**3.3. Carcinogens of physical origins (Radiation)**

early 1980s the high risk of lung, skin, kidney and bladder cancer due to chronic low level arsenic poisoning of water in different countries (Bangladesh, Vietnam, Cambodia, Tibet, Argentina, Chile, China, India, Mexico, Thailand, and US) caused by contamination of water by pesticides and various alloys containing arsenic, which resemble and thus substitute phosphorus in chemical reactions, was discovered [37]. In 1980 it was realized that exposure to formaldehyde (a hazard in embalming and production of plastics and vinyl chloride, from which PVC is manufactured) could cause nasal cancer in rats [38]. In the early 1970s, the carcinogenicity of vinyl chloride was linked to occupational angiosarcoma cancers in workers in industry. A few years later PVC was classified as a carcinogen [39-41]. Since then specific substances: aniline and benzidine, asbestos, wool/wood/leather dust have been linked to different types of cancer in humans bladder cancer, sinuses and lung cancer, mesothelioma, nasal sinuses, respectively [3]. Many drugs, including chemotherapeutic anticancer agents, diuretics, hormones have been recognized as a source of secondary cancers and thus classified as definite carcinogens. Most of anticancer drugs is classified as group 1 agents in IARC

**3.2. Carcinogens of biological origins (Oncogenic viruses/bacteria/parasites)**

The hypothesis that cancer can originate from a virus comes from Danish scientists Oluf Bang (1881-1937) and Vilhelm Ellerman (1871-1924), who was the first to show, in 1908, that avian er‐ ythroblastosis (chicken leukaemia) can be transmitted by cell-free extracts. In 1911, Francis Pey‐ ton Rous (1879-1970), American pathologist, described a solid cancer, sarcoma, in domestic chickens caused by exposing the healthy bird to a cell-free filtrate containing retrovirus later be‐ came known as the *Rous sarcoma virus* [42]. Abbie Lathrop (1868-1918) and Leo Loeb (1869-1959) described breast cancer in mice caused by a transmissible agent as early as in 1915 [43]. Since then several oncoviruses have been linked to different types of cancer [44]. In 1933 Richard Ed‐ win Shope (1901-1966) discovered the first mammalian tumour caused in cottontail rabbit by fi‐ broma virus and papilloma virus (*Shope papilloma virus*). Shortly later, in 1936, a geneticist and cancer biologists John Joseph Bittner (1904-1961) discovered a mouse mammary tumour virus (MMTV), the so-called Bittner virus, causing a breast cancer, which is a promoter in models of human breast cancer [45]. In 1957, Sarah Elizabeth Stewart (1905-1976) and Berenice E. Eddy (1903-1989), pioneers in the field of viral oncology research, discovered the Stewart-Eddy poly‐ oma virus, which produced several types of cancer in a variety of small mammals [46]. John J. Trentin (1908-2005) and others were the first to report of cancer (sarcoma) produced in animals (hamsters) by inoculation of virus of human origin (*Adenovirus*) [47]. Michael Anthony Ep‐ stein, Bert Achong (1928-1996) and Yvonne Barr identified the first human cancer virus (Ep‐ stein-Barr Virus or EBV) from Burkitt lymphoma cells in 1964 [48]. Baruch Blumberg (1925-2011) isolated Hepatitis B virus (HBV), a cause of hepatitis, and suggested that it contrib‐ uted to liver cancer hepatocellular carcinoma. It was confirmed to be an oncovirus in the 1980s. Hepatitis C virus (HCV) was shown to be a major contributor to liver cancer (hepatocellular carcinoma) by Michael Houghton and Daniel W. Bradley in 1987. The first human retroviruses, Human T-lymphotropic virus 1 (HTLV I) and 2 (HTLV 2), linked to T-cell lymphoma/T-cell leu‐ kaemia and Hairy-cell leukaemia, respectively, were discovered by Bernard J. Poiesz, Robert Charles Gallo and Mistuaki Yoshida. In 1984 Harald zur Hausen and Lutz Gissman discovered

classification [3].

