Chemical Education Today
Research Advances: Developing New Treatments for Cancer, Toxoplasmosis, and New Methods of Detection for Mad Cow Disease by Angela G. King Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, United States
[email protected] Toward the First Nose Drops To Treat Brain Cancer Scientists are reporting the development and successful initial testing of a new form of methotrexate (MTX, 1; see Figure 1), a mainstay anticancer drug, designed to be given as nose drops rather than injected (1). It shows promise as a more effective treatment for brain cancer, they say. Tomotaka Shingaki and colleagues note that brain cancer is difficult to treat, partly because current anticancer drugs have difficulty reaching the brain. This is because the so-called bloodbrain barrier (a protective layer of cells surrounding the brain) prevents medication in the blood from entering the brain. But new evidence indicates that some drugs administered through the nose, either as nose drops or nasal spray, can bypass this barrier and travel directly into the brain. Among them are drugs for migraine headaches. Until now, however, nobody knew whether methotrexate might do the same. The scientists tested the delivery of MTX by comparing [MTX] in plasma and cerebrospinal fluid (CSF) after interperitoneal (IP) and intranasal (IN) administration of the drug. 3H-MTX was used to follow the course of the drug after administration. Brain uptake of MTX was determined through multiple-time/graphical analysis by measuring [MTX] in the plasma and brain of rats. The results clearly showed that MTC is transported directly from the nasal cavity to the CSF and brain. The team of scientists also tested MTX nose drops on laboratory rats with brain cancer. Compared to cancer treated with an injectable form of the drug, the nose drop drug reduced the weight of tumors by almost one-third, the scientists said (Figure 2). “The strategy to utilize the nose-brain direct transport can be applicable to a new therapeutic system not only for brain tumors but also for other central nervous system disorders such as neurodegenerative diseases”, the article noted (1). Additional information on methotrexate can be found in this Journal in articles on bioorganic mechanisms (2), the role of molecular modeling in medicinal chemistry (3), and enzyme inhibition (4). Additional articles on chemical methods of drug delivery are also available (5-9). Antibacterial Soap Hints at New Drugs for Toxoplasmosis Triclosan (2; see Figure 3), the antibacterial ingredient in some soaps, toothpastes, odor-fighting socks, and even computer keyboards is pointing scientists toward a long-sought new treatment for toxoplasmosis, a parasitic disease that affects almost 2 billion people worldwide (10).
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Figure 1. Structure of the anticancer drug methotrexate (1). Structure provided by A. King.
Figure 2. The tumor weight of rats receiving 3 doses of MTX 10 days following inoculation. 9L rat glioma cells were inoculated into the right frontal cortex of male Fischer rats. Four days after inoculation, MTX was administered peritoneally (IP; n = 7; hatched bar) or nasally (IN; n = 8; solid bar) three times at 2-day intervals. At each treatment, AZA (10 mg/ mL, 1 mL/kg) was orally administered to the IN group 30 min before MTX administration. On day 10, the rat was decapitated, and the brain tumor was isolated and weighed. According to the test result, statistically significant differences were observed between the control and IN groups (*p < 0.001), and between the IP and IN groups (†p < 0.001). Reprinted with permission from ref 1. Copyright 2010 American Chemical Society.
In the study, Rima McLeod, Suresh Tipparaju, Alan Kowakowski, Ernest Mui, Stephen Muench, David Rice, Sean Prigge, Craig Roberts, and Fiona Henriquez point out that toxoplasmosis is one of the world's most common parasitic infections, affecting about one-third of the world's population, including 80% of the population of Brazil. People can catch the
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r 2010 American Chemical Society and Division of Chemical Education, Inc. pubs.acs.org/jchemeduc Vol. 88 No. 2 February 2011 10.1021/ed1010689 Published on Web 11/19/2010
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Figure 3. The structures of antibacterial triclosan (2) and a new lead compound for inhibiting TgENR (3). Structure provided by A. King.
