Suppression of in vivo growth of human cancer solid tumor xenografts by 1,25-dihydroxyvitamin D3.

It has been demonstrated previously that several human cancer cell lines possess specific, high affinity receptors for 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3, calcitriol] and that 1,25-(OH)2D3 and certain of its metabolites inhibit the growth in vitro of several human breast cancer and malignant melanoma cell lines, i.e., analogous to the effect of estrogens on breast cancer. Furthermore, it has been shown that 1,25-(OH)2D3 and one of its synthetic analogues prolonged the survival in mouse leukemia, induced by inoculation of leukemic cells into syngeneic mice. However, until now no growth-inhibitory effect of 1,25-(OH)2D3 has been demonstrated in vivo for human cancer cells or for solid cancers. This paper describes the suppression by 1,25-(OH)2D3 of the growth of human cancer cell-derived xenografts in immune-suppressed mice. However, the 24-hydroxylated metabolite and the 24-difluorinated analogue of 1,25-(OH)2D3, both of which are active in vitro, were ineffective in this xenograft model system. The suppression by 1,25-(OH)2D3, which was achieved without significant toxicity, was observed with xenografts derived from two 1,25-(OH)2D3 receptor-positive cell lines (COLO 206F, derived from a colonic cancer, and COLO 239F from a malignant melanoma) but not in those from a receptor-negative line (RPMI 7932, also derived from a malignant melanoma). These studies demonstrate that pharmacological doses of 1,25-(OH)2D3 can be tolerated in the presence of a low calcium diet and that these doses can suppress the growth of human solid xenograft tumors in vivo. This is the first report of 1,25-(OH)2D3 growth suppression of solid tumors derived from human cancer cells in an in vivo model system, and it supports the hypothesized potential of the hormone in the treatment of 1,25-(OH)2D3 receptor-positive human cancers.