46 Drug Discovery

Shortly after the discovery of chemical carcinogens, i.e. factors that suppress and activate the cell growth and division, the first physical carcinogens were identified. After discovery of Xrays by Wilhelm Roentgen (1845-1923) in 1895 and radioactive radiation by Henri Becquerel (1852-1908) in 1896, the exposure to radiation has been identified as one of the causes of can‐ cer. Working with early X-ray generators resulted in the acute skin reactions and the first radi‐ ation-induced cancer arising in an ulcerated area of the skin was reported in 1902. In 1910 to 1912, Pierre Marie, Jean Clunet and Gaston Raulot-Lapointe reported the induction of sarco‐ ma in rats by the application of X-irradiation. As early as in 1911 the first report of leukaemia in radiation workers appeared [56]. The 20th century pioneers in X-Ray/radium studies fell vic‐ tims to their work; surgeon Robert Abbe (1851-1928), physicist Marie Skłodowska-Curie (1867-1934) and physician Jean Bergonie (1857-1925) died due to leukaemia. The use of urani‐ um/plutonium based bombs against Hiroshima/Nagasaki during World War II revealed that ionising radiation irrespective of its origin is a cause of cancer [57]. Increased incidence of can‐ cer of bone marrow and essentially all organs was noted in Japan years to decades later. Some physical carcinogens have been discovered as a result of nuclear disasters. In 1957, the cooling system failed and the radioactive wastes chemical explosion of at Mayak nuclear fuel reproc‐ essing plant, Ozyorsk/Mayak, Russia caused radiation contamination which spread over hun‐ dred kilometres and pollution of the Techa River. This accident called Kyshtym disaster belongs to three most serious nuclear accidents ever recorded, although it was revealed only in 1976 [58]. The scarce epidemiological studies suggest very different numbers of cancer deaths among residents associated to radiation exposure. In 1979 the cooling system of Three Mile Is‐ land nuclear power plant near Harrisburg, Pennsylvania failed and the reactor core was parti‐ ally melted. Radiation from the reactor contributed to the premature deaths and cancers in local residents, but the disaster was relatively small [59]. There is still vivid discussion about the carcinogenic effects of nuclear power plant explosion in 1986 in Chernobyl located 80 miles from Kiev, Ukraine, which was the greatest source of long-lived radioactive plutonium and short-lived radioactive caesium (137Cs), iodines (particularly 131I) and strontium (90Sr). The ma‐ jor health effect of Chernobyl was an elevated thyroid-cancer incidence due to iodine absorp‐ tion by the thyroid gland in adolescents and children some of whom were not yet born at the time of the accident, and drastic increase in leukaemia cases caused by distribution the stronti‐ um incorrectly recognized by the body as calcium throughout the bone structure [60]. Radioac‐ tive isotopes of barium, caesium, iodine and tellurium were detected in a radiation plume released by damaged nuclear reactors at the nuclear plant in Fukushima, Japan in 2011. Fu‐ kushima Daiichi disaster was the most serious accident in global scale. As the prolonged expo‐ sure to radiation in the air, ground and food can result in leukaemia and other cancers thus about 160,000 people were evacuated from the region surrounding the plant. According to the‐ oretical 3-D global atmospheric models this nuclear disaster may cause as many as 2,500 cases of cancer, mostly in Japan. Only recently, in the 1990s, much-less energetic UV radiation has been also recognized as carcinogen causing not only genetic mutations but also melanoma or non-melanoma cancers. In 2011 WHO/IARC classified radiofrequency electromagnetic fields as possibly carcinogenic to humans (Group 2B), on the basis of an increased risk of glioma, a malignant type of brain cancer, associated with wireless phone use [3]. Nowadays we are aware that exposure to radiation can be incidental like in Hiroshima, Nagasaki, Chernobyl, Fu‐ kushima [1,61] or systematic due to repeated doses of radiation like UV during sun-bathing or MW during phone-cell use. Anyway the most common radiation induced cancers are basal cell carcinoma and squamous carcinoma of the skin, leukaemia and thyroid cancer. The first two can arise from excessive exposure to UV radiation, while the other are mainly result of ionis‐ ing radiation e.g. γ, X-Ray [1]. The controlled use of ionising radiation in medicine and indus‐ try and annual limits of doses for each individual [62] has reduced the risk connected with ionising radiation but the awareness of UV or MW related risk is still low. Common feature of cancers induced by physical factor is late onset and long period of risk persisting. Most of the physical carcinogens are classified as group 1 or 2 agents in IARC classification [3].

