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Chemotherapy

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 (19011982) 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 (19011997), who worked with hormones; George Hitchings (19051998), purines and pyrimidines to interfere with cell metabolism; Charles Heidelberger, fluorinated compounds; and British scientist Alexander Haddow (19071976), 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 (19031973) 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.

See also Antibiotic resistance, tests for; Antiviral drugs; Bacteria and bacterial infection; Blood borne infections; Cell cycle and cell division; Germ theory of disease; History of microbiology; History of public health; Immunization

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Antimicrobials

Antimicrobials

Definition

Antimicrobial drugs are used to fight infections caused by bacteria, fungi, and viruses.

Description

Antimicrobial drugs are drugs designed to kill, or prevent the growth of microorganisms (bacteria, fungi, and viruses). Bacteria, fungi, and viruses are responsible for almost all of the common infectious diseases found in North America from athlete's foot, to AIDS, to ulcers (as of 2001). Interestingly enough, many disorders formerly thought to be caused by other factors, like stress, are now known to be caused by bacteria. For example, it has been shown that many ulcers are caused by the bacteria Helicobacter pylori, and not by stress, as many originally thought. Thus, antimicrobials represent an important part of medicine today.

The history of antimicrobials begins with the observations of Pasteur and Joubert, who discovered that one type of bacteria could prevent the growth of another. They did not know at that time that the reason one bacteria failed to grow was that the other bacteria was producing an antibiotic. Technically, antibiotics are only those substances that are produced by one microorganism that kill, or prevent the growth, of another microorganism. Of course, in today's common usage, the term antibiotic is used to refer to almost any drug that cures a bacterial infection. Antimicrobials include not just antibiotics, but synthetically formed compounds as well.

The discovery of antimicrobials like penicillin and tetracycline paved the way for better health for millions around the world. Before 1941, the year penicillin was discovered, no true cure for gonorrhea, strep throat, orpneumonia existed. Patients with infected wounds often had to have a wounded limb removed, or face death from infection. Now, most of these infections can be easily cured with a short course of antimicrobials.

However, the future effectiveness of antimicrobial therapy is somewhat in doubt. Microorganisms, especially bacteria, are becoming resistant to more and more antimicrobial agents. Bacteria found in hospitals appear to be especially resilient, and are causing increasing difficulty for the sickest patients-those in the hospital. Currently, bacterial resistance is combated by the discovery of new drugs. However, microorganisms are becoming resistant more quickly than new drugs are being found, Thus, future research in antimicrobial therapy may focus on finding how to overcome resistance to antimicrobials, or how to treat infections with alternative means.

Michael Zuck, Ph.D.

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Meningitis

MENINGITIS

DEFINITION


Meningitis (pronounced meh-nen-JI-tiss) is an inflammation of the meninges (pronounced meh-NIN-jeez). The meninges are the thin layers of tissue that cover the brain and the spinal cord. Meningitis is most commonly caused by infection (by bacteria, viruses, or fungi). It can also be caused by bleeding into the meninges, cancer (see cancer entry), diseases of the immune system, and other factors. The most dangerous forms of meningitis are those caused by bacteria. The disease is very serious and can be fatal.

Meningitis: Words to Know

Blood-brain barrier:
Cells within the blood vessels of the brain that prevent the passage of toxic substances from the blood into the brain.
Cerebrospinal fluid (CSF):
Fluid made in chambers of the brain that flows over the surface of the brain and the spinal cord. CSF provides nutrients to cells of the nervous system and provides a cushion for the structures of the nervous system.
Meninges:
The three-layer membranous covering of the brain and spinal cord.

DESCRIPTION


Any time a part of the body is infected, it is likely to become inflamed and swollen. These symptoms are especially serious in the brain. The brain is enclosed in the skull, a bony structure that cannot change size. If the brain swells, it pushes outward against the skull. Brain cells may become squeezed and begin to die. Brain cells are some of the only kinds of cells in the body that do not regenerate (renew) themselves. Once they die, they cannot be replaced.

An infection in the brain can cause damage in a second way. Brain cells are very delicate. They require just the right balance of chemicals, including sugar, sodium, calcium, potassium, and oxygen. An infection can change the balance of chemicals in the brain. Brain cells may receive too much of one chemical or too little of another. This loss of chemical balance can also kill brain cells.