infection, spread by the parasite Toxoplasma gondii (T. gondii), from contact with feces from infected cats, eating raw or undercooked meat, and in other ways. Many have no symptoms because their immune systems keep the infection under control and the parasite remains inactive. But it can cause eye damage and other problems, even becoming life threatening in individuals with immune systems weakened by certain medications and diseases, such as HIV infection, which allow the parasite to become active again, and in some persons without immune compromise. Most current treatments have some potentially harmful side effects and none of them attack the parasite in its inactive stage. The scientists knew from past research that triclosan is a powerful inhibitor of T. gondii enoyl reductase (TgENR), a key enzyme that T. gondii uses to live. TgENR is a fatty acid synthase enzyme essential in parasites but not present in animals, making it a prime target for inhibition. Triclosan, however, cannot be used as a medication because it does not dissolve in the blood. The report describes using triclosan's molecular structure as the model for developing other potential medications, including some that show promise as more effective treatments for the disease. Researchers assayed 53 compounds for TgENR inhibition and found that six of them have antiparasite MIC90's e 6 μM without toxicity to host cells. The scientists obtained the cocrystal structure of one of the most promising candidates (3) in a complex with TgENR. The crystal structure indicates that inhibitors target the increase in space within the parasitic ENR. On the basis of this knowledge, a new library of compounds will be developed in hopes of increased inhibition and increased bioavailability. The enzyme enoyl reductase has also been exploited in a combinatorial biosynthetic approach to the synthesis of new antibiotics (11). More information on McLeod's research can be found online (12). The Eyes of Madness The eyes may or may not be windows to the soul, as the old adage goes, but scientists are reporting evidence that a peek into the eyes of cattle may become the basis for a long-sought test to detect infection with the agent that causes mad cow disease (bovine spongiform encephalopathy, or BSE). Scientists are hopeful that a test based on the tell-tale glow given off by eyes of an animal infected with any form of a transmissible spongiform encephalopathy (TSE), the agents that are associated with variant Creutzfeldt-Jakob disease (vCJD) in humans, could help prevent the disease from spreading in the food supply (13). Jacob Petrich and colleagues at Iowa State University note that vCJD is linked to eating beef, specifically central nervous system (CNS) tissues from animals infected with abnormal proteins called prions, which are implicated in a range of brain diseases. Detecting the presence of CNS tissue in meat and other 134
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food products is one step toward ensuring a safe food supply. Scientists are also trying to develop tests to detect infected cattle before they enter the food supply. Past studies suggest that chemical changes in an animal's retina, the light sensitive nerve tissue in the back of the eye, may provide a basis for detecting prion diseases. Fluorescence spectroscopy is currently employed to detect fecal contamination on meat during slaughter and can also be used to detect CNS material by identifying the high concentration of lipofuscin, a protein that accumulates in neural tissue. Now Petrich's team has demonstrated that fluorescence spectroscopy can also be used to identify animals with abnormal neurological pathologies. The scientists showed that retinas of sheep infected with scrapie, a TSE disease similar to mad cow disease, emit a characteristic fluorescent signature attributed to the accumulation of lipofuscin in the retina. They suggest that eye tests based on the finding could become important in the future for fast, inexpensive diagnosis of prion diseases and other neurological diseases. Research Advances previously reported on the use of mass spectrometry to monitor animal feed for animal protein that may spread BSE (14). More information on Petrich's interdisciplinary research can be found online (15). Literature Cited 1. Shingaki, T.; Inoue, D.; Furubayashi, T.; Sakane, T.; Katsumi, H.; Yamamoto, A.; Yamashita, S. Transnasal Delivery of Methotrexate to Brain Tumors in Rats: A New Strategy for Brain Tumor Chemotherapy. Mol. Pharmaceutics 2010, 7, 1561–1568. 2. Ferguson, L. Bio-Organic Mechanisms: II. Chemoreception. J. Chem. Educ. 1981, 58, 456–461. Bernardes, L. Medicinal Chemistry and 3. Carvalho, I.; Borges, A; Molecular Modeling: An Integration To Teach Drug StructureActivity Relationship and the Molecular Basis of Drug Action. J. Chem. Educ. 2005, 82, 588–596. 4. Cromartie, T. The Inhibition of Enzymes by Drugs and Pesticides. J. Chem. Educ. 1986, 63, 765–768. 5. King, A. Research Advances: Catch and Release; Mini Mass Spectrometer; Drug Delivery by Magnetic Propulsion. J. Chem. Educ. 2009, 86, 1358–1360. 6. King, A. Research Advances: Potential New Drugs;970 Million and Still Counting; Natural Viagra?; Sugarcoated Quantum Dots for Drug Delivery. J. Chem. Educ. 2010, 87, 3–4. 7. King, A. Research Advances: In a Crisis, Creating DNA Vaccine Could Help Save Lives; Slow Spread of “Bird Flu”; Gold Nanoparticles, Radiation Combo May Slow Alzheimer's; New “SelfExploding” Microcapsules Could Take Sting out of Drug Delivery. J. Chem. Educ. 2006, 83, 522–526. 8. Elder, D. Pharmaceutical Applications of Ion-Exchange Resins. J. Chem. Educ. 2005, 82, 575–587. 9. Smith, D. A Supramolecular Approach to Medicinal Chemistry: Medicine beyond the Molecule. J. Chem. Educ. 2005, 82, 393– 400. 10. Tipparaju, S.; Muench, S.; Mui, E.; Ruzheinikov, S.; Lu, J.; Hutson, S.; Kirisits, M.; Prigge, S.; Roberts, C.; Henriquez, F.; Kozikowski, A.; Rice, D.; McLeod, R. Identification and Development of Novel Inhibitors of Toxoplasma gondii Enoyl Reductase. J. Med. Chem. 2010, 53, 6287–6300. 11. Pohl, N. Developing New Antibiotics with Combinatorial Biosynthesis. J. Chem. Educ. 2000, 77, 1421–1423.
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12. Web Page for Rima McLeod. http://biomed.uchicago.edu/common/faculty/mcleod.html (accessed Nov 2010). 13. Adhikary, R.; Mukherjee, P.; Krishnamoorthy, G.; Kunkle, R. A.; Casey, T. A.; Rasmussen, M. A.; Petrich, J. W. Fluorescence Spectroscopy of the Retina for Diagnosis of Transmissible Spongiform Encephalopathies. Anal. Chem. 2010, 82, 4097–4101.
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14. King, A. Research Advances: Mass Spectrometric Monitoring of Animal Feed for BSE Spread; Ancient Oceans Had Less Oxygen; A Model for the Formation of Piezoelectric Single-Crystal Nanorings and Nanobows. J. Chem. Educ. 2004, 81, 1242–1245. 15. Web Page for Jacob Petrich. http://www.chem.iastate.edu/faculty/ Jacob_Petrich/research.html (accessed Nov 2010).
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