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Submitted on June 25, 2004
Accepted on August 9, 2004
Department of Surgery, University Health Network and Mount Sinai Hospital, and the Department of Medicine, Mount Sinai Hospital and the Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: sylvia.asa{at}uhn.on.ca.
We have previously demonstrated in vitro that 1
,25-dihydroxyvitamin D3 (calcitriol) treatment increases p27 expression and decreases cell proliferation in cultured thyroid carcinoma cell lines. We hypothesized that in vivo treatment with calcitriol would have a beneficial effect on thyroid carcinoma growth and progression. Five x 106 WRO (human thyroid follicular carcinoma-derived) cells were implanted in the neck in 4-5 week old female SCID mice in an orthotopic xenograft model. Animals (n = 15) were treated intraperitoneally 3 times a week for 21 days with 0.75 µg/kg of calcitriol or vehicle. Mice were killed 21 days following tumor implantation, tumor volume was measured, and excised tumor tissue was examined by light microscopy and immunohistochemistry for p27 and thyroglobulin reactivity. Average tumor volume in control mice following 21 days of vehicle treatment was 2002 (± 207) mm3 compared with a mean tumor volume of 1241 (± 115) mm3 in animals receiving calcitriol, reflecting a 38% reduction in tumor volume size (P < 0.003). Tumors from vehicle-treated animals demonstrated morphologic features of epithelial malignancies with characteristics of insular carcinoma and multiple metastases to the lungs. Tumors excised from calcitriol-treated animals demonstrated signs of differentiation with restoration of thyroglobulin staining. This was associated with a marked accumulation of p27 immunoreactivity in the nuclear compartment. These studies demonstrate that in vivo calcitriol administration can effectively restore p27 accumulation in thyroid carcinoma cells, an effect associated with appreciably enhanced cellular differentiation, reduction in tumor burden, and prevention of metastatic growth.
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