interleukin-8 and tetrathiomolybdate

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).. 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.. 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.. Copper depletion with TM did not delay disease progression in patients with asymptomatic metastatic HRPC.

Topics: Adenocarcinoma; Aged; Angiogenesis Inhibitors; Biomarkers; Ceruloplasmin; Chelating Agents; Copper; Disease Progression; Fibroblast Growth Factor 2; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Molybdenum; Neoplasm Metastasis; Prostatic Neoplasms; Vascular Endothelial Growth Factors

Tetrathiomolybdate (TM), a copper-lowering agent, has been shown in preclinical murine tumor models to be antiangiogenic. We evaluated the antitumor activity of TM in patients with advanced kidney cancer in a Phase II trial.. Fifteen patients with advanced kidney cancer were eligible to participate in this trial. TM was initiated p.o. at 40 mg three times a day with meals and 60 mg at bedtime to deplete copper. A target serum ceruloplasmin (CP) level of 5-15 mg/dl was defined as copper depletion. Doses of TM were reduced for grade 3-4 toxicity and to maintain a CP level in the target range. Once copper depletion was attained, patients underwent baseline tumor measurements and then again every 12 weeks for response assessment. Patients not exhibiting progressive disease at 12 weeks after copper depletion continued on treatment. Serum levels of Interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were assayed pretreatment and at various time points on treatment. Dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) was performed on selected patients in an attempt to assess changes in tumor vascularity.. All of the patients rapidly became copper depleted. Thirteen patients were evaluable for response. No patient had a complete response or PR. Four patients (31%) had stable disease for at least 6 months during copper depletion (median, 34.5 weeks). TM was well tolerated, with dose reductions most commonly occurring for grade 3-4 granulocytopenia of short duration not associated with febrile episodes. Serum levels of IL-6, IL-8, VEGF, and bFGF did not correlate with clinical activity. Serial DCE-MRI was performed only in four patients, and a decrease in vascularity seemed to correlate with necrosis of a tumor mass associated with tumor growth.. TM is well tolerated and consistently depletes copper as measured by the serum CP level. Clinical activity was limited to stable disease for a median of 34.5 weeks in this Phase II trial in patients with advanced kidney cancer. Serum levels of proangiogenic factors IL-6, IL-8, VEGF, and bFGF may correlate with copper depletion but not with disease stability in this small cohort. TM may have a role in the treatment of kidney cancer in combination with other antiangiogenic therapies.

Topics: Aged; Angiogenesis Inhibitors; Biomarkers; Ceruloplasmin; Copper; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fibroblast Growth Factor 2; Humans; Interleukin-6; Interleukin-8; Kidney Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Molybdenum; Prognosis; Vascular Endothelial Growth Factor A