SERUM METHIONINE DEPLETION WITHOUT SIDE-EFFECTS BY METHIONINASE IN METASTATIC BREAST-CANCER PATIENTS

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 fr equently occurring, highly effective, tumor selective therapeutic targ et. High purity endotoxin - free methioninase was produced from Pseudo monas putida in older to develop anti - methionine chemotherapy target ing 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 iv. 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 w as administered to patient - 1, patient 2, and patient - 3, respective ly. All patients had advanced breast cancer. Blood and urine samples w ere obtained at frequent intervals between 0 and 24 hours. The toxicit y evaluations were can-led out according to FDA criteria. Pharmacokine tics data were obtained for both methioninase and methionine levels in the serum. No acute clinical toxicity was observed for all the toxici ty criteria measured in patient - 1, patient - 2 and patient 3. The de pletion of serum methionine started within 30 minutes of the infusion, and was maintained for 4 hours after the infusion was completed in pa tient - 1 and patient - 2. The lowest serum methionine levels were 35% and 19% of the pretreatment level, respectively, in patient - 1 and p atient - 2. Patient - 3 received a ten hour i.v. infusion of 20,000 un its of methioninase without any signs of side effects Patient - 3 main tained serum levels of methioninase as high as 50% of the maximum leve l for a subsequent 6 hours after infusion. Methionine was depleted ove r 200 - fold from 23.1 mu M to 0.1 mu M by the 10-hour infusion of pat ient - 3. No clinical toxicity was observed whatsoever in all the toxi city criteria measured in patient - 3. The results of the methioninase pilot Phase I clinical trial suggested that iv. infusion of the methi oninase is safe and effectively depletes serum methionine without any signs' of side effects. Clinical studies are continuing to determine t he maximum length of time complete serum methionine depletion can be t olerated.