Editor's Note: Science Scan is a roundup of recently published biotechnology-relevant research.
Researchers in South Korea have generated a 3-dimensional snapshot of the drug sildenafil citrate, better known as Viagra (Pfizer Inc., of New York). The drug works by binding to and inhibiting the enzyme phosphodiesterase 5 (PDE 5). PDE enzymes are involved in cell communication, so drugs that target them may help treat a range of medical conditions.
Their paper in Nature, dated Sept. 4, 2003, carries the title "Structure of the catalytic domain of human phosphodiesterase 5 with drug molecules." Its co-authors are from Crystal Genomics Inc., of Daejon, Korea.
They explain that phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messenger cyclic AMP (adenosine monophosphate) and cyclic GMP (guanosine 5'-monophosphate). As essential regulators of cyclic nucleotide signaling, with diverse physiological functions, PDEs are drug targets for various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction - Viagra's mission.
Of the 12 PDE gene families, cGMP-specific PDE 5 carries out the principal cGMP-hydrolyzing activity in human corpus cavernosum tissue. Specific to Viagra, the corpus cavernosum penis forms one of two parallel columns of erectile tissue comprising the dorsal part of the penile body. It is well known as the target of sildenafil citrate and similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE 4 structures are currently available.
"Here," the paper notes, "we present the 3-dimensional structures of the catalytic domain of human PDE 5 complexed with the three drug molecules sildenafil, tadalafil and vardenafil. These structures," it points out, "will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles."
EZH2 Protein Overexpressed In Breast, Prostate Carcinoma And Metastases Over Normal Tissues
Like a serial killer charged with multiple murders, a protein already linked to deadly prostate cancer is now implicated in lethal breast cancer. And it might soon help doctors tell cancer patients just how dangerous their tumors are. The double-duty offender apparently helps cancer cells invade nearby tissues and form colonies, according to a paper in the Proceedings of the National Academy of Sciences, released online Sept. 8, 2003. It bears the title "EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells." (EZ derives from Drosophila: "Enhancer of Zeste.")
Its co-authors are led by scientists at the University of Michigan's Comprehensive Cancer Center in Ann Arbor. They report that the more EZH2 found in the tumor tissue, the deadlier the cancer and the worse the patient's prognosis. These findings are based on exhaustive analyses of tissue samples and medical records from 280 patients at U-M and the University of Amsterdam in the Netherlands.
The finding is crucial for aggressive, metastatic forms of breast and prostate cancers, both of which are regulated by steroid hormones. But like many criminals who get caught, EZH2 also leaves fingerprints - copies of the protein, which readily can be detected in cancerous tissue.
"EZH2 may serve as an excellent biomarker for determining a breast cancer patient's prognosis more precisely than current methods," said the paper's lead author, pathologist Celina Kleer, at the U-M medical school. "Just as with prostate cancer, which we have already analyzed," she continued, "its association with the severity of a patient's disease and clinical outcome are striking. And they're easy to detect with an antibody stain."
The actual use of EZH2 as a clinical test is still several years away, though the U-M team is planning a prospective clinical trial to test its use in breast cancer patients. Because EZH2 can be stained using an antibody specific to the protein, it clearly can be screened both in conventional slides of tissue or minute samples arranged in microarrays (chips). At the end of 10 years, only about 25 percent of the patients tested with high EZH2 levels were alive, the paper noted, whereas 59 percent of those with low levels were still living.
Breast cancer is a leading cause of malignancy-related death in women. It accounts for approximately 40,000 deaths per year in the U.S. Despite advances in the early detection and treatment of breast cancer, mortality for the 20 percent of patients who incur recurrence and/or metastases is nearly 100 percent.
Chronic Prion Wasting Disease Spreads From Animal To Animal In Central United States
Chronic wasting disease is a prion-related affliction that affects mule deer (Odocoileus hemionus). It can spread efficiently from animal to animal, according to a brief communication in Nature, dated Sept. 4, 2003. This "horizontal" route of transmission, rather than maternal transfer - where the disease is passed from mother to unborn foal - might account for the zoonosis disease pervading deer populations in central U.S.
Veterinary scientists at the Wildlife Research Center in Fort Collins, Colo., studied the transmission of chronic wasting disease (CWD). The brief communication is aptly titled: "Horizontal prion transmission in mule deer."
The scientists examined two captive populations of Colorado mule deer. One group was born to mothers that had contracted the disease. Animals in the second group were born to disease-free mothers, but joined the first group when they were 3 to 4 months old. All of the former, and almost all of the latter, contracted CWD over a four-year period.
Because the incidence of CWD in the two groups was similar, the research suggests that maternal transmission does not contribute to disease transfer. Instead, horizontal transmission is more likely to be important in sustaining CWD zoonoses. This could happen directly or indirectly, the authors speculate - concentrating deer in captivity or commercially transporting infected animals, which might facilitate transmission.