Pharm 100 - Lesson F.2

• In 1775, Percival Pott, a surgeon in London, England described cancer of the scrotum (thepouch containing the testes) in young chimney sweeps which he attributed to chronic exposure to soot. Chimney sweeps had recognised this relationship and had referred to cancer of the scrotum as the soot-wart.In
• 1910, Clunet in France demonstrated that exposure of rats to x-rays caused cancer in rats. This was followed in 1914 by the demonstration by other French workers that x-rays could causecancer in humans.
• In 1915, two Japanese workers, Yamagiwa and Ichikawa produced cancer of the skin afterprolonged application of coal tar to rabbit ears.
• In 1930, Kennaway and co-workers, who were skilful chemists, isolated highly carcinogenic polycyclic hydrocarbons from coal tar. They utilized the fluorescence of polycyclic hydrocarbons toguide their isolation. A hydrocarbon is an organic chemical made up of hydrogen and carbon and theterm “polycyclic” denotes the fact that the carbon is present in several six-membered rings.
• Bladder cancer was described in 1895 by Rehm in aniline dye workers. 2-Naphthylamine wasused as a dye in the dye industry. In 1938, Hueper showed that 2-naphthylamine caused cancer ofthe bladder when administered to dogs. This led to prohibition of this dye in the dye industry.
• In 1961 in England an epidemic resulted in the death of young turkeys, ducks and chickens. Liver cancer was observed in the dead poultry and was traced to the peanut meal used as poultry feed. The peanuts were found to be contaminated with a common fungus, Aspergillus flavus, whichproduced aflatoxin, a potent cancer-inducing agent in liver. Subsequent studies revealed a correlationbetween liver cancer in humans and aflatoxin in food in the East African country, Uganda. In recentyears, I read a novel entitled “The Human Factor” by the well known author, Graham Greene. In thisnovel, one reads that the British Secret Service poisons one of their own agents, suspected of being aspy, by adding aflatoxin to his whisky drink; it turns out later that he was innocent.

While the above are figures for Canada, there is a marked difference between the major cancersaffecting the developing world and the developed world. Thus, cancer of the liver is the most frequentin China, and other Asian countries as well as west and central Africa. Cancer of the liver isattributable in these countries to the high incidence of hepatitis B infection and contamination of foodsby aflatoxin. On the other hand, colon-rectal cancer is more prevalent in North America, Europe andAustralia, apparently associated with a western diet – high in saturated fat and low in fibre, fresh fruitand vegetables.

• Smoking, mainly cigarettes, causes cancer of the lung, upper respiratory tract, esophagus, bladderand pancreas. Smoking may also play a role in other cancers. We have discussed previously theimportance of the dose-response relationships in pharmacology and toxicology. Consequently, itcomes as no surprise to learn, that whether smoking causes cancer, will depend upon tar content of thecigarettes smoked, frequency of smoking, and the duration of the habit. Smokers are eight times morelikely to develop cancer of the lung than are non-smokers. There is a latent period of approximately 20 years between smoking and lung cancer. Thus, smoking among men increased greatly between 1900 and 1960 and the incidence of lung cancer began increasing markedly after 1920. Women increasingly took up smoking in the 1920’s and 1930’s and the incidence of lung cancer amongstwomen began rising 20 years later.
• Passive smoking, that is inhaling tobacco from the environment, as expected from dose-response relationships, will cause much less lung cancer than active smoking. However, in the United States several thousand people die each year from cancer due to this cause.

• Saturated animal fat and red meat are strongly linked to cancer of the colon and of the rectum, aswell as to cancer of the prostate. High intake of salt has been linked to stomach and other cancers.
• It has been shown that skimping on fresh vegetables and fruits can contribute to many differenttypes of cancer. It is thought that vegetables and fruit contain constituents that block cancer-inducingchemicals produced in our own bodies.
• Children who eat more than necessary and exercise too little often grow more and are at higher risk of developing certain cancers.

• Viruses: DNA viruses are responsible for inducing some cancers. These viruses invade the living cells ofa host and utilize the host cells’ DNA- synthesizing and protein-synthesizing machinery to makecopies of themselves. Hepatitis B and Hepatitis C can cause liver cancer. It is estimated that up to 80% of global liver cancer is caused by hepatitis.
• The human papilloma viruses, which are sexually transmitted, can cause cancer of the cervix. The Epstein-Barr virus can cause a variety of cancers. Human immunodeficiency virus (HIV) cancause Kaposi’s sarcoma.
• Bacteria: Helicobacter pylori, the bacterium responsible for causing stomach ulcers, has also been stronglyassociated with stomach cancer.

In the developed world, strict control measures have cut down on cancer caused by occupational exposure to carcinogens. However, as the developing countries race to industrialize, strict controlmeasures are not instituted and it is likely that carcinogens in the workplace will be a major hazard. The preceding table shows examples of carcinogens in the workplace and examples of workers at risk.

