title: Serum methionine depletion without side effects by methioninase in metastatic breast cancer patients.
abstract: The growth dependence of human tumors on elevated levels of methionine has been shown in preclinical in vitro and in vivo studies to be a frequently occurring, highly effective, tumor-selective therapeutic target. High purity endotoxin-free methioninase was produced from Pseudomonas putida in order to develop anti-methionine chemotherapy targeting of human tumors. A pilot Phase I clinical trial has been initiated in order to determine methioninase toxicity, the pharmacokinetics of methioninase and methionine-depletion and maximum tolerated dose. A two hour i.v. infusion of 5,000 units (0.4 g) and 10,000 units (0.8 g) and a ten hour i.v. infusion of 20,000 units (1.6 g) of methioninase was administered to patient-1, patient-2, and patient-3, respectively. All patients had advanced breast cancer. Blood and urine samples were obtained at frequent intervals between 0 and 24 hours. The toxicity evaluations were carried out according to FDA criteria. Pharmacokinetics data were obtained for both methioninase and methionine levels in the serum. No acute clinical toxicity was observed for all the toxicity criteria measured in patient-1, patient-2 and patient-3. The depletion of serum methionine started within 30 minutes of the infusion, and was maintained for 4 hours after the infusion was completed in patient-1 and patient-2. The lowest serum methionine levels were 35% and 19% of the pretreatment level, respectively, in patient-1 and patient-2. Patient-3 received a ten hour i.v. infusion of 20,000 units of methioninase without any signs of side effects. Patient-3 maintained serum levels of methioninase as high as 50% of the maximum level for a subsequent 6 hours after infusion. Methionine was depleted over 200-fold from 23.1 microM to 0.1 microM by the 10-hour infusion of patient-3. No clinical toxicity was observed whatsoever in all the toxicity criteria measured in patient-3. The results of the methioninase pilot Phase 1 clinical trial suggested that i.v. infusion of the methioninase is safe and effectively depletes serum methionine without any signs of side effects. Clinical studies are continuing to determine the maximum length of time complete serum methionine depletion can be tolerated.
authors.affiliation: AntiCancer Inc., San Diego, CA 92111, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Tan
authors.forename: J
authors.initials: J
authors.lastname: Zavala
authors.forename: M
authors.initials: M
authors.lastname: Xu
authors.forename: J
authors.initials: J
authors.lastname: Zavala
authors.forename: R M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy*; D013437:Carbon-Sulfur Lyases / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006207:Half-Life; D006801:Humans; D008715:Methionine / Q000097:blood*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood*; D010865:Pilot Projects
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D008715:Methionine; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase