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| Newer Treatments |
Many of the factors that affect normal cell growth are hormones. Although cancer cells have lost some of the normal responses to growth factors, some cancer cells still require hormones for growth. Hormone therapy for cancer attempts to starve the cancer cells of these hormones. This is usually done with drugs that block the activity of the hormone, although some drugs can block synthesis of the hormone. For example, some breast cancer cells require estrogen for growth. Drugs that block the binding site for estrogen can slow the growth of these cancers. These drugs are called selective estrogen receptor modulators (SERMs) or anti-estrogens. Tamoxifen and Raloxifene are examples of this type of drug. A ten-year clinical trial of these two drugs with 20,000 women began in 1999 to determine their effectiveness in preventing breast cancer. Similarly, testosterone (an androgen hormone) stimulates some prostate cancer cells. Selective androgen receptor modulators (SARMs) are drugs that block the binding of testosterone to these cancer cells, inhibiting their growth and possibly preventing prostate cancer.
Newer chemotherapeutic drugs target specific, active proteins or processes in cancer cell signal transduction pathways, such as receptors, growth factors, or kinases (see Fig. 1). Because the targets are cancer-specific proteins, the hope is that these drugs will be much less toxic to normal cells than conventional cancer drugs.
The oncogene RAS is mutated in many types of cancer, particularly pancreatic cancer, which has a poor rate of survival for those afflicted. The RAS protein is only active after it is modified by the addition of a specific chemical group. Scientists are developing drugs to inhibit the action of the enzyme that adds the chemical group to the RAS protein, resulting in an inactive form of RAS. Early tests indicate that these drugs show promise for reducing tumors in cancer patients.
A drug called Gleevec® inhibits cancer cell growth and causes cancer cells to undergo apoptosis, or programmed cell death. It binds to abnormal proteins in cancer cells, blocking their action in promoting uncontrolled cell growth. Because it binds only to these abnormal proteins, Gleevec® does not show the high levels of toxicity of other chemotherapy drugs. Gleevec® was developed to treat a relatively rare cancer called chronic myeloid leukemia; however, it also appears to help other cancers.
Chemotherapy may fail because the cancer cells become resistant to the therapeutic drugs. One of the characteristics of cancer cells is a high frequency of mutation. In the presence of toxic drugs, cancer cells that mutate and become resistant to the drug will survive and multiply in the presence of the drug, producing a tumor that is also resistant to the drug. To overcome this problem, combinations of chemotherapy drugs are given at the same time. This decreases the probability that a cell will develop resistance to several drugs at once; however, such multiple resistances do occur. Some drug-resistant cancer cells express a gene called MDR1 (multiple drug resistance). This gene encodes a membrane protein that can not only prevent some drugs from entering the cell, but can also expel drugs already in the cell. Some cancer cells make large amounts of this protein, allowing them to keep chemotherapy drugs outside the cell.
Another promising target for cancer therapy is angiogenesis. Several drugs, including some naturally occurring compounds, have the ability to inhibit angiogenesis. Two compounds in this class are angiostatin and endostatin; both are derived from naturally occurring proteins. These drugs prevent angiogenesis by tumor cells, restricting tumor growth and preventing metastasis. One important advantage of angiogenesis inhibitors is that, because they do not target the cancer cells directly, there is less chance that the cancer cells will develop resistance to the drug.
One contributing factor in cancer is the failure of the immune system to destroy cancer cells. Immunotherapy encompasses several techniques that use the immune system to attack cancer cells or treat the side effects of some types of cancer treatment. The least specific of these are the immunostimulants, such as interleukin 2 and alpha interferon, which enhance the normal immune response.
A technique called chemoimmunotherapy attaches chemotherapy drugs to antibodies that are specific for cancer cells. The antibody then delivers the drug directly to cancer cells without harming normal cells, reducing the toxic side effects of chemotherapy. These molecules contain two parts: the cancer-cell-specific antibody and a drug that is toxic once it is taken into the cancer cell. A similar strategy, radioimmunotherapy, couples specific antibodies to radioactive atoms, thereby targeting the deadly radiation specifically to cancer cells.
Another immunological approach uses antibodies that inactivate cancer-specific proteins, such as growth factors or tumor cell receptors, which are required by tumor cells. For example, many breast and ovarian cancer cells over-express a receptor protein called HER2. An antibody called Herceptin, which binds HER2, inhibits tumor growth by preventing the binding of growth factors to these cells.
Some cancers, particularly leukemia, are treated with very high doses of chemotherapy drugs and radiation intended to kill all the cancer cells. The side effect of this harsh treatment is destruction of the bone marrow, which contains stem cells. Stem cells, immature cells that develop into blood cells, are essential. After treatment, the patient's bone marrow must be restored, either from bone marrow removed from the patient before drug therapy or from a compatible donor. Although the patient's own bone marrow is best, it can contain cancer cells that must be destroyed before it is returned to the patient.