Meningitis is a serious medical problem because it is difficult to treat. Blood flows into the brain from the neck through a network of blood vessels. This network contains special cells that prevent many chemicals from passing into the brain. This system is known as the blood-brain barrier.

The blood-brain barrier prevents harmful substances from getting into the brain. The blood-brain barrier "knows" which substances the brain needs and which will damage brain cells.

The problem is that the blood-brain barrier usually does not recognize drugs as "good" chemicals. It prevents them from passing into the brain, where they could help clear up an infection. Doctors often have to find other ways to treat the kinds of infection that cause meningitis.

CAUSES


Meningitis may be caused by bacteria, viruses, fungi, head injuries, infections in other parts of the body, and other factors. The type of meningitis a person is most likely to contract depends on his or her age, habits, living environment, and health status.

Bacteria are not the most common cause of meningitis. But they produce the most serious and most life-threatening forms of the disease. The most common kinds of meningitis in newborns are those caused by streptococci (pronounced STREP-tuh-KOK-see) bacteria. These bacteria pass from the mother to the child through the blood system they share before birth. The highest incidence (rate) of meningitis occurs in babies under the age of one month. Children up to the age of two years are also at relatively high risk for the disease.

Adults are usually infected by a different kind of bacterium. This bacterium produces a form of meningitis that has some symptoms like those of pneumonia (see pneumonia entry).

One type of bacterium causes a contagious form of meningitis. A person with this form of meningitis can pass it to others with whom he or she comes into contact. Epidemics (mass infections) of meningitis have been known to occur in crowded day-care centers and military training camps.

Meningitis is often caused by a virus. The virus is usually the same one that causes other viral infections such as mumps (see mumps entry), measles (see measles entry), chickenpox (see chickenpox entry), rabies (see rabies entry), and herpes infections (like cold sores; see herpes infections entry).

A person's general health can also increase his or her risk of developing meningitis. For example, a person with a weakened immune system is at greater risk for meningitis than one who has a healthy immune system. People with AIDS (see AIDS entry) have damaged immune systems and are less able to fight off fungal infections. These fungal infections can lead to infections of the brain and meningitis.

People who have had their spleens removed are also at higher risk for meningitis. Spleen removal may be necessary to solve some other medical problem, such as cancer of the spleen. But it may also expose the patient to greater risk for meningitis.

The most common cause of meningitis is blood-borne spread. This term means that a person already has an infection in some other part of his or her body. If that infection is not treated properly, it can become more serious and start to spread through the body by way of the bloodstream. Normally, the blood-brain barrier would keep the infectious agents out of the brain. But if huge numbers of infectious agents accumulate in the blood, some of them may get through the blood-brain barrier. They will then be able to infect the meninges and cause meningitis. Infections that occur close to the brain, such as an ear or sinus infection, pose an especially high risk for meningitis.

Meningitis can also develop because of openings in the skull. These openings can occur because of a skull fracture or a surgical procedure. These openings provide a way for infectious agents to get into the brain because the blood-brain barrier cannot prevent the infection.

SYMPTOMS


The classic symptoms of meningitis include fever, headache, vomiting, sensitivity to light, irritability, severe fatigue, stiff neck, and a reddish-purple rash on the skin. If the infection is not treated quickly, more serious symptoms develop, including seizures, confusion, and coma.

SARA ELIZABETH BRANHAM

Before the discovery of antibiotics, meningitis was a dreaded diseases. There was no way to stop its progress. Those who survived an attack of the disease were likely to be left blind, deaf, or mentally retarded. The disease was also feared because of the ease with which it spread. During World War I (191418), for example, meningitis often swept through groups of soldiers who lived and fought together. The only way to stop its spread was to isolate infected soldiers from others who were still healthy.

Important breakthroughs in the treatment of meningitis came as the result of the work of Dr. Sara Elizabeth Branham (18881962). Dr. Branham worked for many years at the National Institutes of Health. Initially, she was interested primarily in food poisoning caused by bacteria. But the tragedies of World War I encouraged her to focus on ways of treating meningitis.

When she began her research, the only treatment available for meningitis was antiserum obtained from horses. Horse antiserum is a chemical produced in horses when they have been exposed to meningitis bacteria. As horse antiserum lost its effectiveness, Dr. Branham developed another form of antiserum, produced in rabbits.

