Chemotherapy
Chemotherapy is the treatment of a disease or condition with chemicals that have a specific effect on its cause, such as a microorganism or cancer cell. The first modern therapeutic chemical was derived from a synthetic dye. The sulfonamide drugs developed in the 1930s, penicillin and other antibiotics of the 1940s, hormones in the 1950s, and more recent drugs that interfere with cancer cell metabolism and reproduction have all been part of the chemotherapeutic arsenal.
The first drug to treat widespread bacteria was developed in the mid-1930s by the German physician-chemist Gerhard Domagk. In 1932, he discovered that a dye named prontosil killed streptococcus bacteria, and it was quickly used medically on both streptococcus and staphylococcus. One of the first patients cured with it was Domagk's own daughter. In 1936, the Swiss biochemist Daniele Bovet, working at the Pasteur Institute in Paris, showed that only a part of prontosil was active, a sulfonamide radical long known to chemists. Because it was much less expensive to produce, sulfonamide soon became the basis for several widely used "sulfa drugs" that revolutionized the treatment of formerly fatal diseases. These included pneumonia, meningitis, and puerperal ("childbed") fever. For his work, Domagk received the 1939 Nobel Prize in physiology or medicine. Though largely replaced by antibiotics, sulfa drugs are still commonly used against urinary tract infections, Hanson disease (leprosy), malaria, and for burn treatment.
At the same time, the next breakthrough in chemotherapy, penicillin, was in the wings. In 1928, the British bacteriologist Alexander Fleming noticed that a mold on an uncovered laboratory dish of staphylococcus destroyed the bacteria. He identified the mold as Penicillium notatum, which was related to ordinary bread mold. Fleming named the mold's active substance penicillin, but was unable to isolate it.
In 1939, the American microbiologist René Jules Dubos (1901–1982) isolated from a soil microorganism an antibacterial substance that he named tyrothricin. This led to wide interest in penicillin, which was isolated in 1941 by two biochemists at Oxford University, Howard Florey and Ernst Chain.
The term antibiotic was coined by American microbiologist Selman Abraham Waksman, who discovered the first antibiotic that was effective on gram-negative bacteria. Isolating it from a Streptomyces fungus that he had studied for decades, Waksman named his antibiotic streptomycin. Though streptomycin occasionally resulted in unwanted side effects, it paved the way for the discovery of other antibiotics. The first of the tetracyclines was discovered in 1948 by the American botanist Benjamin Minge Duggar. Working with Streptomyces aureofaciens at the Lederle division of the American Cyanamid Co., Duggar discovered chlortetracycline (Aureomycin).
The first effective chemotherapeutic agent against viruses was acyclovir, produced in the early 1950s by the American biochemists George Hitchings and Gertrude Belle Elion for the treatment of herpes. Today's antiviral drugs are being used to inhibit the reproductive cycle of both DNA and RNA viruses. For example, two drugs are used against the influenza A virus, Amantadine and Rimantadine, and the AIDS treatment drug AZT inhibits the reproduction of the human immunodeficiency virus (HIV).
Cancer treatment scientists began trying various chemical compounds for use as cancer treatments as early as the mid-nineteenth century. But the first effective treatments were the sex hormones, first used in 1945, estrogens for prostate cancer and both estrogens and androgens to treat breast cancer. In 1946, the American scientist Cornelius Rhoads developed the first drug especially for cancer treatment. It was an alkylating compound, derived from the chemical warfare agent nitrogen mustard, which binds with chemical groups in the cell's DNA, keeping it from reproducing. Alkylating compounds are still important in cancer treatment.
In the next twenty years, scientists developed a series of useful antineoplastic (anti-cancer) drugs, and, in 1954, the forerunner of the National Cancer Institute was established in Bethesda, MD. Leading the research efforts were the so-called "4-H Club" of cancer chemotherapy: the Americans Charles Huggins (1901–1997), who worked with hormones; George Hitchings (1905–1998), purines and pyrimidines to interfere with cell metabolism; Charles Heidelberger, fluorinated compounds; and British scientist Alexander Haddow (1907–1976), who worked with various substances. The first widely used drug was 6-Mercaptopurine, synthesized by Elion and Hitchings in 1952.
