© 1995 Oxford University Press
research-article |
Toxicity of the Protein Kinase C Inhibitor Safingol Administered Alone and in Combination with Chemotherapeutic Agents1
*Sphinx Pharmaceuticals Corporation Durham, North Carolina 27717
Hazleton Wisconsin Inc. Madison, Wisconsin 53704
Received January 7, 1994; accepted July 29, 1994
Safingol [(2S,3S)-2-amino-1,3-octadecanediol] potentiates the toxicity of doxorubicin (DOX) and cisplatin (CIS) against tumor cells in vitro and in vivo. The present studies were conducted in rats and dogs to evaluate safingol toxicity when administered iv as a single agent and to evaluate safingol's ability to potentiate the toxicity of established chemotherapeutic agents to normal tissues in vivo. In an escalating dose study, dogs were administered safingol iv at 5, 10, 20, 30, 40, and 75 mg/kg on Days 1 through 6. Necropsies were performed on Day 7. Red urine was observed at 10 mg/kg and higher. Icterus was observed following 40 mg/kg with additional signs of hypoactivity and anorexia occurring after 75 mg/kg. Clinical and microscopic pathology revealed marked hepatotoxicity, venous degeneration and necrosis at injection sites, and evidence of intra-vascular hemolysis. Doses of 5, 20, or 40 mg safingol/kg were utilized in single iv dose rat and dog studies. No evidence of adverse systemic toxicity was seen up to 20 mg/kg in either species [for rats: Cmax = 12,600 (males) or 17,133 (females) ng/ml, AUC = 3853 (males) or 4365 (females) ng x hr/ml; for dogs: Cmax = 2533 ng/ml, AUC = 2851 ng x hr/ml (no sex differences)]. Local effects of venous irritation or intravascular hemolysis were observed at all doses in rats and at 20 and 40 mg/kg in dogs. A dose of 40 mg/kg [for rats: Cmax = 31,233 (males) or 91,300 (females) ng/ml, AUC = 11,519 (males) or 18,620 (females) ng x hr/ml; for dogs: Cmax = 9033 ng/ml, AUC = 11,094 ng x hr/ml (combined sex)] was associated with clinical pathologic and renal histomorphologic changes considered consequent to intravascular hemolysis in both species, lethality and testicular toxicity in rats, and clinical biochemical changes indicative of hepatobiliary injury in dogs. Studies indicated that hemolysis occurred during infusion, was not caused by circulating levels of safingol, and was a function of dose concentration and vein of delivery. Safingol at 10 or 20 mg/kg was administered iv to rats 30–60 min prior to myelosuppressive iv doses of DOX, CIS, or cyclophosphamide (CYP). Hematology, plus renal function and morphology for CIS-treated animals, was assessed 4 and 14 days later. Safingol did not potentiate DOX-, CIS-, or CYP-mediated leukopenia/thrombocytopenia. A minimal enhancement of CIS-mediated decrease in GFR and increase in creatinine was observed at 20 mg safingol/kg. Dogs were administered 20 mg safingol/kg iv followed 60 min later by 0.5 or 1.25 mg DOX/kg or 0.75 or 2.0 mg CIS/kg. A complete toxicologic assessment 4 and 29 days postdose failed to show potentiation of DOX toxicity by safingol or vice versa. A renal lesion was inferred in dogs administered 20 mg/kg safingol and 2 mg/kg CIS based on minimal to slight renal tubular regeneration observed 4 weeks post-treatment. There were no effects of safingol on the pharmacokinetic profiles of DOX or CIS or vice versa.