Enhancement of the activity of phenoxodiol by cisplatin in prostate cancer cells

Phenoxodiol is a novel isoflav-3-ene, currently undergoing clinical trials, that has a broad in vitro activity against a number of human cancer cell lines. Phenoxodiol alone inhibited DU145 and PC3 in a dose- and time-dependent manner with IC50 values of 8±1 and 38±9 μM, respectively. The combination of phenoxodiol and cisplatin was synergistic in DU145, and additive in PC3, as assessed by the Chou–Talalay method. Carboplatin was also synergistic in combination with phenoxodiol in DU145 cells. The activity of the phenoxodiol and cisplatin combination was confirmed in vivo using a DU145 xenograft model in nude mice. Pharmacokinetic data from these mice suggest that the mechanism of synergy may occur through a pharmacodynamic mechanism. An intracellular cisplatin accumulation assay showed a 35% (P<0.05) increase in the uptake of cisplatin when it was combined in a ratio of 1 μM: 5 μM phenoxodiol, resulting in a 300% (P<0.05) increase in DNA adducts. Taken together, our results suggest that phenoxodiol has interesting properties that make combination therapy with cisplatin or carboplatin appealing

NEW IDENTIFIED 15-BETA-HYDROXYLATED 21-DEOXY-PREGNANES IN CONGENITAL ADRENAL-HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY

The identification of 3 new 15beta-hydroxylated 21-deoxy-pregnanes in the urinary steroid profile of a 4-month-old girl with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is reported here. These steroids were identified by gas chromatography and gas chromatography-mass spectrometry as 3alpha,15beta,17-trihydroxy-5alpha-pregnan-20-one (5alphaII), 3alpha,15beta,17,20alpha-tetrahydroxy-5alpha-pregnane, and 3alpha,15beta,17,20alpha-tetra-hydroxy-5beta-pregnane (20alpha DH-11). Two other compounds in the urine, 3beta,15beta,17-trihydroxy-5alpha-pregnan-20-one and 3beta,15beta,17-trihydroxy-5beta-pregnan-20-one were also characterized. The identification of the former 3 steroids was obtained by comparing their methylene unit values and mass spectral data with the corresponding data of the standard steroids synthesized from 15beta,17-dihydroxy-4-pregnene-3,20-dione. Seven other synthesized and identified 15beta-hydroxylated steroids were 3alpha,15beta,17-trihydroxy-5beta-pregnan-20-one (II), 3alpha,15beta,17,20beta-tetrahydroxy-5beta-pregnane, 15beta,17-dihydroxy-5alpha-pregnane-3,20-dione, 15beta,17-dihydroxy-5beta-pregnane-3,20-dione, 15beta,17-dihydroxy-5beta-pregnane-3,20-dione, 3alpha,15beta-dihydroxy-5alpha-androstan-17-one (15betaOH-An), 3alpha,15beta-dihydroxy-5beta-androstan-17-one (15betaOH-Et) and 3alpha,15beta,17,20beta-tetrahydroxy-5alpha-pregnane. Of these the latter two have not been reported previously. This study supports the findings that 15beta-hydroxylated steroids are common in the neonate and could play an important role in the diagnosis of CAH due to 21OHD, where II and the newly identified steroids from this investigation viz., 5alphaII and 20alphaDH-II appear the most important 15beta-hydroxysteroid markers for this disease