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October 2000
Vol. 3, No. 8, p. 17.

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Analog-ous research

The vitamin D derivative calcitriol (1α,25-dihydroxy-vitamin D3) functions in many cellular processes, including calcium phosphate homeostasis, inhibition of cell growth, and stimulation of cell differentiation. A potent inhibitor of multistage skin tumor formation, it has the unfortunate side effect of causing hypercalcemia, which can result in bone loss, renal calcification, and coma. As a result, researchers have been searching for vitamin D analogues—deltanoids—that will inhibit tumor growth without triggering hypercalcemia.

Little is known about calcitriol’s mechanism of action, but chemical modifications to and near its extended side chain can enhance its antiproliferative and chemopreventive activities. Similarly, changes in the opposing six-member carbon ring reduce calcitriol’s toxicity. Recently, Thomas Kensler and his colleagues at Johns Hopkins University in Baltimore reported that sulfonation of the side chain not only proves antiproliferative in mouse skin cells and melanomas in vitro but also is noncalcemic in rats in vivo.

Vitamin D-rivatives. Comparison of the structures of calcitriol and two synthetic detanoids. Derivative 1 is sulfonated on the extended side chain, whereas 2 is modified on both the side chain and the six-member carbon ring (A),

On the basis of this finding, the Baltimore researchers studied calcitriol and five other deltanoids to determine the characteristics of certain analogues in vivo (Carcinogenesis 2000, 21, 1341–1346). Thomas Kensler and his team treated mice first with a tumor-producing agent and then topically with one of six deltanoids: calcitriol, one ineffective as an inhibitor, and four analogues—three with sulfonated side chains and one with changes in both the side chain and ring. They used tumor incidence and multiplicity to study chemopreventive activity, and animal weight and urinary calcium levels to observe any calcemia.

The four analogues significantly reduced the number of tumors per mouse, and three significantly delayed tumor development. Further, the analogues showed no calcemic effects, leading the researchers to believe that these compounds have the potential to provide “more potent and safe vitamin D analogues for cancer chemoprevention and other medicinal uses.”


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