TOXICOLOGICAL PROFILE OF A LOW-MOLECULAR-WEIGHT SPLEEN PEPTIDE FORMULATION USED IN SUPPORTIVE CANCER-THERAPY

The toxicity of Polyerga(R) (GP-1), a mixture of low molecular weight spleen peptides, extracted from porcine spleen was examined in in vitr o and in vivo experiments. The following endpoints were examined: sing le dose toxicity, repeated dose toxicity, reproduction toxicity, mutag enic potential, local tolerance, immunotoxicity and general pharmacolo gy. The standard therapeutic dose is 3x1 mi GP-1/week. The dosage can be increased temporarily to 2 ml/d. 1 mi injection solution contains 3 0 mu g oligopeptides. The LD50 was determined in rats as 3.76 ml/kg b. w. i.v. Following repeated intramuscular administration of GP-1 no tox icity appeared in rats up to a dose level of 2 ml/kg b.w./d during the 13-week treatment period. In dogs the no-effect level of GP-I was 0.3 2 ml/kg b.w./d i.m. (marginal body weight reduction at 0.80 ml/kg b.w. /d i.m.). In an embryotoxicity study in rats, GP-1 possessed no terato genic properties tested at dose levels exceeding the human therapeutic dose by a factor of 1000. No mutagenic potential was observed for GP- I in the AMES test. No local irritations were observed at the intended injection sites and at injection sites made in error. None of the in vitro and in vivo pharmacological studies revealed any effect on the p arameters tested, at doses up to 500 times the clinical dose. Hence, u nder the present test conditions, based on a daily therapeutic dose of 1 mi GP-1/patient (approximately 0.014 ml/kg b.w./d), the therapeutic ratio is at least 50 for the most sensitive endpoint 'repeated dose t oxicity' reflecting the wide margin of safety for GP-1.