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Editor, Shana Sturla
In this Issue:
Message from the Chair
Message from the Division Chair, Professor Lisa A. Peterson
We are gearing up for the National ACS meeting with Washington DC. The programming is set: Kaushik Mitra has put together a terrific program and we have received many outstanding contributed papers. In addition, the short course entitled "Chemical Toxicology: A Chemist's Roadmap to Reduce Bioactivation Liabilities in Drug Candidates" will be given on Saturday August 15 by Kaushik Mitra, Griff Humphreys, Fred Guengerich and Christine Fandozzi. To learn about the course and register, visit the ACS Short Course Website.
This year the business meeting, which is open to all members of the division, will be held just prior to the Poster Session and dinner. To encourage member attendance, we will be serving refreshments this year. The first 100 entrants will receive a ticket for one free drink. In addition to reporting on the past year's activities at the business meeting, we will be soliciting nominations for the elections upcoming this fall. The open positions include Secretary, Treasurer, Nominations Committee (3 members) and a member-at-large. If you are interested or know of someone who is interested in running for these position, please contact Larry Marnett (chair) , Peter Dedon or Kent Gates . It is also time to start thinking about programming for the National Meeting in 2010. Please contact Kaushik Mitra with your programming ideas.
We have also initiated a strategic planning process. The strategic planning committee will meet just prior to the Washington DC meeting to assess our current status and future directions. As part of this process, we will be surveying the membership in the next month or so. I strongly encourage all members to take part in this survey process so that we can better determine the needs and desires of the division. The outcome of the planning process is dependent on the information gathered in the survey. We welcome your input to ensure the continued success of the division.
See you in Washington!
Lisa
AACR Award to Fred Guengerich
By Stephen S. Hecht, University of Minnesota
A standing room only crowd gathered at the 100th American Association for Cancer Research (AACR) Annual Meeting in Denver, April 19, 2009, to see former TOXI Chair Fred Guengerich accept the 3rd Annual AACR Award for Outstanding Achievement in Chemistry in Cancer Research. The award is given for outstanding, novel, and significant chemistry research which has led to important contributions to the fields of basic cancer research, translational cancer research, cancer diagnosis, the prevention of cancer and the treatment of patients with cancer. The two previous winners were Samuel Danishefsky and Steven Tannenbaum.
Pictured is Professor Guengerich (center) with , Professor Stephen S. Hecht (right) and Dr. Perry D. Nisen (left) from GlaxoSmithKline . ©2009 AACR/Todd Buchanan
Professor Guengerich (Vanderbilt University) was honored for his seminal studies on the identity and enzymology of cytochrome P450 enzymes which are critical in the conversion of environmental and endogenous carcinogens to intermediates that mutate DNA thus initiating the carcinogenic process. He presented a superb lecture entitled "Mechanisms of Mutations: Interactions of DNA Polymerases with Carcinogen-Damaged DNA" in which he described his current exciting work on bypass polymerases. Professor Guengerich discussed his passion for chemistry, and the special significance of applying chemistry to cancer research, as cancer is a disease that touches virtually every family, including his own. The lecture was warmly received by the throngs of chemists in the audience, most of whom are members of the Chemistry in Cancer Research (CICR) Working Group, a group within the AACR with the mission of highlighting the critical role of chemistry in effective cancer research. The CICR sponsors chemistry-oriented symposia, special lectures, educational sessions, mentoring sessions, town meetings, and abstract submission categories at each national meeting, and organizes, together with ACS, a bi-annual specialty meeting on the vital partnership between chemistry and cancer research. All TOXI members with an interest in cancer research should become members of AACR and CICR.
Quarterly chemical Report: Palmerolide A
By Bill Baker
Palmerolide A is a polyketide macrolide isolated from the circumpolar colonial tunicate Synoicum adareanum. The sea squirt is native to the waters of Antarctica and can be found in abundance near Palmer Station, the U.S. research facility located on the Antarctic Peninsula. Palmerolide A is comprised of a 20-membered macrolide ring core adorned with a number of oxygenated moieties and a highly functionalized, pendant side chain attached at the ester linkage. This secondary metabolite generated a great deal of interest due to the potent cytotoxicity and selectivity demonstrated against melanoma cells along with low toxicity when screened against the National Cancer Institute's sixty cancer cell line panel (NCI60). The assay results revealed that the natural product not only exhibits impressive activity against the UACC-62 melanoma cell line (LC50=18 nM) but modest cytotoxicity against the HCC-2998 colon cancer cell line (LC50 = 6.5 µM) and the RXF-393 renal cancer cell line (LC50 = 6.5 µM) as well. Based on the NCI COMPARE algorithm, palmerolide A's activity profiles in the NCI60 suggested that palmerolide A might have the same mode of action as salicylihalimide A and bafilomycin A1, inhibiting vacuolar-ATPase. Further bioassay revealed that palmerolide A is in fact a potent inhibitor of the proton pumping activity of mammalian v-ATPase with an IC50 at 2 nM, but does so in a manner that lacks the neurotoxic effect demonstrated by other v-ATPase inhibitors. The importance of v-ATPases as a potential therapeutic target has become increasingly appreciated during the past two decades. Current research on palmerolide A is focused on further developing the compound as a drug candidate and validating v-ATPases as a therapeutic target
Bill J. Baker is Professor of Chemistry at the University of South Florida in Tampa, Florida. His research interests concern marine natural products, their biosynthesis, chemical synthesis, role in chemical ecology, and potential as chemotherapeutic agents.