Finally, in 1937, Dr. Branham decided to try the newly discovered sulfonamide drugs on meningitis. The sulfonamides were the first antibiotics to be widely used. Dr. Branham found that they could be used effectively against the bacteria that cause meningitis. Largely as a result of her research, meningitis was kept under control during World War II (193945).

These symptoms may not be present in very young babies or the elderly. The immune system of babies is usually not developed enough to fight off an infection of the meninges. So symptoms that accompany an immune response, such as fever, are not observed. Seizures may be the only symptom of meningitis in young children. The same is true of older people who have other kinds of medical disorders that leave them in a weakened state.

DIAGNOSIS


The first clues that a person may have meningitis can be obtained from a simple physical examination. The doctor may try to move the patient's head in various directions. For a person with meningitis, these movements can be difficult and painful.

The standard test for diagnosing meningitis is called a lumbar puncture (LP), or spinal tap. An LP involves the insertion of a thin needle into the space between the vertebrae that make up the spine. A small sample of cerebrospinal fluid is removed. Cerebrospinal fluid (CSF) is a clear liquid present in the space between cells in the brain and the spinal cord. It serves a number of important functions. It provides a cushion for the brain and spinal cord, brings nutrients to these structures, and carries away waste products.

CSF normally contains certain fixed amounts of various chemicals, such as sugar, sodium, potassium, and calcium. An infection in the meninges will cause a change in these amounts. For example, bacteria "eat" sugar, so the presence of bacteria in the meninges causes a reduction in the amount of sugar in the CSF.

The presence of white blood cells in the CSF is also a clue to the presence of meningitis. The immune system produces white blood cells to fight off infections. A healthy body would normally not have white blood cells in the CSF. If they are present, the immune system is probably fighting an infection in the brain or spinal cord, such as meningitis.

TREATMENT


Meningitis infections caused by bacteria can be treated with antibiotics. Penicillin and cephalosporins (pronounced seff-a-lo-SPORE-inz) are commonly used. Special methods are necessary for giving these drugs, however, because of the blood-brain barrier. The usual procedure is to inject large quantities of an antibiotic directly into a person's bloodstream. If the concentration of drugs is high enough, some will get through the blood-brain barrier and into the meninges.

Antiviral and antifungal medications can be used similarly. Antiviral drugs usually do not kill viruses, but they can lessen some of the effects of the viruses.

Steroids may also be used to treat meningitis. Steroids tend to reduce inflammation and swelling, lessening possible harm to brain cells. The balance of sugar, sodium, potassium, calcium, and other substances in the CSF must also be carefully monitored. It may be necessary to inject one or more of these chemicals into the patient's body to maintain a proper balance.

PROGNOSIS


Viral meningitis is the least severe type of the disease. Patients usually recover with no long-term effects. Bacterial infections are far more serious and progress quickly. Very rapid treatment with antibiotics is necessary. If the infection is not halted, the patient may fall into a coma and die in less than a day.

Death rates for meningitis vary depending on the cause of the infection. Overall, the death rate from the disease is just less than 20 percent.

Long-term effects of meningitis are not unusual. For example, damage to cells in certain parts of the brain can cause deafness and/or blindness. Some patients develop permanent seizure disorders. These disorders may require lifelong treatment with antiseizure medications. Scarring of brain tissue can block normal flow of CSF. This condition may be serious enough to require the installation of shunt tubes, surgically implanted devices that help to restore normal circulation of CSF.

PREVENTION


There are no specific recommendations for avoiding meningitis. People should try to avoid developing any kind of infection that might spread to the meninges, especially those of the ear and sinus.

Some preventive treatments are available for specific types of meningitis. For example, there is a vaccine for individuals who have to be in areas where contagious meningitis exists. These individuals may also take antibiotics to protect them from infection by the bacterium that causes this form of the disease. A vaccine is available for one of the forms of meningitis that occurs in young children.

FOR MORE INFORMATION


Books

Stoffman, Phyllis. The Family Guide to Preventing and Treating 100 Infectious Diseases. New York: John Wiley & Sons, 1995.

Willett, Edward. Meningitis. Hillside, NJ: Enslow Publishers, Inc. 1999.

Periodicals

Meissner, Judith W. "Caring for Patients with Meningitis." Nursing (July 1995): pp. 50+.

Organizations

American Academy of Neurology. 1080 Montreal Avenue, St. Paul, MN 55116. (612) 695-1940. http://www.aan.com.

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