referred as well to antibacterial chemotherapy and treatment of autoimmune diseases, in general use of chemicals to treat disease. Chemotherapy, generally assumed as the youngest method of cancer treatment, is in fact rooted in ancient times. Although cutting out the cancer changed tissue was early found as the main treatment, it was not always effective. Thus various substances of natural origin were applied as complementary medications. Many even ancient cultures had proposed theories explaining the cause of cancer. These theories influenced the search for medicaments. For example Egyptians believed that natural substances similar in look or function to human organs can be used to treat ailments in those organs, thus the use

Anticancer Drug Discovery — From Serendipity to Rational Design

http://dx.doi.org/10.5772/52507

49

Although the products of animal and mineral origin had made an important contribution to drug development, the main source of drugs for millennia have been green plants. The most frequently used included castor oil plant (*Ricinus communis* L.), exploding cucumber (*Ecballium elateritum* L.), belladonna (*Atropa belladonna* L.), myrrh (dried sap from trees *Commiphora Myrcha L.*), incense (dried sap from trees *Boswellia thurifera L.*, *Boswellia frereana Birdw.*, *Boswellia bhawdajiana* Birdw.), stinging nettle (*Urtica dioica* L.), gingers (*Zingiber Boehm.* L.), red clover (*Trifolium pratense* L.) and autumn crocus (*Colchicum autumnale* L.). Although, in nature most of them cause sickness, but in small doses or after chemical modifications, they revealed therapeutic effects. Some of them were rediscovered by modern medicine. For example from *Colchicum autumnale* L. described by Pedanius Dioscorides (40-90 A.D.) in De Materia Medica a toxic alkaloid colchicine was extracted in 1820 by Pierre Joseph Pelletier (1788-1842) and Joseph Bienaimé Caventou (1795–1877). Albert Pierre Dustin (1914-1993), described its antymitotic properties in 1934 [63]. In 2009 it was accepted by Food and Drug Administration (FDA) as a drug for gout and Familial Mediterranean Fever. Another interesting case described by Dioscorides is red viscous sap called the dragon's blood mostly collected from *Dracaena cinnabari* Balf. f or *Croton lechleri* L. and used as a dye and anti-inflammatory, antimicrobial and anticancer folk remedy not only by ancient Greek but also Romans and Arabs. Recently methanolic extract of *Croton lechleri* was shown to exert cytotoxic effects on HeLa (Human epithelial carcinoma cell line) cells and its antitumor effect in HeLa tumour in mice was documented [64]. Two other commonly used antileukemic drugs, vinblastine and vincristine, were extracted in 1950 from the species of Madagascar periwinkle (*Catharanthus roseus* L.), for centuries known as folk remedy, and shortly after approved by FDA. Nowadays vinblastine, which binds tubulin, thereby inhibiting the assembly of microtubules, is an important component of a number of chemotherapy regimens, including ABVD for Hodgkin lymphoma, advanced testicular cancer, breast and lung cancers, and Kaposi's sarcoma [65]. Realgar widely used in Chinese traditional medicine because of its anti-inflammation, antiulcer, anticonvul‐ sion, and anti-schistosomiasis activity was recently found capable to induce cell apoptosis and thus effective in the treatment of hematological malignant diseases [66]. As early as in 1021, Avicenna described the medicinal use of *Taxus baccata* L. (Zarnab) as cardiac remedy in The Canon of Medicine. Various parts of *Taxus brevifolia* Peattie*, Taxus Canadensis* Marshall, *Taxus baccata* L. have been used by several Native American Tribes mainly for the treatment of noncancerous diseases [65] but the use for the treatment of cancer was noted only in the Hindu Ayurvedic medicine. Paclitaxel (Taxol®), used in treatment for breast, ovarian, small and nonsmall cell lung cancer and Kaposi sarcoma, was isolated in 1967 by Monroe E. Wall and

of mixtures of pigs eyes or ears was popular.
