Preclinical safety profile of tanespimycin (KOS-953) - a heat shock protein 90 (Hsp90) inhibitor
Cancer Research(2007)
Abstract
1568 Tanespimycin (KOS-953, 17-AAG, 17-allylamino-17-demethoxygeldanamycin) is a potent Hsp90 inhibitor that inhibits the binding of Hsp 90 to its “client proteins” (e.g. oncoproteins, nuclear hormone receptors and protein kinases) leading to their proteasomal degradation and cancer cell death. The anticancer activity of tanespimycin is being evaluated in Phase I and II clinical trials in multiple myeloma and breast cancer, both as a single agent and in combinations with bortezomib or trastuzumab. In single dose one-hour IV infusion studies, tanespimycin was well tolerated to 40 mg/kg in Sprague Dawley rats and to 36 mg/kg in cynomolgus monkeys. In 2-cycle one-hour IV infusion studies that mirror the clinical cycle regimen (each cycle is 4 doses/2 wks then 10-day recovery period, then repeat; 2-cycle = 7 weeks), adverse effects of tanespimycin were seen in the rat at doses of 40 mg/kg and above. These included mortality, inappetance, decreases in body weight, renal tubular degeneration, cecum/colon necrosis, bile duct hyperplasia, spleen/thymus necrosis, uterine atrophy and ovary necrosis. Hematology showed increases of reticulocytes and WBC; serum chemistry showed decreases of A/G ratios, increases of triglyceride and cholesterol. No statistically significant changes in AST/ALT were observed. This is in contrast to previous studies that showed increases of AST/ALT and liver necrosis in Fischer 344 rats after five daily bolus IV injections at doses of 15 mg/kg and above using a tanespimycin formulation containing egg phospholipid and dextrose in water. In the 2-cycle monkey study, tanespimycin was better tolerated than in rats. No mortality was observed up to 50 mg/kg, the highest dose administered. At doses above 30 mg/kg, adverse effects observed were inappetance, soft feces/diarrhea, emesis and decreases in thyroid/parathyroid weight. Hematology showed increases of platelets and lymphocytes; serum chemistry showed changes of AST/ALT. No histopathological changes were observed in the liver or in any major organs examined. A cardiovascular safety pharmacology study in dogs and in vitro/in vivo genetic toxicology studies did not show adverse effects. Importantly, no adverse effects on QTc interval were observed. As compared to the recommended Phase II clinical dose of 340 mg/m2, given twice weekly, the dose multiples of the 2-cycle studies, based on surface area, are 0.7 for the dose of 40 mg/kg in rats and 1.8 for the 50 mg/kg in monkeys. Chronic toxicology studies (6-months) are on-going in these two species.
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Key words
Hsp70 and Hsp90,Heat Shock Proteins
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