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115a

"p, < 0.01 vs. control; n = 5/group. 'Intact parathyroid hormone.

"p, < 0.01 vs. control; n = 5/group. 'Intact parathyroid hormone.

to 26%, and albumin was decreased 17 to 26% at >1 mg/kg (Table 2, male data only). In addition, PTH levels were decreased in a dose- dependent fashion (60 to 77%) at >1 mg/kg. On day 15, phosphorus levels were increased 21% in males at 3 mg/kg, and albumin was decreased 8 to 32% at >0.3 mg/kg. PTH levels were decreased 77 to 89% at 3 mg/kg. Changes in urinary excretion of calcium and phosphorus were observed in both sexes at > 1 mg/kg and included increased excretion of phosphorus on day 15. Although increases in excretion of calcium were observed on day 4 in females, males exhibited decreases in urinary calcium. In this study, PD0325901 administration resulted in significantly decreased levels of serum albumin without changes in serum (total) calcium levels (Payne et al., 1979; Meuten et al., 1982; Rosol and Capen, 1997). This indicates that free, non-protein-bound calcium levels were increased. Hyperphosphatemia and hypercalcemia result in an increased Ca x P product, which is associated with induction of vascular mineralization (Block, 2000; Giachelli et al., 2001). The changes observed in urinary excretion of calcium and phosphorus probably reflected the alterations in serum levels.

After completion of the two studies in rats described above it was concluded that PD0325901 produces significant multiorgan toxicities in rats with no margin between plasma drug levels associated with antitumor efficacy, pharmacologic inhibition of pMAPK (as an index of MEK inhibition), and toxicity in rats. Systemic mineralization was considered the preclinical toxicity of greatest concern, due to the severity of the changes observed and expectation of irreversibility, and the data suggested that it was related to a dysregula-tion in serum phosphorus and calcium homeostasis. Furthermore, skeletal lesions were seen in the rat studies that were similar to those reported with vitamin D toxicity and may be related to the calcium-phosphorus dysregula-tion. In concurrent toxicology studies in dogs and monkeys, neither systemic mineralization nor skeletal changes were observed, despite higher plasma drug exposures, lethal doses, or pharmacologic inhibition of MEK. Therefore, the following questions were posed regarding PD0325901--nduced systemic mineralization: (1) What is a potential mechanism? (2) Is this toxicity relevant to humans or rat-specific? and (3) Can this toxicity be monitored clinically?

The ability of an anticancer agent that modulates various signal transduc-tion pathways to produce dysregulation in serum calcium homeostasis is not unprecedented. 8-Chloro-cAMP is an experimental compound that has been shown to modulate various protein kinase signal transduction pathways involved in neoplasia. In preclinical models, this compound produced growth inhibition and increased differentiation in cancer cells (Ally et al., 1989). In a clinical trial, 8-chloro-cAMP was administered to patients with advanced cancer via intravenous infusion and resulted in dose-limiting toxicity of reversible hypercalcemia, as serum calcium was increased by up to approximately 40% (Saunders et al., 1997). This drug produced a parathyroid hormone-like effect in these patients, resulting in increased synthesis of 1,25-dihydroxyvita-min D (up to 14 times baseline value) as a mechanism for the hypercalcemia. Intravenous administration of 8-chloro-cAMP to beagle dogs also resulted in hypercalcemia (serum calcium increased 37 to 46%), indicating similar actions across species (Brown et al., 2000). Experience with this compound was important with respect to designing investigative studies with PD0325901 in which the hormonal control of serum calcium and phosphorus were evaluated.

An investigative study was designed in rats to examine the time course for tissue mineralization in target organs and to determine whether clinical pathology changes occur prior to, or concurrent with, lesion development (Brown et al., 2005a) . These clinical pathology parameters may therefore serve as biomarkers for systemic mineralization. Male rats (15/group) were used due to their increased sensitivity for this toxicity compared with females. Oral doses tested were 1, 3, or 10mg/kg (6, 18, or 60mg/m); respectively). Five animals per group were necropsied on days 2, 3, or 4 following 1, 2, or 3 days of treatment, respectively. Clinical laboratory tests were conducted at necropsy that included serum osteocalcin, urinalysis, and plasma intact PTH, calcitonin, and 1,25 - dihydroxy vitamin D. Lung samples were evaluated for inhibition of pMAPK, and microscopic evaluations of the aorta, distal femur with proximal tibia, heart, and stomach were conducted for all animals.

Administration of PD0325901 resulted in inhibition of pMAPK in lung at all doses, demonstrating pharmacologic activity of the drug. On day 2, mineralization of gastric fundic mucosa and multifocal areas of necrosis of the ossifying zone of the physis were present only at 10 mg/kg. Necrosis of the metaphysis was present at >3 mg/kg. Serum phosphorus levels increased 33 to 43% and 1,25-dihydroxyvitamin D increased two- to sevenfold at all doses (Table 3). Osteocalcin increased 14 to 18%, and serum albumin decreased 8 to 14% at >3 mg/kg (Table 4). Osteocalcin is a major noncollagenous protein of bone matrix and synthesized by osteoblasts (Fu and Muller, 1999). Changes in serum osteocalcin can reflect alterations in bone turnover (resorption/

TABLE 3 Mean Serum Phosphorus and Plasma 1,25-Dihydroxyvitamin D in Male Rats Administered PD0325901 for Up to 3 Days of Dosing
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