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Poised for Breakthroughs
There are many possible approaches to reducing deaths and suffering from cancer, including prevention, early diagnosis, and treatment after cancer is discovered. Within the improved treatment realm are advances in diagnosis (e.g. identifying the particular genetic cause of the cancer), better imaging technologies, new “small molecule” drugs to kill cancer cells with as few side effects as possible, immunotherapies (that enhance the bodies own ability to destroy cancers), and gene therapies that attempt to correct underlying genetic defects that cause cancer.
Although the war on cancer has been waged for three decades, cancer death rates have declined very little. This has led some critics to suggest that this research effort has been a waste of money. However, the truth is that this research has led to tremendous advances in understanding the molecular and genetic causes of cancer and in fields that can build on this knowledge to develop, if not cures, at least therapies to control the disease. The following gives a non-technical overview of one of the cancer treatment approaches—“small molecule” cancer drug development. The purpose is to provide the interested lay person a better understanding of the cancer research process and the reasons why many are optimistic about winning the war on cancer.
Chemistry and Medicine
The impact of chemistry is ubiquitous in our everyday lives although the average citizen may not recognize or appreciate that fact. Advances in the chemical sciences are directly responsible for many of the improvements in the standard of living we enjoy. In no area is this truer than in modern medicine, especially as it relates to the development of new drugs.
Although the pharmaceutical industry is less than two centuries old, its roots are firmly embedded in the chemical industry (1). In fact, in its early history, the pharmaceutical industry was considered a special branch of the chemical industry, especially in Europe where large chemical companies also were the leading manufacturers of medicines. During the first century of the drug industry, chemistry was involved in two primary ways. One was the domain of the analytical chemist who was concerned with the isolation and purification of the active ingredients of medicinal plants. One of the earliest examples of this was in 1815 when morphine was isolated from opium extract. A modern example of this type of chemistry is the isolation of taxol (paclitaxel) from the bark of the Pacific Yew tree. The second domain was that of the synthetic chemist who was concerned both with making compounds that occur in nature and with creating new compounds. A modern example of this type of chemistry is the invention by Robert A. Holton of the semi-synthesis process for making taxol, which allowed taxol to be used clinically on a large scale, thus saving or extending millions of lives.
Modern chemistry is characterized by the ability to both examine and manipulate matter at the molecular scale. The modern synthetic chemist is increasingly able to construct molecules with specific atoms in specific locations and having a particular structure or shape. Synthetic organic chemistry is one of the cornerstones of the modern pharmaceutical industry. Synthetic organic chemists work hand-in-hand with biologists and doctors to invent, manufacture and test new chemical compounds that can treat human disease. The tremendous improvements in life spans are a testament to the success of this partnership.
The Need for Improved Drugs
Cancer is the second leading cause of death in the U.S. behind cardiovascular disease. And, although the most recent statistics show a slight decline in the cancer death rate over the past 6 years (6), it is projected that cancer will become the leading cause of death in the U.S. (4). (See Cancer Statistics for more details). One reason for this shift is that the medical treatment of cancer still has many unmet needs. Presently the primary therapies for cancer are surgery and radiation—but generally these are only successful if the cancer is found early and is localized. If the cancer has advanced locally or has spread (metastasized), the existing chemotherapeutic treatments are generally ineffective, particularly in lung, colorectal, breast, prostate, and pancreatic cancers. Although a few chemotherapeutic treatments have yielded lasting remissions or cures, it is clear new therapeutic options are needed (4).
Several issues need to be addressed in developing new chemotherapeutic cancer agents, including (4):
- enhancement and prolongation of antitumor efficacy
- reduction of toxicities (which can prevent effective dosing of potentially efficacious drugs).
- prevention of drug resistance (caused by the inherent genomic instability of cancer cells).
