Chemotherapeutic Agents: Definition and History | Microbiology

In this article we will discuss about:- 1. Introduction to Chemotherapeutic Agents 2. Definition of Chemotherapeutic Agents 3. Short History 4. Groups.

Introduction to Chemotherapeutic Agents:

For centuries, physicians believed that heroic measures were necessary to save patients from the ravages of infectious diseases. They prescribed frightening courses of purges and bloodlettings, enormous doses of strange chemical concoctions, ice water baths, starvation, and other drastic remedies. These treatments probably complicated an already bad situation by reducing the natural body defenses to the point of exhaustion.

But a revolution in medicine took place about 1825 when a group of doctors in Boston and London experimented to see what would happen if such treatments were withheld from diseases patients. Surprisingly, they found the survival rate essentially the same and, in some cases, better.

Over the next few decades, the lessons from their experiments spread, and as the worst features of heroic therapy disappeared, doctors adopted a conservative, non-meddling approach to disease. It became the doctor’s job to diagnose the illness, explain it to the family, predict what would happen in the next several days, and then stand by the care for the patient within the limits of what was known.

When the germ theory of disease emerged in the late 1800s, the information about microorganisms added considered to the understanding of disease and increased the storehouse of knowledge available to the doctor. However, it did not change the fact that little, if anything, could be done for the infected patient from all causes; and Stereptococcal disease was a fatal experience, as were Pneumococcal pneumonia and Meningococcal meningitis.

Then, in the 1940s, the chemotherapeutic agents burst on the scene, and another revolution in medicine began. Doctors were astonished to learn that they could kill bacteria in the body without doing substantial harm to the body itself.

Medicine experienced a period of powerful, decisive therapy for infectious disease, and doctors found they could successfully alter the course of disease. The chemotherapeutic agents effected a radical change in medicine and charted a new course that has followed through to the present day.

The antimicrobial drugs that have become mainstays of our health-care delivery system. We shall explore their discovery and examine their uses, while noting the important side effects attributed to many of them.

When Pasteur performed his experiments a hundred years ago, he implied that microorganisms could be destroyed and that someday, a way would be found to successfully treat many diseases. Only since the 1940s has Pasteur’s prophecy become reality.

Definition of Chemotherapeutic Agents:

Chemotherapeutic agents are chemical substances used within the body for therapeutic purposes. The term generally implies a chemical that has been synthesized by chemists or produced by a modification of a preexisting chemical. By contrast, an antibiotic is a product of the metabolism of a microorganism.

Although many antibiotics are currently produced by synthetic or semisynthetic means and are more correctly “chemotherapeutic agents.” Our discussion of chemotherapeutic agents will begin with a brief review of their developments.

Short History of Chemotherapy:

In the drive to control and cure disease, the efforts of early microbiologists were primarily directed toward enhancing the body’s natural defenses. Sera containing antibodies lessened the impact of diphtheria, typhoid fever and tetanus; and effective vaccines for smallpox and rabies (and later, tuberculosis, diphtheria, and tetanus) reduced the incidence of these diseases.

Among the leaders in the effort to control disease was an imaginative investigator named Paul Ehrlich. Ehrlich envisioned antibody molecules as “magic bullets” that seek out and destroy disease organisms in the tissues without harming the tissues. His experiments in stain technology indicated that certain dyes also had antimicrobial qualities, and by the early 1900s, his attention had turned to magic bullets of a purely chemical nature.

One of Ehrlich’s collaborators was the Japanese investigator Sahachiro Hata. Hata wished to perform research on the chemical control of the syphilis spirochete Treponema pallidum, and Ehrlich was happy to oblige. Previously, Enrich and his staff had synthesized hundreds of arsenic-phenol compounds, and Hata set to work testing them for antimicrobial qualities.

After months of painstaking study, Hata’s attention focused on arsphenamine, compound #606 in the series. Hata and Ehrlich successfully tested arsphenamine against syphilis in animals and human subjects, and in 1910, they made a derivative of the drug available to doctors for use against the disease. Arsphenamine, the first modern chemotherapeutic agent, was given the common name Salvarsan because it offered salvation from syphilis and contained arsenic.

Salvarsan met with mixed success during the ensuring years. Its value against syphilis was without question, but local reactions at the injection site and indiscriminate use by some physicians brought adverse publicity. Moreover, some church officials used the threat of syphilis as a deterrent to immoral behaviour, and they were less than enthusiastic about Salvarsan’s therapeutic effect.

Ehrlich’s death in 1915 together with the general ignorance of organic chemistry and the emerging world war further eroded enthusiasm for chemotherapy. Instead, interest strengthened in serum and vaccine therapy for war-related wounds and diseases.

Significant advances in chemotherapy would not be made for another 20 years. During this interval, German chemists continued to synthesize and manufacture dyes for fabrics and other industries, and they routinely tested their new products for antimicrobial qualities. Among these products was a red dye, prontosil, synthesized in 1932. Prontosil had no apparent effect on bacteria in culture.

