OCTOBER 2000 VOLUME 13, NUMBER 10 © Copyright 2000 by the American Chemical Society
Editorial Highlights from a Symposium on the Mechanisms of Action of Cytotoxic Agents The formation of the Division of Chemical Toxicology four years ago was heralded nearly a decade earlier by the creation of the journal Chemical Research in Toxicology to “...focus on research that employs chemical methodology to solve complex biological problems” (1). The intervening years have seen the Division flourish as a medium for chemists and biochemists to apply their talents to problems lying at the chemistry-biology interface. Many members of the Division have begun to merge the traditional tools and perspectives of chemistry with molecular biology, combinatorial chemistry, genomics, and proteomics as the toxicological problems of interest move to higher levels of complexity (2). One of the most vexing of these complex problems shared by toxicologists and pharmacologists alike is unraveling the mechanisms involved in cell death caused by chemicals. Pete Dedon and Chris Michejda organized a symposium entitled “Mechanisms of Action of Cytotoxic Agents”, under the auspices of the Division of Chemical Toxicology at the 219th National Meeting of the American Chemical Society in San Francisco on March 29, 2000, to focus attention on the problem of chemical cytotoxicity. The symposium brought together a group of leading chemists and biologists to discuss recent breakthroughs in our understanding of how chemicals kill cells. Emphasis was placed on new technologies for identifying novel pathways of cytotoxicity and for exploring these pathways in the context of drug development and understanding the mechanisms of action of cytotoxic agents. We are delighted to bring to the readers of Chemical Research in Toxicology a set of brief papers by the symposium speakers, which constitute a “symposium-in-print”. The first two articles address cell cycle-targeted toxins and drugs. In a presentation entitled “Cytolethal Distending Toxin: A Bacterial Toxin That Disrupts the Eukaryotic Cell Cycle”, Prof. David Schauer from the Massachusetts Institute of Technology (MIT) discusses his recent work with a family of polypeptide cell cycle toxins, termed cytolethal distending toxins. These cytotoxins are produced by a diverse group of pathogenic bacteria and cause mammalian cells to arrest irreversibly in the G2 phase of the cell cycle. Prof. Schauer’s work with bacterial toxins that disrupt the human cell cycle represents an important breakthrough in our understanding of the mechanisms by which infectious agents cause cell death, and his research provides an opportunity for exploiting these pathways in other cells. Dr. Kevin Webster from Bristol-Myers Squibb discusses the role of the cell cycle in cell death in a paper entitled “Therapeutic Potential of Targeting the Cell Cycle”. His focus is on the family of cyclin-dependent kinases (cdks) that play a pivotal role in progression through the cell cycle. Several 10.1021/tx000496y CCC: $19.00 © 2000 American Chemical Society Published on Web 09/29/2000
934
Chem. Res. Toxicol., Vol. 13, No. 10, 2000
members of the cdk family appear to be inappropriately activated in many tumor types, and Dr. Webster discusses recent advancements made in developing small molecule anticancer agents, such as flavopiridol, that inhibit specific cdks, and the impact they will have on antitumor drug development. The second pair of papers deals with chemicals that inhibit signal transduction pathways. In a presentation entitled “Cyclic 3′,5′-Nucleotide Phosphodiesterases: Potential Targets for Anticancer Therapy”, Prof. Gerhard Eisenbrand from the University of Kaiserslautern discusses recent discoveries of chemicals that target cAMP-specific phosphodiesterases. Compared to their nontransformed counterparts, many cancer cell lines show elevated levels of various cAMP-specific phosphodiesterase enzymes, which may be related to the altered growth and physiology of the cells. Prof. Eisenbrand has demonstrated that specific inhibitors of the overexpressed phosphodiesterases cause cell cycle arrest and apoptosis selectively in cancer cells. The second paper in the signal transduction area is by Dr. Paul Kirschmeier from Schering-Plough, whose paper is entitled “Biological Effects and Mechanism of Action of Farnesyl Transferase Inhibitors”. Farnesyl transferase catalyzes the essential post-translational lipidation of the Ras protein and several other cellular signal transduction proteins, modifications that determine their cellular location, and thus their function. This enzyme represents an important target for new anticancer therapeutics, and Dr. Kirschmeier presents recent work on the development of selective inhibitors of farnesyl transferase. The next two papers deal with DNA-related targets for cytotoxins. Prof. Kent Gates from the University of Missouri describes his work on a novel DNAinteracting antibiotic in a paper entitled “Mechanisms of DNA Damage by Leinamycin”. Leinamycin is one of several related natural products that selectively produce DNA damage and cause cell death by both reductive alkylation and polysulfide-mediated oxidative pathways. Prof. Gates unraveled the mechanisms of action of leinamycin as well as the clinically promising tirapazamine, which targets hypoxic tumor cells. The second DNA-oriented paper is by Prof. David Corey from the University of Texas Southwestern Medical Center, entitled “Telomerase: An Unusual Target for Cytotoxic Agents”. Prof. Corey and coworkers have made significant contributions to the development of telomerasetargeted therapeutics. His approach involves the design of chemically modified nucleic acid substrates that target the RNA component of telomerase. This paper summarizes this group’s work on antisense oligonucleotides that target telomerase. These agents effectively shorten telomere length, which in time causes the affected cells to die. Corey and co-workers have also targeted telomerase RNA with peptide nucleic acids, which also caused the shortening of telomeres and presumably accelerated the senescence and death of cells. Many of the pathways of cytotoxicity discussed in the previous talks ultimately lead to activation of apoptotic mechanisms in cells. To address the role of apoptosis as the final common denominator for cell death caused by many cytotoxic agents, Dr. Sophie Roy from the Merck Frosst Centre for Therapeutic Research discusses some of the critical factors involved in the apoptotic pathways in a paper entitled “Caspases at the Heart of the Apoptotic Cell Death Pathway”. In a twist on the mechanisms of cytotoxicity theme of the symposium, Dr. Roy discusses that it may be possible to prevent cell death by selective inhibition of caspases, the cysteine proteases that cleave a discrete number of proteins involved in cellular homeostasis and structural integrity, and mediate the systematic disassembly of dying cells. This targeting of cell death pathways may find therapeutic application in the prevention of cell death following ischemia/reperfusion injury and in protection against neuronal death and amyloid deposition in Alzheimer’s disease, among many other maladies. These seven articles present the state-of-the-art of research directed at understanding some of the new pathways by which chemicals kill cells. We hope that readers of Chemical Research in Toxicology and members of the Division of Chemical Toxicology will find this symposium-in-print to be a useful and stimulating synopsis of an exciting field of research. Chemical Research in Toxicology welcomes contributed research papers that focus on the exploration of these pathways, and of the chemicals that target them.
Editorial
Editorial
Chem. Res. Toxicol., Vol. 13, No. 10, 2000 935
References Marnett, L. J. (1988) Editorial. Chem. Res. Toxicol. 1, 7A. Stevens, J. L., and Marnett, L. J. (1999) Defining molecular toxicology: A perspective. Chem. Res. Toxicol. 12, 747-748. Christopher J. Michejda, Molecular Aspects of Drug Design Section, SBL, National Cancer Institute
Peter C. Dedon, Division of Bioengineering and Environmental Health, MIT
Lawrence J. Marnett, Editor, Chemical Research in Toxicology TX000496Y