Synthetic Organic Chemistry in Cancer Drug Discovery
Historically, cancer chemotherapy began in the 1940’s as a result of toxicological studies of nitrogen-based mustard gas, when it was discovered it had anticancer activity. For the next fifty years, the identification of successful anticancer agents with clinical value was largely an empirical process. Large numbers of compounds, isolated by chemists from natural sources or created by synthetic organic chemists, were screened in cell-culture cytotoxicity assays and animal tumor models. In some cases, it was only after a potential anticancer agent was found, that subsequent biological studies determined its biological mechanism of action. For example, after taxol (paclitaxel) was isolated and identified as a potentially effective agent for killing cancer cells, studies by Dr. Susan Horowitz determined that it worked by stimulating tubulin polymerization, thus inducing cell death.
While the “empirical” approach remains an important strategy in cancer drug discovery, over the past 20 years or so there has been a revolution in the way cancer drug discovery is approached (4). Advances in molecular biology and genomics make it possible to identify genes that go awry and thus understand the molecular mechanisms underlying cancer formation. Unfortunately, it is now known that a great many genes different genes can be involved to initiate cancer and to then cause tumors to grow rapidly and spread (metastasize) to other parts of the body; therefore, it is difficult to know which genes to target. Nevertheless, new cancer drugs are no longer developed solely by the imagination of the synthetic organic chemist, but result from the integrated research of cancer biologists and synthetic organic chemists. (Please refer to the diagram Synthetic Organic Chemistry and Cancer Research.) From an understanding of biological structure and function comes data on biochemical mechanisms of action, which in turns leads the synthetic organic chemist to design and make novel chemical structures to target specific biological molecules. Advances in the techniques of organic synthesis promise to dramatically increase the efficiency with which new molecules can be prepared and the diversity of new molecules available for medical and other biological applications. (Note: New drugs can also come from biologists—so-called “biotech” drugs that are proteins: either recombinant proteins or monoclonal antibodies). The translation of mechanism-based target identification to new cancer therapies is just now beginning to be realized on a large scale (4). One of the best-known and successful examples of this approach is Gleevec™, the recent remarkable drug targeted against a rare form of Leukemia.
Within the domain of synthetic organic chemistry as directed to cancer and other diseases, there are two fundamental research strategies: target-oriented synthesis and diversity-oriented synthesis (5). Target-oriented synthesis has a long history in organic chemistry. The “target” for the synthetic organic chemist can be: (1) a natural product with known medical value; (2) drug candidates that will bind to a specific biological molecule or receptor; or (3) collections (libraries) of drug candidates that will bind to preselected biological molecules. The semi-synthesis of taxol (paclitaxel) is an example of target oriented synthesis of a natural product, whereas the collection of taxol analogues invented by Dr. Robert A. Holton at Florida State University is an example of the target-oriented synthesis of a library of drug candidates.
In contrast, diversity-oriented synthesis is a newer strategy of the organic chemist in which the goal is to simultaneously identify therapeutic cellular targets and their molecular regulators. In this approach, large numbers of structurally complex and diverse molecules are made (synthesized) and then screened in a variety of biological tests to determine if they have biological (e.g. anticancer) activity; and, if so, what cellular processes are being affected. Organic synthesis, especially diversity-oriented synthesis, will play an even greater role in the future in discovering new, effective anticancer drugs (5).
References
- Pharmaceutical Innovation: Revolutionizing Human Health, edited by Landau, Achilladelis and Scriabine, Chemical Heritage Press, Philadelphia, 1999.
- Modern Molecular Vision, Book Review by Shenda Baker of “The New Chemistry”, published in Science, April 13, 2001, page 226-227.
- Drug Discovery: A Historical Perspective, Jurgen Drews, Science, March 17, 2000, p.1960-1964.
- Mechanism-Based Target Identification and Drug Discovery in Cancer Research, Jackson B. Gibbs, Science, March 17, 2000, p. 1969-1973.
- Target-Oriented and Diversity-Oriented Organic Synthesis in Drug Discovery, Stuart L. Schreiber, Science, March 17, 2000, p. 1964-1969.
- Annual Report to the Nation on the Status of Cancer, 1973-1998, Featuring Cancers with Recent Increasing Trends, Journal of the National Cancer Institute, June 6, 2001 (Vol. 93, Issue 11, pages 824-842).
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