Since prostate cancer reaches the advanced and non curable stage in the absence of any specific symptom or sign, it seems reasonable to diagnose this cancer at an early and curable stage. Screening by prostate-specifi...Since prostate cancer reaches the advanced and non curable stage in the absence of any specific symptom or sign, it seems reasonable to diagnose this cancer at an early and curable stage. Screening by prostate-specific antigen （PSA） has been the common technology used. The last follow-up of the first two prospective and randomized screening studies for prostate cancer, namely the Quebec and ERSPC （European Randomized Study of Screening for Prostate Cancer） clinical trials started in 1988 and 1991, respectively, have shown reductions of prostate cancer death of 62% （P〈0.002） and 21% （P〈0.001） （38% in the tenth and eleventh years of follow-up, P〈0.003）, respectively, while the PLCO （Prostate Lung Colorectal and Ovarian Cancer） screening trial reported no benefit. It has been estimated, however, that 85% of men in the planned ＇non-screened＇ group of the US study have been screened. With such a serious flaw, the PLCO study does not have the statistical power to reach any valid conclusion. In the Quebec study, only 7.3% of men were screened in the control arm. The important benefit observed in the ERSPC study was achieved using a less than optimal 4-year PSA screening interval which misses a significant number of cancers while the Quebec study used the optimal 1-year interval. With proper information obtained from their physicians or otherwise using data collected only from the clinical trials having the required statistical power, men should be in a good position to decide about being or not being screened for prostate cancer.展开更多
Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the biosynthesis of the most potent natural estrogen 17β-estradiol (E2) from estrone (E1) in the ovary and peripheral tissues, playing a pivotal ro...Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the biosynthesis of the most potent natural estrogen 17β-estradiol (E2) from estrone (E1) in the ovary and peripheral tissues, playing a pivotal role in the progression of estrogen-dependent diseases. N-n-Butyl-N-methyl-ll-(16'α-chloro-3',17'β-dihydroxyestra-1',3',5'(10')-trien-7'α-yl)undecanamide (EM-139) was previously described as a dual-site inhibitor that can inhibit 17β-HSD1 transforming E1 into E2 and also inhibit estrogen receptor. In the present report, we describe the co-crystallization of EM-139 with 17β-HSD1 as well as the analysis of the three-dimensional structure of the enzyme/inhibitor complex. The crystal is grown under similar condition as native crystals, whereas the space group is changed to I121 never observed in other 17β-HSD1 crystals before. The steroidal moiety of the bound EM-139 molecule has shown a binding pattern similar to E2 in the E2 binary complex. The O-3 of the inhibitor develops hydrogen bonds with residues His221 and Glu282, whereas the O-17 makes hydrogen bonds with Ser142 and Tyr155. The bulky 7α-alkyl moiety of the inhibitor, which is essential for its anti-estrogenic activity but cannot be defined in the electron density, may compromise the inhibitory effect of EM-139 to 17β-HSD1. Moreover, the 16α-Cl atom shows no obvious interaction with surrounding residues. The atomic level understanding of the inhibitory mechanism of EM-139 provides important information for the inhibitor design of 17β-HSD1, which will facilitate future development of more potent and selective inhibitors of the enzyme for therapeutic purposes.展开更多
文摘Since prostate cancer reaches the advanced and non curable stage in the absence of any specific symptom or sign, it seems reasonable to diagnose this cancer at an early and curable stage. Screening by prostate-specific antigen （PSA） has been the common technology used. The last follow-up of the first two prospective and randomized screening studies for prostate cancer, namely the Quebec and ERSPC （European Randomized Study of Screening for Prostate Cancer） clinical trials started in 1988 and 1991, respectively, have shown reductions of prostate cancer death of 62% （P〈0.002） and 21% （P〈0.001） （38% in the tenth and eleventh years of follow-up, P〈0.003）, respectively, while the PLCO （Prostate Lung Colorectal and Ovarian Cancer） screening trial reported no benefit. It has been estimated, however, that 85% of men in the planned ＇non-screened＇ group of the US study have been screened. With such a serious flaw, the PLCO study does not have the statistical power to reach any valid conclusion. In the Quebec study, only 7.3% of men were screened in the control arm. The important benefit observed in the ERSPC study was achieved using a less than optimal 4-year PSA screening interval which misses a significant number of cancers while the Quebec study used the optimal 1-year interval. With proper information obtained from their physicians or otherwise using data collected only from the clinical trials having the required statistical power, men should be in a good position to decide about being or not being screened for prostate cancer.
文摘Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the biosynthesis of the most potent natural estrogen 17β-estradiol (E2) from estrone (E1) in the ovary and peripheral tissues, playing a pivotal role in the progression of estrogen-dependent diseases. N-n-Butyl-N-methyl-ll-(16'α-chloro-3',17'β-dihydroxyestra-1',3',5'(10')-trien-7'α-yl)undecanamide (EM-139) was previously described as a dual-site inhibitor that can inhibit 17β-HSD1 transforming E1 into E2 and also inhibit estrogen receptor. In the present report, we describe the co-crystallization of EM-139 with 17β-HSD1 as well as the analysis of the three-dimensional structure of the enzyme/inhibitor complex. The crystal is grown under similar condition as native crystals, whereas the space group is changed to I121 never observed in other 17β-HSD1 crystals before. The steroidal moiety of the bound EM-139 molecule has shown a binding pattern similar to E2 in the E2 binary complex. The O-3 of the inhibitor develops hydrogen bonds with residues His221 and Glu282, whereas the O-17 makes hydrogen bonds with Ser142 and Tyr155. The bulky 7α-alkyl moiety of the inhibitor, which is essential for its anti-estrogenic activity but cannot be defined in the electron density, may compromise the inhibitory effect of EM-139 to 17β-HSD1. Moreover, the 16α-Cl atom shows no obvious interaction with surrounding residues. The atomic level understanding of the inhibitory mechanism of EM-139 provides important information for the inhibitor design of 17β-HSD1, which will facilitate future development of more potent and selective inhibitors of the enzyme for therapeutic purposes.