Research Highlight:
Human AKRs display Quinone Reductase Activity with PAH Quinones and Equilenin-o-quinone
By Carol A. Shultz
Previous studies have showed that following treatment of cells with PAH o-quinones or 4-OHEN-o-quinone, large amounts of ROS are observed, but the mechanism for such ROS formation has not yet been identified. ROS amplification following quinone exposure may be explained with enzymes that catalyze quinone reduction. We found that human aldo-keto reductases (AKRs) AKR1A1, 1B1, 1B10, 1C1-4, and 7A2 display substantial quinone reductase activity with polycyclic aromatic hydrocarbon (PAH) o-quinones. AKRs reduce o-quinones to catechols, which auto-oxidize back to o-quinones, generating reactive oxygen species. We compared benzo[a]pyrene-7,8-dione, benzo[a]pyrene-1,6-dione, and benzo[a]pyrene-3,6-dione as substrates for quinone reduction. The extended benzo[a]pyrene-quinones gave depressed rates of quinone reduction, suggesting that AKRs preferentially reduce o-quinones produced from PAH-trans-dihydrodiols. Furthermore, we examined equilenin-o-quinone (4-OHEN-o-quinone), a hormone replacement therapy drug metabolite, as a quinone reductase substrate. AKR1B1, 1C1-3, and 7A2 catalyzed the reduction of 4-OHEN-o-quinone at rates 14-500 fold greater than the non-enzymatic rate depending on the enzyme isoform. In endometrial cancer, AKR1C1 and AKR1C3 expression is elevated (Mol. Cell. Endocrinol. 248 (2006) 126) and may contribute to a depressed Progesterone:17β-Estradiol ratio. The reduction of quinones by AKRs may cause increases in cellular oxidative stress inflicted by PAH quinones and 4-OHEN-o-quinone, which can contribute to chemical and hormonal carcinogenesis (supported by R01 CA39504, P30-ES013508).
Carol A. Shultz was recently awarded a Ph.D. in Biochemistry and Molecular Biophysics at the University of Pennsylvania following the successful completion of her graduate training with Dr. Trevor Penning. Her scientific interests include biochemistry, toxicology, and enzymology. Currently, she is a Process Scientist in Global Vaccine Technology & Engineering at Merck.
Announcements from the Division of Chemical Toxicology Committees
Program Committee
238th ACS National Meeting, Washington, DC, August 16-20, 2009
The final programming for the Division of Chemical Toxicology sponsored programming at the Washington DC ACS meeting is set and features a diverse group of presentations unified by a focus on modern strategies in chemical toxicology that are being used to address concerns for human health and the environment in areas ranging from aquatic toxicology and risk assessment to the study of human drug metabolites, drug-induced mitochondrial dysfunction, and development of cancer therapeutics. Summaries of selected symposia are presented below; these will be rounded out by Sunday's Founders Award Symposium, organized by recipient Stephen S. Hecht, and contributed and young investigator symposiums. On Tuesday evening, the division will host its trademark student poster session, dinner and social event, with poster competitions and awards recognitions for outstanding student and postdoctoral contributions.
Advances in Aquatic Toxicology: Alternative Nontraditional Endpoints.
Organizers: Professors Bryan Brooks and Richard Brian
Baylor University, Waco, Texas
This symposium concerns advances in alternative nontraditional endpoint identification and application, i.e. biomarkers or bioindicators, in aquatic toxicology. Recent developments in this area are critical in understanding exposures to and potential effects of environmental contaminants. For environmental risk assessment, it is useful to classify sub-lethal organism contaminant responses as either measures of exposure or effect. Effect measurements are indicators of aquatic toxicity that may link physiologically and ecologically important endpoints with population-level relevance. Alternative nontraditional endpoints of exposure and effect in risk assessment is projected to increase as emerging environmental contaminants may impact receptor/enzyme interactions, providing an impetus towards "intelligent" aquatic toxicity testing.
