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Three 5'-phosphorodiamidate derivatives of 5-fluoro-2'-deoxyuridine (FdUrd), 5-fluoro-2'-deoxyuridine 5'-phosphorodiamidate (4a), 5'-phosphorodiimidazolidate (4b), and 5'-phosphorodimorpholidate (4c), were synthesized by aminolysis of 5-fluoro-2'-deoxyuridine 5'-phosphorodichloridate with the respective amine. In culture, these 5'-phosphorodiamidates inhibited the growth of murine leukemia (L5178Y) cells. 5-Fluoro-2'-deoxyuridine 5'-phosphorodiamidate (4a) was the most active derivative and, on a molar basis, produced a cytostatic effect comparable to that of FdUrd and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUrd-5'-P). Compounds 4b and 4c were less active than 4a, with relative rates of activity 4a > 4b > 4c that corresponded to their rates of hydrolysis to FdUrd-5'-P. None of the 5'-phosphorodiamidates inhibited thymidylate synthetase of concentrations up to 1 mM.

An in vitro assay has been developed for the rat yolk sac 25-hydroxyvitamin D3 1 alpha-hydroxylase (1 alpha-hydroxylase). The subcellular location and some properties of the enzyme are described. 1,25-Dihydroxyvitamin D3 produced from incubations of yolk sac homogenates was extracted, purified by Sephadex LH-20 chromatography and straight- and reverse-phase high-performance liquid chromatography (HPLC), and measured by a competitive binding assay using chick intestinal receptor. The reaction is linear with time for up to 45 min at a substrate concentration of 80 microM and 4-6 mg/mL microsomal protein. The enzyme, located in the microsomes, requires molecular oxygen and NADPH. Metyrapone (1 X 10(-3) M) was found to inhibit 1-hydroxylation, but a 90% carbon monoxide-10% oxygen atmosphere did not, leaving open the question of involvement of cytochrome P-450. Diphenyl-p-phenylenediamine, a lipid peroxidase inhibitor, inhibited 1 alpha-hydroxylation.

Substitution of Cerelose (glucose monohydrate) for complex carbohydrate (whole wheat flour) does not alter plasma calcium levels in vitamin D-deficient rats, contrary to a previous report. It is suspected that whole wheat flour may contain traces of vitamin D that result in a slower rate of depletion than found with Cerelose diets. Vitamin Ddeficient rats showing low plasma 1,25-dihydroxyvitamin D3 levels and no detectable 25-hydroxyvitamin D3 levels in their blood show a hypocalcemia (5.6 mg/dl) and normal phosphatemia whether fed whole wheat or Cerelose diets.The product of the calcium concentration and the phosphorus concentration in blood was used to diagnose rickets in children as early as the 1920s (1 [1,2D3] was detected in the plasma of rats on the Cerelose diet while some 1,25-(OH)2D3 was detected in the rats fed the whole wheat diet. However, the whole wheat diet did not increase plasma calcium or phosphorus in vitamin D-deficient rats as reported (5). Rats on the whole wheat diet did grow better than rats on a Cerelose diet, as shown by the body weight and the femur weight ( Table 2). The percentage ash is significantly less (P < 0.001) in the vitamin Ddeficient rats than in vitamin D-dosed controls fed both Cerelose and whole wheat diets, but the rats on the whole wheat diet have significantly higher amounts of mineral in the feAbbreviations: 25-OH-D3, 25-hydroxyvitamin D3; 1,25-(OH)2D3, 1,25-dihydroxyvitamin D3. tTo whom reprint requests should be addressed. 2352The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.