We have spent a lot of time discussing cisplatin: from its serendipitous discovery to its use as a chemotherapeutic agent to combat certain forms of cancer. In this module, we will discuss some other treatments for cancer and describe how cisplatin and chemotherapy in general fit into the big picture.
Chemotherapy is one of three forms of treatment conventionally used to combat cancer. Surgery and radiation are two other options. In the majority of cases, a combination of at least two of these three types of therapy is used to treat cancer, either as the primary therapy (when cancer first occurs) or as therapy for a recurrent tumor. Combination therapies have been shown to be effective in attaining the three main goals of cancer treatment: removing all of the known tumor, preventing its recurrence, and minimizing negative side effects.1
Surgery is used to diagnose or treat most people with cancer. Surgery is a local treatment, meaning that it only affects one part of the body. When surgery is used as a diagnostic aid, a biopsy is done. A biopsy is the removal of a suspicious piece of tissue for microscopic examination. (Biopsies need not involve surgery, but for tumors deep within the body, surgical biopsies give the most definitive results. Biopsies may also be carried out using a needle or an endoscope, which is a lighted, cylinder-shaped magnifying instrument that is narrow enough to pass through one of the body’s natural openings.) When surgery is used to treat cancer, the tumor and possibly some of the surrounding tissue is removed. Removal of the tumor at an early stage in the cancer often results in a complete cure.1
Radiation is also a local treatment for cancer, and is used to treat 60 percent of cancer patients. Radiation uses x-rays, electron beams, or radioactive isotopes (from naturally occurring radioactive elements such as radium, or from artificially produced radioactive isotopes of nonradioactive elements such as cesium) to shrink tumors either by destroying cancer cells or by damaging them so much that they can no longer multiply. Radiation is an extremely useful cancer treatment because it kills cancer cells while causing only minimal damage to normal cells. (If exposed to radiation, normal tissue is usually able to recover with little or no permanent damage; nonetheless, healthy tissue is shielded from radiation as well as possible.) Radiation works by ionizing atoms in cells, usually atoms in DNA; once a cancer cell’s DNA is destroyed, it can no longer undergo replication (see module on DNA), and the cell dies. Radiation is most effective when the cancer cell is actually dividing, that is, when the cancer cell is in the M (mitosis) phase of its cell cycle (see module on cancer). Cancers with rapidly dividing cells, such as leukemia (cancer of the blood cells) and lymphoma (cancer of the lymph nodes) are more sensitive to radiation than cancers in which the cells divide more slowly. The effectiveness of radiation is enhanced when it is used in combination with either surgery or chemotherapy. For example, radiation may be used before surgery to shrink the tumor so that it can be more easily removed. Alternatively, radiation may be used after surgery to kill any remaining cancer cells.1
Chemotherapy, unlike surgery and radiation, is a systemic treatment because the chemotherapeutic agents enter the bloodstream and are distributed throughout the body; chemotherapy drugs can therefore attack cancer cells wherever they are in the body.
Most people with cancer receive one or more of some 50 available anticancer drugs (among them, cisplatin) during the course of their treatment. Chemotherapy drugs are designed to disrupt the cell cycle of rapidly dividing cells; some drugs target cancer cells when they are dividing, or in the M phase of the cell cycle, and other drugs destroy both resting and dividing cells. Unfortunately, chemotherapy drugs also affect rapidly dividing cells of certain normal tissues, such as those found in hair follicles, bone marrow, and the lining of the gastrointestinal tract. Such drug treatment can lead to problems during cancer chemotherapy, such as alopecia (hair loss), myelosuppression (suppression of the bone marrow), and nausea. (See module on toxic side effects). To minimize the occurrence of toxic side effects, two or more chemotherapeutic agents are often used in combination. Again, like radiation, chemotherapy works best on cancers having a high proportion of dividing cells, such as leukemias and lymphomas. Chemotherapy is less effective on cancers characterized by a low proportion of dividing cells, such as solid tumors found in the colon, rectum, lung, and breast. Malignant tumors of the latter type, the solid tumors, are more common and are unfortunately much harder to treat by drugs alone. For this reason, chemotherapy is used in conjunction with either radiation or surgery. When used in combination with radiation, chemotherapy can either render cancer cells more sensitive to radiation or kill cells independently.
Chemotherapy can also be used either before or after surgery; the more common case is to administer chemotherapy drugs after a tumor has been surgically removed in order to destroy cancer cells that may remain near the tumor or that have spread to other parts of the body.1 In addition to the three conventional approaches to cancer treatment described above, there are a number of new treatments—some that are still being developed and others that are currently undergoing clinical trials.