Chemotherapy is used alone, in combination, and along with radiation and/or surgery, with varying success rates, depending on the type of cancer and whether it is localized or has spread to other parts of the body. They are also used after treatment to keep the cancer from recurring (adjuvant therapy). Since many of the drugs have severe side effects, their value must always be weighed against the serious short-and long-term effects, particularly in children, whose bodies are still growing and developing.
In addition to the male and female sex hormones androgen, estrogen, and progestins, scientists also use the hormone somatostatin, which inhibits production of growth hormone and growth factors. They also use substances that inhibit the action of the body's own hormones. An example is Tamoxifen, used against breast cancer. Normally the body's own estrogen causes growth of breast tissues, including the cancer. The drug binds to cell receptors instead, causing reduction of tissue and cancer cell size.
Forms of the B-vitamin folic acid were found to be useful in disrupting cancer cell metabolism by the American scientist Sidney Farber (1903–1973) in 1948. Today they are used on leukemia, breast cancer, and other cancers.
Plant alkaloids have long been used as medicines, such as colchicine from the autumn crocus. Cancer therapy drugs include vincristine and vinblastine, derived from the pink periwinkle by American Irving S. Johnson (1925– ). They prevent mitosis (division) in cancer cells. VP-16 and VM-16 are derived from the roots and rhizomes of the may apple or mandrake plant, and are used to treat various cancers. Taxol, which is derived from the bark of several species of yew trees, was discovered in 1978, and is used for treatment of ovarian and breast cancer.
Another class of naturally occurring substances are anthracyclines, which scientists consider to be extremely useful against breast, lung, thyroid, stomach, and other cancers.
Certain antibiotics are also effective against cancer cells by binding to DNA and inhibiting RNA and protein synthesis. Actinomycin D, derived from Streptomyces, was discovered by Selman Waksman and first used in 1965 by American researcher Seymour Farber. It is now used against cancer of female reproductive organs, brain tumors, and other cancers.
A form of the metal platinum called cisplatin stops cancer cells' division and disrupts their growth pattern. Newer treatments that are biological or based on proteins or genetic material and can target specific cells are also being developed. Monoclonal antibodies are genetically engineered copies of proteins used by the immune system to fight disease. Rituximab was the first moncoclonal antibody approved for use in cancer, and more are under development. Interferons are proteins released by cells when invaded by a virus. Interferons serve to alert the body's immune system of an impending attack, thus causing the production of other proteins that fight off disease. Interferons are being studied for treating a number of cancers, including a form of skin cancer called multiple myeloma. A third group of drugs are called anti-sense drugs, which affect specific genes within cells. Made of genetic material that binds with and neutralizes messenger-RNA, anti-sense drugs halt the production of proteins within the cancer cell.
Genetically engineered cancer vaccines are also being tested against several virus-related cancers, including liver, cervix, nose and throat, kidney, lung, and prostate cancers. The primary goal of genetically engineered vaccines is to trigger the body's immune system to produce more cells that will react to and kill cancer cells. One approach involves isolating white blood cells that will kill cancer and then to find certain antigens, or proteins, that can be taken from these cells and injected into the patient to spur on the immune system. A "vaccine gene gun" has also been developed to inject DNA directly into the tumor cell. An RNA cancer vaccine is also being tested. Unlike most vaccines, which have been primarily tailored for specific patients and cancers, the RNA cancer vaccine is designed to treat a broad number of cancers in many patients.
As research into cancer treatment continues, new cancer-fighting drugs will continue to become part of the medical armamentarium. Many of these drugs will come from the burgeoning biotechnology industry and promise to have fewer side effects than traditional chemotherapy and radiation.
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