• In early studies, it was difficult to understand how so many chemicals with no apparent similarityin chemical structure could be carcinogenic. However, advances in our understanding of drugmetabolism has helped to clarify the process. Thus, it is now clear that the carcinogens are in general inactive as such but undergo metabolic activation by drug metabolising enzymes in the body. Theh ighly chemically reactive forms, termed the ultimate carcinogens, react irreversibly with a DNAmolecule, thus causing a change in the chemistry of the gene. This change is perpetuated insubsequent divisions of the cell in which it occurs; in other words, a mutation has been induced. Thegenes affected may be oncogenes or tumor suppressor genes. Experimental studies have shown thatthe cells must divide (cell proliferation) to make the genetic change permanent.
• There are two different categories of carcinogens – initiators and promoters. The chemicals described above fit into the first category, namely initiators. These agents damage genes involved incontrol of cell division and facilitate the division and proliferation of cells. Cancer arises when asingle cell accumulates a number of mutations and escapes restraints on cell division.
• The secondcategory, promoters, do not damage genes but selectively enhance the growth of cancer cells or precursors of cancer cells.

• Delaney amendment to the Food and Drug Act in the U.S.A. In 1958, the Delaney amendmentwas passed in the U.S. Congress. This act prohibits the use in foodstuffs of any substance that hasbeen shown, at any dose, to produce cancer in any experimental animals.
• The only officially recognized way to test a chemical for carcinogenicity is to determine whetherit causes cancer in laboratory animals. Such tests require two to three years to conduct and are verycostly to perform.
• There is therefore a great interest in the development of cheaper tests. One such test, developedby Bruce Ames of Berkeley, California, employs a mutant of the bacterium Salmonella typhimurium that has lost the ability to make the amino acid, histidine. When this mutant* is maintained in a histidine-free culture medium it cannot grow. However, the mutant bacterium regains the ability togrow when exposed to mutagenic chemicals that repair the original defect. When 174 different knowncarcinogens were tested by the Ames test, 156 (90%) caused mutations in the bacterial mutant. It wasthus deduced that if a chemical causes a mutation in the bacterial system there is a high likelihood thatit will be a carcinogen.
• While tests such as the Ames test are not officially recognised, they are nevertheless useful in research and in industry. An industry would not want to proceed with development of a chemical as aherbicide or insecticide if at an early stage it was found to be carcinogenic in the Ames test.

There are six categories of cancer treatment. These are surgery, chemotherapy (use of drugs tokill cancer cells), radiation, biological therapies, hormone blocking and hormone-supplementing therapies, and bone marrow transplantation.

• The major goal of cancer chemotherapy is cure. Cure has, however, been achieved in only a few cancers; for example, testicular cancer, Hodgkin’s disease and childhood leukemias.
• A second important goal is to prolong survival,
• while a third goal is the relief of symptoms.
• A fourth goal isto provide psychological support to patients.
• A final goal is ongoing clinical research to provideimproved chemotherapy for the future. Details of modern treatment methods and five-year survivalrates for twelve major cancers are provided in Scientific American, September 1996.

• Benefit-risk assessment: The physician, in consultation with the patient, must weigh thepossible benefits of chemotherapy versus the adverse effects of treatment in each clinical situation. The decision whether or not to continue chemotherapy will need to be re-evaluated prior to eachtreatment. Questions which will need to be asked prior to each treatment are: Is the goal set beingachieved in this patient? Are the adverse effects too severe to warrant continuance of chemotherapy?
• Mechanism of action: Drugs used in cancer chemotherapy act to kill tumour cells by inhibitingprotein synthesis, DNA synthesis, or cell division (mitosis).
• Adverse effects: Rapidly dividing normal cells in the body are also harmed by drugs employedin cancer chemotherapy. Cells in the bone marrow which are the source of the red cells, white cellsand platelets in the blood are affected; as a result there will be a decreased number of these cells in theblood (cytopenia). The cells lining the gastrointestinal tract will be harmed resulting in nausea,vomiting, and ulceration. Hair roots cells are harmed resulting in baldness.
• Dosage and schedule: This is designed to maximize anticancer effect while minimizingtoxicity.
• Combination chemotherapy: Drugs are frequently used in combination. The rationale is thatcancer cells are less likely to defend themselves when attacked by a variety of drugs which attack indifferent ways. A second reason is that one can select drugs for the combination which have differenttoxicities. If one used a single drug, it would not be possible to increase the dose beyond a certainlevel because drugs employed in cancer chemotherapy have a low therapeutic index. The results aregood with combination chemotherapy in certain types of cancer such as Hodgkin’s disease which istreated with a combination of four drugs.

• Drugs employed in cancer chemotherapy may be classified by subdivision into the six groupsdescribed below:
• 1. Alkylating agents: An example is the nitrogen mustard, mechlorethamine, which alkylatesDNA, thereby damaging DNA.
• 2. Antimetabolites: An example is the folic acid antagonist, methotrexate, which disruptscellular metabolism.
• 3. Natural products: An example is vincristine which is isolated from the Periwinkle plant; it actsby arresting cell division. Another example is Paclitaxel (Taxol) isolatedfrom the Western Yew. It has been approved for use in ovarian and breastcancer and acts by arresting cell division.
• 4. Antibiotics: An example is doxorubicin which acts by damaging DNA.
• 5. Hormones: An example is prednisone which suppresses cell division. Tamoxifensuppresses the effect of the female hormone estrogen. It is used in helping toprevent breast cancer in some women at high risk.
• 6. Biologicals: A number of drugs derived through molecular biological techniques inhibitcell replication by blocking cytokines, which normally control cell growth. Some drugs are also antibodies to these cytokines.
• 7. Miscellaneous: An example is procarbazine which acts by damaging DNA.