Two examples of these newer types are therapy are immunotherapy and bone marrow transplants. In immunotherapy, which is also referred to as biological therapy or biotherapy, the body’s own immune system is used to recognize, attack, and destroy cancer cells. At first, the immune system does not fight cancer cells because the cancer cells are "self" cells and are not recognized as foreign. Activating the immune system to combat cancer requires the use of any of a number of biological response modifiers. Immunotherapy is appealing because the body’s own immune system is used to combat cancer. Unfortunately, this form of treatment has many temporary side effects, including fatigue, fever, rashes, and diarrhea. Furthermore, biological therapy does not replace the more conventional forms of treatment, but it is often used in conjunction with surgery and chemotherapy.1 Bone marrow transplants, once used only to treat leukemia and lymphoma, are now used to help people who are undergoing chemotherapy or radiation for other types of cancers, such as breast cancer. Bone marrow transplants are used in two ways: in some cases, the bone marrow of a cancer patient is removed before he or she undergoes chemotherapy or radiation and is replaced after the other treatments are complete. In other cases, bone marrow from a healthy donor is used to replace the depleted bone marrow of a cancer patient. Bone marrow is essential to life because bone marrow tissue (which is found within the cavities of bones) constantly replenishes the blood supply. However, like cancer cells, cells of the bone marrow divide rapidly and are consequently targeted by chemotherapeutic agents. Suppression of the bone marrow (called myelosuppression) is a major side effect of cancer chemotherapy. Furthermore, the amount of radiation needed to kill cancer cells also destroys bone marrow. For these reasons, replacing the bone marrow with healthy cells is critically important for cancer patients undergoing other forms of treatment. Complications of bone marrow transplants include increased chance of infection, veno-occlusive disease (a very serious disease of the liver), rejection of the donor’s bone marrow by the recipient, graft versus host disease (in which the white blood cells in the newly transplanted bone marrow recognize the recipient as foreign and attack the recipient’s own cells), and pneumonia. Modern medicine can counteract many of these problems, but they do remain risks nonetheless.1 Finally, several new classes of drugs with novel mechanisms of action also hold promise for the treatment of cancer. Among these are telomerase inhibitors, angiogenic inhibitors, and pro-apoptotic compounds. Telomerase is an enzyme found in cancer cells that allows them to keep growing indefinitely. Telomerase restores short sequences of DNA to the tips of DNA, as shown in Figure 1; these short sequences, or telomeres, are required for DNA replication, which is necessary before cell division can occur. Each time a cell divides, its telomeres shorten. When telomeres get down to a minimum length, the cell stops dividing. The telomerase gene is present in all cells but lies dormant in normal cells, meaning that normal cells will eventually stop proliferating. On the other hand, telomerase is active in cancer cells and allows them to grow indefinitely. The development of telomerase inhibitors—compounds that bind to telomerase and halt DNA replication and cell division—should be an effective treatment for cancer and could be used in conjunction with the existing conventional therapies.2-4
Figure 1. Telomere replication. This figure shows how telomeres, the repeating G-rich sequences (red) that make up the ends of chromosomes, are formed. Telomere replication requires the action of telomerase (light green), which is a protein–RNA complex that carries an RNA strand (blue) that serves as a template for the formation of the G-rich telomere DNA sequence. After telomere replication, DNA synthesis can continue, and a new DNA strand (dark green) formed. Reprinted with permission.4
Angiogenesis is the process by which a new blood capillary forms by sprouting from an existing small vessel, as shown in Figure 2. When the new capillary encounters and connects with another capillary, blood can circulate. Angiogenesis is important in tumor growth, which is limited by its blood supply. Indeed, if a tumor does not have a direct blood supply, it must depend on the diffusion of nutrients from its surroundings and even then will not grow very big. Thus, it is beneficial for tumors to induce the formation of a capillary network so that nutrients can be supplied directly to the tumor; in this way, tumor cells are said to parasitize the blood vessels of normal cells. Inhibition of this form of angiogenesis should limit tumor growth, and the search for anti-angiogenic drugs is an active area in cancer research. Two proteins, angiostatin and endostatin, have been shown to possess anti-angiogenic activity. Converting proteins into effective drugs is challenging, and scientists are now trying to use their knowledge about the way these proteins work to design marketable anti-angiogenic drugs.2,4
Figure 2. Angiogenesis. A new blood capillary forms by the sprouting of an endothelial cell from the wall of an existing small vessel; endothelial cells line all blood vessels. (Courtesy of C.C. Speidel) Reprinted with permission.4
Apoptosis, or programmed cell death, is the body’s way of ridding itself of old or unnecessary cells, as shown in Figure 3. Normal cells undergo apoptosis in an orderly fashion when the cell shrinks and is absorbed by neighboring cells; in this way, cells are believed to commit suicide. Research has shown that programmed cell death works in a similar way in worms and humans, suggesting that apoptosis is a fundamental property of animal cells. Unlike normal cells, however, cancer cells do not undergo apoptosis but continue to grow unchecked. Drugs able to induce cell suicide, or proapoptotic compounds, would be a valuable addition to the arsenal of anticancer agents. There are two possible ways that pro-apoptotic compounds induce cell death: by attacking the cell’s main energy source, the mitochondria, or by destroying the cell’s DNA. Researchers in Sweden have found that one of the most abundant proteins in human breast milk, a-lactalbumin, induces apoptosis in cancer cells; they are now trying to understand exactly how this occurs.2,4,5
Figure 3. Apoptosis. Normal cell deaths are believed to be suicides that occur in response to signals from within the cell itself. This picture represents apoptotic cell death in the nematode worm C. elegans. Reprinted with permission.4
- 1) Murphy, G. P., Morris, L. B., Lange, D. Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery. Viking Penguin: New York, 1997.
- (2) Weinberg, R. In an interview on Fresh Air with Terry Gross, National Public Radio, 1999.
- (3) Menon, S. Discover, 1999, 20, pp. 33-34. (4) Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., Watson, J. D. Molecular Biology of the Cell, 3rd ed. Garland Publishing, Inc.: New York, 1994. (5) Radetsky, P. Discover, 1999, 20, pp. 68-75.