The active metabolite of vitamin D, l,25(OH)2D or calcitriol, is most widely known for its role in regulation of bone and mineral metabolism. Vitamin D, however, has also been shown to modulate cell growth and differentiation of several normal and malignant cell types. In vitro, vitamin D inhibits cell proliferation and in vivo, prolongs survival and inhibits tumor growth in a variety of murine leukemia/tumor and human xenograft tumor model systems. Clinical efforts, however, have been hampered due to hypercalcemia, the dose limiting toxicity. As a result, vitamin D analogues such as l,25(OH)2-16-ene-23-yne-D, have been developed that maintain anti-tumor activity without inducing hypercalcemia. We have demonstrated here that both vitamin D parent (calcitriol) and the analogue had significant anti-tumor activity in vitro and in vivo. At high doses, the parent induced tumor inhibition with severe hypercalcemia whereas, the analogue resulted in an increase in tumor growth inhibition without significant hypercalcemia. In addition, significant enhancement of anti- tumor activity was observed when vitamin D was combined with either glucocorticoids or cisplatin. Therefore, we propose to examine the anti- tumor mechanisms and therapeutic efficacy of vitamin D parent or analogue in animal tumor models and to determine whether they can be exploited for clinical use.
The aims of this study include: l) To characterize and compare the anti- tumor response of the vitamin D parent and analogue using murine tumor model systems; 2) To determine whether relationships exist between vitamin D receptor expression in vivo, state of differentiation and/or therapeutic efficacy with vitamin D parent or analogue and can these activities be enhanced when combined with glucocorticoids; 3) To examine the anti-tumor activity of vitamin D parent or analogue when administered in combination with cisplatin; and 4) To determine in the phase I setting the maximum tolerated dose and pharmacokinetics of vitamin D parent (Calcijex) by subcutaneous injection in patients with advanced solid tumors with and without steroid therapy.
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