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Introduction to Chemotherapy

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Steven M. Belknap

Paul Ehrlich introduced the term chemotherapy in 1907 to describe his important early studies of Trypanosoma brucei, the tsetse fly-borne parasite that causes African trypanosomiasis (sleeping sickness). The term chemotherapy, initially referring to antiparasitic therapy, now refers more broadly to the use of any chemical compound that selectively acts on microbes or cancer. Ehrlich had previously developed selective chemical stains for the microscopic examination of Mycobacterium tuberculosis and other microorganisms, using the coal-tar derivative dyes. He tested many of these organic compounds for their selective toxicity against trypanosomes but failed to find an effective non-toxic antischistosomal agent. Turning to the chemotherapy of syphilis, Ehrlich eventually discovered the arsenical compound salvarsan, which was both remarkably nontoxic to humans and remarkably toxic against a number of treponemal diseases, including syphilis and yaws. Ehrlich called salvarsan the magic bullet.

The search for safe, effective chemotherapeutic drugs is hindered by the common evolutionary legacy humans share with all living organisms; success requires exploitation of metabolic or structural differences between normal human cells and disease-producing cells. The more closely related the undesirable cells are to normal human cells, the more difficult the task of finding a magic bullet. For example, it is easier to cure malaria than cancer. Since viruses commandeer human cells to provide the necessary structural and metabolic apparatus for their functioning, they also are difficult to kill; transformed virus-infected human cells are only slightly altered normal human cells.

Humans were not the first to exploit the selective toxicity of chemicals. Many fungi and bacteria make toxic substances that kill or suppress the growth of competing microorganisms or facilitate infection of a host. Plants make a vast array of toxins for their self-defense. Exploitation of the selective toxicity of chemicals is an ancient and widely employed technique.

Humans first discovered this process in 1928 with Alexander Fleming's chance observation of the antibacterial effect of a substance secreted by Penicillium notatum mold. Howard Florey subsequently had the insight that this substance could be purified and injected into patients so as to provide systemic treatment of infection. Once scientists had learned of penicillin, they found many other naturally synthesized antibiotics, including tetracycline, streptomycin, and the cephalosporins. When the structures of these natural antibiotics were elucidated, chemists began to experiment with semisynthetic derivatives of the natural products and invented entire classes of related drugs that were safer or more effective than the naturally produced drug. The new semisynthetic or wholly synthetic drugs had improved pharmacokinetic properties, greater stability, and extended spectrums of action.

The emergence of microbial antibiotic drug resistance was speeded by the indiscriminate use of antibiotics in humans and livestock. Exposure to very low concentrations of antibiotic in meat or milk may have provided a path whereby human pathogens could eventually evolve high-level antibiotic drug resistance. Recently some strains of enterococcus and tuberculosis have developed resistance to all known antibiotic drugs. Inappropriate use of antibiotics is very common, and it accelerates the development of resistance in pathogens.

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