calcitriol and Kidney-Neoplasms

1,25-Dihydroxyvitamin D₃ [1,25(OH)₂D₃] has shown strong promise as an antiproliferative agent in several malignancies, yet its therapeutic use has been limited by its toxicity leading to search for analogues with antitumor property and low toxicity. In this study, we evaluated the in vitro and in vivo properties of 1,25-dihydroxyvitamin D₃-3-bromoacetate [1,25(OH)₂D₃-3-BE], an alkylating derivative of 1,25(OH)₂D₃, as a potential therapeutic agent for renal cancer. Dose response of 1,25(OH)₂D₃-3-BE in 2 kidney cancer cell lines was evaluated for its antiproliferative and apoptotic properties, and mechanisms were evaluated by Western blot and FACS analyses. Therapeutic potential of 1,25(OH)₂D₃-3-BE was assessed both by determining its stability in human serum and by evaluating its efficacy in a mouse xenograft model of human renal tumor. We observed that 1,25(OH)₂D₃-3-BE is significantly more potent than an equivalent concentration of 1,25(OH)₂D₃ in inhibiting growth of A498 and Caki 1 human kidney cancer cells. 1,25(OH)₂D₃-3-BE-mediated growth inhibition was promoted through inhibition of cell-cycle progression by downregulating cyclin A and induction of apoptosis by stimulating caspase activity. Moreover, 1,25(OH)₂D₃-3-BE strongly inhibited Akt phosphorylation and phosphorylation of its downstream target, caspase-9. 1,25(OH)₂D₃-3-BE seemed to be stable in human serum. In xenograft mouse model of human renal tumor, 1,25(OH)₂D₃-3-BE was more potent at reducing tumor size than 1,25(OH)₂D₃, which was accompanied by an increase in apopotosis and reduction of cyclin A staining in the tumors. These results suggest a translational potential of this compound as a therapeutic agent in renal cell carcinoma. Data from this study and extensive studies of vitamin D for the prevention of many malignancies support the potential of 1,25(OH)₂D₃-3-BE for preventing renal cancer and the development of relevant in vivo prevention models for assessing this potential, which do not exist at present.

Topics: Alkylating Agents; Alkylation; Animals; Apoptosis; Blotting, Western; Calcitriol; Caspases; Cell Cycle; Cell Proliferation; Cyclin A; Humans; Immunoenzyme Techniques; Kidney Neoplasms; Mice; Mice, Nude; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Calcitriol; Tumor Cells, Cultured; Vitamin D; Xenograft Model Antitumor Assays

To determine the cause of refractory hypercalcemia in a patient with metastatic renal cell carcinoma.. We describe the clinical, pathologic, and immunostain findings in a patient with metastatic renal cell carcinoma and hypercalcemia of malignancy refractory to intravenous bisphosphonates.. A 57-year-old man with a remote history of clear cell renal cell carcinoma was referred to our clinic for evaluation of resistant hypercalcemia 12 years after nephrectomy. The patient had simultaneous elevation of serum 1,25-dihydroxyvitamin D and parathyroid hormone-related peptide. Computed tomographic scan of the chest and abdomen demonstrated numerous ring-enhancing lesions in the liver, and histologic examination of a biopsy specimen revealed liver tissue infiltrated by a malignant neoplasm composed of cells with clear and eosinophilic cytoplasm, arranged in tubules and nests. Findings were morphologically consistent with renal cell carcinoma of clear cell type, and positive immunostaining with the epithelial markers EMA and CAM 5.2 were supportive of the morphologic impression of renal cell carcinoma. The tumor showed expression of 25-hydroxyvitamin D 1alpha-hydroxylase by immunostaining. After failing to respond to intravenous bisphosphonates, the hypercalcemia improved with prednisone treatment.. In some patients with renal cell carcinoma, hypercalcemia of malignancy is associated with simultaneous elevation in serum 1,25-dihydroxyvitamin D and parathyroid hormone-related peptide. As our case exemplifies, it is imperative to identify such patients because hypercalcemia due to elevated 1,25-dihydroxyvitamin D levels may respond better to glucocorticoid treatment than to the conventional bisphosphonate therapy.

Topics: Carcinoma, Renal Cell; Humans; Hypercalcemia; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Parathyroid Hormone-Related Protein; Up-Regulation; Vitamin D