Recombinant methioninase infusion reduces the biochemical endpoint of serum methionine with minimal toxicity in high-stage cancer patients.
The tumor-specific increased minimal requirement for methionine has been shown to be a highly promising therapeutic target. To attack this target we have previously cloned the methioninase gene from Pseudomonas putida and produced recombinant methioninase (rMETase). A pilot Phase I clinical trial has been carried out to determine rMETase toxicity, rMETase pharmacokinetics, and serum MET-depletion in cancer patients. Patients with advanced breast cancer, lung cancer, renal cancer and lymphoma were given a single rMETase treatment at doses ranging from 5,000 to 20,000 units by i.v. infusion over 6-24 hours. No clinical toxicity was observed in any patient after rMETase treatment. rMETase levels reached 0.1 to 0.4 units per ml of serum in the patients which correspond to therapeutic levels in vitro. The lowest serum methionine levels in rMETase-treated patients were 0.1% of the pre-treatment levels corresponding to approximately 0.1 microM, which also correlates to therapeutic levels in vitro. The results of the rMETase pilot Phase I clinical trial therefore indicate that i.v. infusion of rMETase is safe and effectively depletes its biochemical target of serum methionine suggesting potential efficacy in future clinical trials.
Tan
Y
Y
AntiCancer, Inc., San Diego, CA 92111, USA.
Zavala
J
J
Han
Q
Q
Xu
M
M
Sun
X
X
Tan
X
X
Tan
X
X
Magana
R
R
Geller
J
J
Hoffman
R M
RM
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D013437:Carbon-Sulfur Lyases / Q000008:administration & dosage / Q000096:biosynthesis / Q000097:blood* / Q000493:pharmacokinetics; D006801:Humans; D008715:Methionine / Q000097:blood*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D010865:Pilot Projects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D011994:Recombinant Proteins; D008715:Methionine; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase