancer. In tumor models, the copper-chelating agent tetrathiomolybdate (TM) has been shown to be antiangiogenic. We evaluated the antitumor activity of TM in patients with hormone-refractory prostate cancer (HRPC).


METHODS
Nineteen patients with asymptomatic HRPC enrolled. Copper depletion was monitored using serum ceruloplasmin levels. Once the target ceruloplasmin level of 5-15 mg/dl was attained, patients underwent staging evaluation. Patients were reassessed every 12 weeks, and TM was continued until they developed evidence of disease progression or intolerable toxicity. Prostate-specific antigen and levels of vascular endothelial growth factor, basic fibroblast growth factor, interleukin (IL)-6 and IL-8 were measured at study entry, at the time of copper depletion, and monthly while on therapy.


RESULTS
Seventeen of 19 patients achieved copper deficiency on TM therapy. Of the 16 evaluable patients, 14 developed progressive disease, 1 discontinued therapy because of toxicity and 1 patient opted to discontinue therapy because of rising prostate-specific antigen level without objective evidence of progressive disease. Levels of vascular endothelial growth factor, IL-6 and IL-8, but not basic fibroblast growth factor, were elevated when compared to normal controls prior to TM therapy, but there was no significant change during therapy. There was no correlation between prostate-specific antigen and levels of angiogenesis factors.


CONCLUSIONS
Copper depletion with TM did not delay disease progression in patients with asymptomatic metastatic HRPC.
Henry
N Lynn
NL
Department of Internal Medicine, Division of Hematology, University of Michigan School of Medicine, Ann Arbor, Mich., USA.
Dunn
Rodney
R
Merjaver
Sofia
S
Pan
Quintin
Q
Pienta
Kenneth J
KJ
Brewer
George
G
Smith
David C
DC
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002570:Ceruloplasmin / Q000378:metabolism*; D002614:Chelating Agents / Q000627:therapeutic use*; D003300:Copper / Q000097:blood; D018450:Disease Progression; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008875:Middle Aged; D008982:Molybdenum / Q000627:therapeutic use*; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D042442:Vascular Endothelial Growth Factors / Q000097:blood
D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D002614:Chelating Agents; D015850:Interleukin-6; D016209:Interleukin-8; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D002570:Ceruloplasmin