Human Drug Metabolites in Safety Testing: Guidelines & Strategies
Organizers: F. Peter Guengerich, Vanderbilt University School of Medicine,
Memphis, TN. Nicholas A. Meanwell, Bristol-Myers Squibb, Princeton, NJ
The new Food and Drug Administration (FDA) guidance (Feb,'08), often referred by the acronym MIST (Metabolites in Safety Testing), provides recommendations to the pharmaceutical industry on when and how to identify and characterize drug metabolites whose non-clinical toxicity needs to be evaluated. This symposium brings together speakers from the FDA, academia and pharmaceutical companies to discuss the fundamental and practical issues to testing the safety of drug metabolites in the light of the FDA guidance. Key points to be addressed include questions on isolating metabolites, quantitative approaches to measure metabolites in early clinical studies, timing strategies for addressing full bioanalytical validations, non-traditional tests for characterizing potential metabolite targets, and assessment relevance of single dose clinical data to make our assessments. A goal of the session is to evaluate the value, from a drug development perspective, to understand metabolites early. A special early 2009 issue of Chemical Research in Toxicology will be dedicated to this topic.
Drug-Induced Mitochondrial Dysfunction and Human Disease: New Insights and Applications
Organizers: Dr. Kevin Leach, Merck Research Laboratories, Boston, MA,
David Thompson, Pfizer Global Research, St. Louis, MO
Interest in mitochondrial dysfunction as a potential mechanism for the etiology of drug-induced toxicity has significantly increased over the past few years due to advances in the knowledge of the molecular biology and biophysics of mitochondrial bioenergetics, new insights into the role that mitochondria play in oxidative stress and human disease, as well as the development of new higher throughput in vitro tools for measuring and assessing effects on mitochondrial function and animal models that perturb the normal mitochondrial state. In particular, subtle perturbations in mitochondrial function have recently been hypothesized to underlie the adverse effects of many currently marketed drugs. This symposium will explore recent exciting progress in this field and will focus in particular on the association of mitochondrial dysfunction with adverse clinical effects and the availability of new screening tools for assessing mitochondrial function.
DNA Adducts and Human Health
Organizer: Paul T. Henderson, Department of Internal Medicine, UC Davis Medical Center, Sacramento, CA
DNA adducts are increasingly associated with mechanisms of human pathogenesis, particularly for diseases related to aging and cancer. This symposium features a survey of timely topics relating to DNA damage and repair including structure-based mechanistic studies of DNA repair, DNA oxidation and Huntington's disease, characterization mitochondrial DNA adducts induced by oxidative stress and alcohol metabolism. In aggregate, these talks will support the view that the contribution of DNA damage to human disease is substantial and requires much additional study.
American Chemical Socienty National Meeting
Washington DC, August 15-20, 2009
- Sunday Morning
- General Papers, Oral Presentations
Kaushik Mitra, Organizer
- Sunday Afternoon
- Founders' Award Symposium
Stephen S. Hecht, Organizer
- Monday Morning
- Young Investigators, Oral Presentations
Kaushik Mitra and Shana Sturla, Organizers
- Monday Afternoon
- Advances in Aquatic Toxicology: Alternative Non-traditional Endpoints
Bryan Brooks and Richard Brain, Organizers
- Tuesday Morning
- Human Drug Metabolites in Safety Testing: Guidelines & Strategies
Fred Guengerich, Organizer
- Tuesday Afternoon
- Drug-Induced Mitochondrial Dysfunction and Human Disease: New Insights and Applications
Kevin Leach and David Thompson, Organizers
- Tuesday Evening
- General Papers, Poster Presentations
Kaushik Mitra, Organizer
- Wednesday Morning
- DNA Adducts and Human Health
Paul Henderson, Organizer
- Wednesday Afternoon
- Platinum-based Chemotherapeutics: New Approaches for Cancer Treatment
Paul Henderson, Organizer
Listing of our Program and Abstracts
Announcements from the Publications Committee
ACS Symposium Series in EBook Format
The ACS has announced that by mid-July every volume in the ACS Symposium Series will be available for license by institutional libraries as a single digitized archive. The EBooks will benefit from the same levels of discoverability, accessibility, content linking, and visual display available for e-journals. Print copies of the ACS Symposium Series will continue. In addition, ACS is moving towards online proposal and manuscript submission for EBooks. The first stage of the site enables proposals for series volumes to be submitted and reviewed on-line and was launched in 2008. The second stage will enable book chapters to be submitted and reviewed on-line and will launch later this year.
