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Treatment
of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic
agent: Phase I study
Brewer
GJ, Dick RD, Grover DK, LeClaire V, Tseng M, Wicha M, Pienta K, Redman BG, Jahan
T, Sondak VK, Strawderman M, LeCarpentier G, Merajver SD
Department
of Human Genetics, University of Michigan Health System, Ann Arbor 48109, USA
Preclinical
and in vitro studies have determined that copper is an important cofactor for
angiogenesis.
Tetrathiomolybdate (TM) was developed as an effective anticopper therapy for the
initial treatment of Wilson's disease, an autosomal recessive disorder that
leads to abnormal copper accumulation.
Given the potency and uniqueness of the anticopper action of TM and its lack of
toxicity, we hypothesized that TM would be a suitable agent to achieve and
maintain mild copper deficiency to impair neovascularization in metastatic solid
tumors. Following preclinical work that showed efficacy for this anticopper
approach in mouse tumor models, we carried out a Phase I clinical trial in 18
patients with metastatic cancer who were enrolled at three dose levels of oral
TM (90, 105, and 120 mg/day) administered in six divided doses with and
in-between meals.
Serum ceruloplasmin (Cp) was used as a surrogate marker for total body
copper.
Because anemia is the first clinical sign of copper deficiency, the goal of the
study was to reduce Cp to 20% of baseline value without reducing hematocrit
below 80% of baseline.
Cp is a reliable and sensitive measure of copper status, and TM was nontoxic
when Cp was reduced to 15-20% of baseline. The level III dose of TM (120 mg/
day) was effective in reaching the target Cp without added toxicity.
TM-induced mild copper deficiency achieved stable disease in five of six
patients who were copper deficient at the target range for at least 90 days.
PMID:
10656425 [PubMed - indexed for MEDLINE]
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