Development of chemotherapy may be viewed in three phases:- 1. Pre Ehrlich Period 2. Period of Paul Ehrlich 3. Period highlighted by discovery of sulfonamides and antibiotics.
Phase # 1. Pre Ehrlich Period:
In this period some compounds were used empirically to treat different diseases. Sometimes adverse effects were also monitored due to empirical use of the compounds. Cinchonabark was used for the treatment of malaria. Syphilis was also a problem to the society and to treat this mercury was used.
Phase # 2. Paul Ehrlich (1854-1915):
Paul Ehrlich was an organic chemist who coined the word chemotherapy and is believed to be the father of chemotherapy. He observed that certain dyes like methylene blue specifically killed and stained certain bacterial cells. He generated the idea that some chemical substances may be produced that can combine with and kill the invading organisms without toxicity to the host cells. Ehrlich called such compounds “Magic bullets”.
In 1891, he demonstrated the efficiency of methylene blue in the treatment of malaria. He also synthesized a series of arsenical compounds effective against syphilis. For the therapeutic utility of the compounds he introduced the term “chemotherapeutic Index”, a ratio of maximum tolerated dose of a drug to its minimum curative dose. Further, the term chemotherapeutic index was replaced by therapeutic index, a ratio of LD50 to ED50.
Ehrlich expressed an idea that cell membrane contains chemical groups or ‘receptor’ which combines with essential materials like oxygen and caused their uptake by cells. He told that chemicals contain two groups-one group attach to the cell receptor (haptophore) and another group which caused specific pharmacological effect or toxic effect (toxophore).
It is his idea that a drug can produce curative or toxic effect depending upon its affinity for the parasite or host. Therefore, a compound which has high affinity for the host tissue (organotropic) may be toxic. Whereas, if the compound has high affinity for parasite (parasitotropic) may be curative. Based on the above hypothesis, Ehrlich introduced arsephenamine, the first really effective chemotherapeutic agent in man, for the treatment of syphilis.
The poineering work of Ehrlick established the importance of cellular chemistry to express drug action and encouraged many workers to synthesize newer antimicrobials. Paul Ehrlich was awarded Nobel Prize in 1908 in medicine.
Phase # 3. Period Highlighted by Discovery of Sulfonamide:
Domagk, Mietsch and co-workers (1935) were working on azo dyes demonstrated the efficacy of ‘Prontosil’ a dye with a sulfonamide side chain inhibiting the growth of streptococci in-vitro and in- vivo. Nitti, Bovet and Fuller are also known as trefuel brothers, pointed that prontosil produced its therapeutic efficacy to its conversion into sulfanilamide in the body.
Since then a variety of sulfonamides have been synthesized. Though, sulfonamide was prepared by Gelmo in 1908, but 30 years passed before its therapeutic value was discovered. The idea of using one microorganism to cure the infection caused by another was suggested during the last century.
Thus, Pasteur and Joubert in 1887 demonstrated that “Common bacteria” prevented the growth of anthrax bacilli in urine, and Babes in 1885, using culture media, established that one bacterium could elaborate a substance that would stop the growth of another.
Emmerich and Low in 1889, while working on the organism pseudomonas aeruginosa, discovered that extract of this organism in high dilution could destroy a variety of pathogenic cocci as well as diphtheria, cholera, typhoid and plague organisms.
Sir Alexander Fleming (1928), while working Staphylococcal variants, found one of his culture plates contaminated by a fungus prevented the growth of surrounding bacterial colonies. This fungus was identified as genus penicillium and the antibiotic was named penicillin.
Finally, penicillin was isolated from penicillium-notatum which inhibited a large number of gram-positive microorganisms. Further Chain, Folk and Florey in 1941, during second world war established penicillin as the most potent anti- infective agent.
In 1945, Fleming, Chain and Florey were awarded, the Nobel prize for revolutionary contribution. The 6-aminopenicillanic acid nucleus of penicillin was isolated in 1959 and this has led to development of a variety of semisynthetic penicillins.
In 1944, streptomycin was reported by Schatz, Bugie and Waksman from Steptomyces griseus waksman defined ‘antibiotic’ as a chemical substance produced by micro-organisms having the property of inhibiting the growth or destroying other micro-organisms in high dilution.
The streptomycin was found effective against many gram-negative microorganisms and Mycobacterium tuberculosis. Since, then a large number of antibiotics have been developed and tested for their efficacy against various microorganisms.