4.  Carcinogens are agents that have the ability to initiate the formation of cancer.  They are divided into four groups  Chemical Carcinogens  Physical Agents  Ionizing Radiation  Oncogenic Viruses

5.  80 - 90% of all cancers may be related to environmental agents including : diets, lifestyles, and viruses  Several environmental agents often act together - co-carcinogens

6.  Sir Percival Pott in 1775, associated the increased incidence of scrotal skin cancer to chronic exposure to soot in chimney sweepers  Hundreds of chemicals have been shown to transform cells in culture and to cause tumors in experimental animals and in humans exposed to them  These chemicals are known as carcinogens and the process by which they cause tumors or cancers is known as carcinogenesis

7.  The carcinogenesis is a multistep process – demonstrated in experimental models of chemical carcinogenesis  Initiation : exposure of cell to a sufficient dose of carcinogenic agent (initiator) causes nonlethal permanent DNA damage  It is rapid, irreversible and has memory  Initiation alone is not sufficient to cause tumor

8.  Promoters can induce tumours in initiated cells, but they are non- tumourigenic by themselves  Promoting agents do not affect DNA directly  Cellular changes caused by them are reversible

9.  Promoters are usually irritants or substances that enhance proliferation of initiated cells, may contribute to additionalmutations  Promotors cannot induce neoplasia : i) alone, ii) if applied before initiator, iii) if applied in too small an amount iv) if too much time elapses between applications.

10. Experiments demonstrating initiation and promotion phase in chemical carcinogenesis for induction of skin cancer in mice

11. I. Direct Acting Carcinogens:  Require no metabolic conversion to become carcinogenic  Most of them are weak carcinogens  Some of them are chemotherapeutic drugs which have successfully cured, controlled or delayed recurrence of certain tumors & later induce 2 nd form of cancer usually AML e.g Alkylating agents : Cyclophosphamide Commonly mutated oncogene & tumor supressor gene,RAS & p53 are particular targets

12.  All initiating carcinogens are highly reactive electrophiles (electron def atoms) that can react with nucleophilic (electron rich) sites in the cells MOLECULAR TARGETS :  DNA is the primary target, RNA and proteins  Nonlethal damage on DNA that cannot be repaired  Commonly mutated gene RAS & p53 are particular targets Commonly mutated oncogene & tumor supressor gene,RAS & p53 are particular targets

13. 2. Indirect Acting Carcinogens : require metabolic conversion to an ultimate carcinogen before they are active.  Some of the most potent indirect chemical carcinogens are:-  Polycyclic hydrocarbons – present in fossil fuels  Benzo[a] pyrene – present in high- temp combustion of tobacco in cigg smoking ; cause Ca lung Commonly mutated oncogene & tumor supressor gene,RAS & p53 are particular targets

14.  Polycyclic hydrocarbons may be produced from animal fats during broiling meat – smoked meat & fish  Natural products : Aflatoxin  Other examples : aromatic amines, Azo dyes, Vinyl chloride, turpentin

15.  Principal active products in hydrocarbons are EPOXIDES, which form covalent adducts with DNA & RNA  Metabolic pathways for activation and/or inactivation (detoxification) of procarcinogen or its derivative  Most of the known carcinogens are metabolized by cytochrome p-450 - dependent mono- oxygenase

16. Aflatoxin B1  Produced by some species of Aspergillus a mold that grows on improperly stored grains or nuts  Causes mutations in p53  “signature mutation” in p53 gene ( G:C →TA 249 transversion in codon 249 )  Strong correlation between dietry levels of Aflatoxin & hepatocellular carcinoma in parts of Africa & Far East  By contrast p53 mutation much less common in HCC not associated with Aflatoxin

17.  Direct – acting Carcinogens

20.  Unrepaired alterations in the DNA are essential first steps in the process of initiation.  For the change to be heritable, the damaged DNA template must be replicated  Thus, for initiation to occur, carcinogen- altered cells must undergo at least one cycle of proliferation so that the change in DNA becomes fixed PROCESS OF CHEMICAL CARCINOGENESIS

21.  In quiescent tissues, mitogenic stimulus may be provided by carcinogen itself, or concurent exposure to biologic agent e.g virus, dietry factors or hormonal influences  Carcinogenecity of initiators is augmented by subsequent administration of promoters  Process of tumor promotion includes multiple steps : clonal expansion of preneoplastic cells, malignant conversion, and eventually tumor progression PROCESS OF CHEMICAL CARCINOGENESIS

22. General schema of events in chemical carcinogenesis

23.  Radiant energy is well established carcinogen  UV rays of sunlight  Ionizing electromagnetic & particulate radiation (medical or occupational exposure, nuclear plant accidents, atomic bomb detonation)  Radiation has possible additive or synergistic effects with other potential carcinogenic influencies  Well known latent period for damage caused by radiation and its cummulative effect require extremely long periods of observation RADIATION CARCINOGENESIS

24.  Strong epidemiologic relationship to squamous cell Ca, basal cell Ca, and melanoma of skin  Degree of risk depends on type of UV rays intensity of exposure, & quantity of “protective mantle” – melanin  Incidence of skin Cancers is higher in Europeans (fair skin, less melanin) ULTRAVOILET RADIATION

25.  UV portion of solar spectrum divided into UVA, UVB and UVC. UVB responsible for induction of skin Cas  Causes formation of pyrimidine dimers in the DNA leading to mutations  Individuals with defects in DNA nucleotide excision-repair are especially susceptible ; high frequency of skin Cas in xeroderma pigmentosum ULTRAVOILET RADIATION

26.  Electromagnetic radiation ( X-rays, gamma rays) particulate radiations ( α particles, β particles, protons, neutrons ) all forms are carcinogenic  In survivors of atomic explosion of Hiroshima & Naga- saki initially there was marked ↑ incidence of leukemia specially Ac & Ch Myeloid leukemia after latent period of about 7 yrs  subsequently incidence of other solid tumors with longer latent periods (Ca breast, colon, thyroid & lung) increased IONIZING RADIATION

27.  There is difference in vulnerability of diff tissues to radiation induced Cas, most frequent - AC & chronic Myeloid leukemia followed by CA Thyroid in young  SKIN, BONE & GIT relatively resistent to radiation –induced Ca IONIZING RADIATION

28. Radiation Carcinogenesis Ionizing radiation  dysjunction  random fusion  mutation. X Ray workers – Leukemia,skin Ca Radio-isotopes – Thyroid carcinoma Atomic explosion – Skin cancer, Leukemia Mutations Neoplasia