But things were different in animals. When the German chemist Gerhard Domagk tested prontosil in animals he found a pronounced inhibitory effect on staphylococci, streptococci, and other Gram-positive bacteria. In February 1935, Domagk injected the dye to his daughter Hildegarde, who was gravely ill with septicemia. She had pricked her finger with a needle, and blood infection had followed rapidly.

Hildegarde’s condition gradually improved, and, to many historinas, her recovery set into motion the age of modern chemotherapy. For his discovery, Gerhand Domagk was awarded the 1939 Nobel Prize in Physiology or Medicine (in absentia, however, because Hitler forbade him to accept it).

Later in 1935, a group at the Pasteur Institute headed by Jacques and Therese Trefouel isolated the active principle in prontosil. They found it to be sulfanilamide, a substance first synthesized by Paul Gelmo in 1908. Sulfanilamide quickly became a mainstay for the treatment of wound-related infections sustained during World War II.

Groups of Chemotherapeutic Agents:

Sulfanilamide and Other Sulfonamides:

Sulfanilamide was the first of a group of chemotherapeutic agents known as sulfonamides. In 1940, the British investigators D.D. Woods and E.M. Fildes proposed a mechanism of action for sulfanilamide and other sulfonamides, and gave insight on how they interfere with the metabolism of bacteria without damaging body tissues. The mechanism came to be known as competitive inhibition.

According to the mechanism of competitive inhibition, certain bacteria synthesize an important molecule called folic acid for use in nucleic acid production. Humans cannot synthesize folic acid for use in nucleic acid production. Humans cannot synthesize folic acid and must consume it in foods or vitamin capsules. However, bacteria possess the necessary enzyme to manufacture folic acid and are incapable of absorbing folic acid from the surrounding environment.

In the production of folic acid, the bacterial enzyme joins together three important components, one of which is para-aminobenzoic acid (PABA). This molecule is similar to sulfanilamide in chemical structure. Therefore if the environment contains large amounts of sulfanilamide, the enzyme selects the sulfanilamide molecule instead of the PABA molecule for use in folic acid production.

Once combined with the enzyme, the molecule binds tightly and effectively inhibits the enzyme, thus making it unavailable for folic acid synthesis. As the production of folic acid is reduced, nucleic acid synthesis ceases, and the bacteria die.

Modern sulfonamides are typified by sulfamethoxazole. Doctors prescribe this drug for urinary tract infections due to Gram-negative rods, and for meningococcal meningitis. Frequently the drug is combined with trimethoprim, a drug that inhibits another step in folic acid synthetis.

Commercially the drug combination is known as Bactrim. It is frequently used to treat Pneumocystis pneumonia. Another common sulfonamide, sulfisoxazole, is marketed as Gantrisin cream for vaginal infections due to Gram-negative bacteria. In some patients, a drug allergy to sulfonamides develops, with a skin rash, gastrointestinal distress, or type II cytotoxic hypersensitivity.

Other Chemotherapeutic Agents:

The discovery and development of sulfanilamide led to the development of numerous other chemotherapeutic agents, many of which are currently in wide use. One example is the antituberculosis drug isoniazid (isonicotinic acid hydrazide, INH). Biochemists believe that isoniazid interferes with cell-wall synthesis in Mycobacterium species by inhibiting the production of mycolic acid, a component of the wall.

Isoniazid is often combined in therapy, with such drugs as rifampin and ethambutol. Ethambutol is a synthetic, well-absorbed drug that is tuberculocidal. Visual disturbances limit its use to treatment of tuberculosis.

Another chemotherapeutic agent, a quinolone called nalidixic acid, blocks DNA synthesis in certain Gram-negative bacteria that cause urinary tract infections. Synthetic derivatives of nalidixic acid called fluoroquinolones are also used in urinary tract infections as well as for gonorrhea and chlamydia and for intestinal tract infections due to Gram-negative bacteria. Examples of the fluoroquinolone drugs are ciprofloxacin (Cipro), enoxacin, and norfloxacin.

Nitorfurantoin is a drug actively excreted in the urine for urogenital infections. Metronidazole (Flagyl) has been used for decades against trichomoniasis, amebiasis and giardiasis. However, evidence that the drug causes tumors in mice has prompted physicians to prescribe it with caution. The treatment of malaria has long depended upon the consumption of quinine.

When the tree bark used in its production became unavailable during World War II, researchers quickly set to work to develop two alternatives – chloroquine and primaquine. Chloroquine is effective for terminating malaria attacks; primaquine destroys the malaria parasites outside red blood cells.

Two other chemotherapeutic drugs, both inhibitory to Mycobacterium species, bear brief mention. The first is para-aminosalicylic acid (PAS), a drug that closely resembles sulfonamides and is used for tuberculosis. The second agent is diaminodiphenylsulfone, or dapsone, used to treat leprosy.