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The incidence of cancer in the United States has fluctuated over the last century. However, progress in eliminating this major disease has been made in several tumor types; mainly due to advances in prevention, diagnosis and treatment. Still, some tumor types remain extremely difficult to treat such as mesothelioma and pancreatic cancer. Cancer treatment has evolved considerably since its initial development in the late 1940's when alkylating agents were introduced into the clinic. Since that time, a large number of agents have been developed that have unique mechanisms of action and toxicity profiles. The continued development of new cancer drugs is driven by increased understanding of cancer biology as well as the significant revenue that is generated for pharmaceutical companies. The overall interest and productivity of this field is reflected in the relatively large number of chemotherapeutic drugs approved by the FDA in the last decade (see graph below). This pace is likely to accelerate as investment continues to be directed towards devleoping and improving cancer chemotherapy. This site provides an overview of the mechanism of action of both classic and newly developed anticancer drugs in a manner that is easy to understand. It also provides information on other web resources that can assist patients and professionals.
 Principle of Cancer Chemotherapy The prevailing dogma that explains the effectiveness of chemotherapy is simply that a tumor consists of rapidly dividing cancer cells and these cells are more sensitive to anticancer drugs than non-dividing, normal cells. This also explains why toxicities that occur with chemotherapeutic drug treatment tend to harm dividing normal cells, such as those found in the bone marrow or the lining of the gastrointestinal tract. Thus the therapeutic index of a drug reflects the difference between its efficacy (tumor cell killing) versus its toxicity to normal cells. Classic chemotherapeutic drugs such as alkylating agents can be quite toxic and the number of cycles that may be administered is limited. Therefore, a goal of cancer drug development is to find agents that are effective at killing tumor cells while sparing normal cells in the process. Cancer Drug Development Cancer drugs may be identified using two major methods: 1) empirically through the rational design of drugs to interact with specific targets or 2) to randomly screen chemical libraries in a high-throughput format to isolate active compounds. Both of these strategies have been successful and are currently used. Once a candidate drug is identified, further testing of its activity in tumor cells grown in the laboratory is usually done. Testing the drug's ability to kill tumors that are implanted in mice is also necessary. These experiments provide researchers with an idea of how the activity of a new drug compares to that of existing drugs. Also, the animal studies can give an early indication of toxicity associated with treatment. The pharmacology and toxicology of the drug may also be assessed in non-tumor bearing animals. If the drug appears both safe and effective, trial in humans may begin. Clinical trials are conducted in at least three stages or phases. The initial phase (I) involves finding a safe, tolerable dose for humans and to identify potentially dangerous side effects. In the second phase, the efficacy of the drug is assessed in a specific group of advanced stage cancer patients. In phase III trials, the safety and efficacy of the new drug is compared to that of the standard drug(s) used for treating that particular tumor type. Clinical trials may vary with respect to the type of cancer under study, the combination of agents, the drug schedule used, and the endpoints of the study. But the overall goal is to find the most effective drugs or drug combinations for the treatment of a particular tumor type. New Drug Targets An exciting and very promising new area of cancer drug development is the identification of molecular targeted therapies. Driven by increased knowledge of cancer cell biology, new agents are being designed to inhibit specific cellular proteins and signal transduction pathways. These new molecules have anticancer activity when used alone, but are often more effective when combined with traditional, cytotoxic chemotherapy. The concept of molecular targeted therapies is based on the idea that during the process of malignant transformation, tumor cells become dependent on specific signaling pathways or other processes, which in some cases, may act as an Achille's heal. Interfering with these pathways using small molecules or biological agents can be readily accomplished while avoiding undesirable toxicity. Some of these new targeted drugs have shown remarkable activity such as Gleevec for chronic myeloid leukemia (CML) and bevacizumab, which inhibits tumor blood vessel formation (angiogenesis). Further development of targeted therapies will be acheived as we continue to understand which pathways and systems are dysregulated in each type of cancer. These insights will usher in a new age of cancer treatment based on "individualized" therapy. |