TOXI has a history of sponsoring ACS Symposium Series developed on themes presented at the ACS National Meetings. With the advent of EBooks we now have a venue to increase the visibility and publicity of chemical toxicology research conducted by our Division members. In addition, Editors of symposium booklets will receive royalties on licenses of EBooks. If you are planning a symposium for TOXI now or in the future you are encouraged to think about publishing the content and associated posters in an ACS Symposium Series EBook. For further information you can contact Bob Hauserman, Senior Acquisitions Editor at: b_hauserman@acs.org
Publication of Annual Meeting Content On-Line
Last year TOXI initiated the process by which posters and Powerpoint presentations made at the ACS National Meeting were made available to TOXI members on-line for up to 6-weeks after the meeting. Last year 14 presenters took advantage of this service. This system creates the opportunity for TOXI members to review this material in a relaxed manner rather than take hurried notes. It also provides the opportunity for TOXI members who are unable to attend the meeting to look at the presentations they missed. All presenters are encouraged to take advantage of this system to help their colleagues. If your presentation contains previously published material it is recommended that you contact the journal to resolve any possible copyright issues. Further, details on how to post these presentations will be forth coming. As usual meeting abstracts will be published in the Dec/Jan issue of Chemical Research in Toxicology.
Trevor Penning
Chair of the Publications Committee
Nominations Committee
The Nomination Committee is formulating a slate of candidates for the upcoming election. We would like to encourage all division members to seriously consider running for open division officer positions which are listed below. This is an excellent opportunity to get involved in the division and assist in developing outstanding scientific programs and policies for the future. The open positions include:
Secretary (2010-2011) . The duties of the Secretary include: (1) keeping an active role of the Division and communicating the role to other officers as may be needed by them, (2) taking minutes at the Executive and Buisness meetings, (3) filing yearly report to the ACS, (4) attending conferences conducted by the national organization for Secretaries of Divisions, (5) communicating with members of the Division, (6)informing the Nominations Committee of the open offices, (7) conducting the elections, including getting biosketches of the candidates, preparing ballot and informing the executive committee of results.
Treasurer (2010-2011)The Treasurer is the Chief Financial Officer of the Division of Chemical Toxicology. It is the responsibility of that individual to be bonded. The Treasurer is responsible for setting up the bank accounts for the Division, for receiving income to the Division and for making disbursements. The Treasurer must also prepare a financial statement for presentation to the Executive Committee and file the report to the ACS. It is also the responsibility of the Treasurer to attend special meetings for Division Treasurers as organized by the national ACS.
Executive Committee, Member-at-Large (1 member, 2010 - 2012) . There are three members-at-large of the Executive Committee that are elected for three-year terms. The terms are staggered so that a new member of the Executive Committee is elected each year. In nominating members for the position of Executive Committee member-at-large, be mindful of the importance of keeping the leadership both geographically broad, and representative of the many scientific interests and professions that embody the membership of the Division. It is also important when nominating these positions to consider issues of diversity in all respects, and then to think about people who could then be nominated later for other positions as officers of the Division.
Nominations Committee (3 members, 2010) . The Nominating Committee shall consist of three members elected annually. The candidate who receives the greatest number of votes shall serve as Chair. In making the nominations, the committee should be attentive to issues of diversity and look for broad representation within the membership of the division.
Please send the Nominations Committee your suggestions for candidates, including their agreement to serve, for the open positions prior to July 31, 2009. Please note that self-nominations are welcome. The candidates will be announced at the August ACS meeting in Washington DC.
Larry Marnett (chair) marnett@toxicology.mc.vanderbilt.edu
Peter Dedon pcdedon@mit.edu
Kent Gates GatesK@missouri.edu
ACS National Announcements
Nominations for 2011 ACS National Awards
The American Chemical Society awards program is one of the means by which the society meets its obligation "to encourage ... the advancement of chemistry in all its branches, the promotion of research in chemical science and industry, [and] the improvement of the qualifications and usefulness of chemists." The continuing excellence of the ACS awards program requires that a number of highly qualified chemistry professionals be nominated and that great care be taken in preparing the nominations.
Nominating Procedure for ACS National Awards
- Nominations for the national awards administered by ACS to be presented in 2011 will be solicited on July 1, 2009.
- Forms for nominations and supporting information as well as a detailed description of ACS national awards are available online at www.acs.org/awards.
- Any individual may submit a nomination for an award, unless that individual is a member of the selection committee for the same award. However, selection committee members may submit nominations for other awards.
- Nominations and inquiries concerning awards should be directed to the Office of the Awards Programs, e-mail: awards@acs.org.
- The deadline date for all nominating material for 2011 ACS National Awards is November 1, 2009. Earlier transmittal is encouraged.
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