Neoplasia 6 by akashyap

VIEWS: 12 PAGES: 21

									CHEMICAL
RADIANT ENERGY MICROBIAL

CHEMICAL CARCINOGENESIS

CHEMICAL CARCINOGENESIS
 Initiation: Results from exposure of cells to a

sufficient dose of a carcinogenic agent (Initiator ).  Initiated cell : altered, capable of giving rise to a tumor  Initiation alone: insufficient.  Causes permanent DNA damage : irreversible, rapid, and has memory.  Phenotype of tumor cell influenced by tissue of origin.

PROMOTERS: Nontumorigenic by themselves. Induce tumors in initiated cells - by clonal expansion. Cellular changes are reversible. Do not affect DNA directly. Growth of altered cell depends on continued presence of stimulus.

General scheme of events:
CARCINOGEN
Excretion

Initiation

Electrophilic intermediates

DNA repair

Binding to DNA: Adduct formation.

Normal cell Cell death

Permanent DNA lesion: Initiated cell

Cell proliferation: Altered differentiation.

Promotion

PRENEOPLASTIC CLONE
Proliferation Additional mutations

MALIGNANT NEOPLASM

INITIATION:
 Direct acting compounds: Do not require chemical transformation for

carcinogenicity  Indirect acting compounds or procarcinogens: Require metabolic conversion in vivo ULTIMATE CARCINOGENS capable of transformation  Both : highly reactive electophiles, react with nucleophilic sites : DNA, RNA, protein  Non-enzymatic reactions  Covalent adducts formed between chemical carcinogen and a nucleotide in the DNA

METABOLIC ACTIVATION OF CARCINOGENS

 The inherent reactivity of electrophilic

derivative & the balance between metabolic activation and inactivation reactions.  Most carcinogens metabolized by cytochrome P-450-dependent mono-oxygenases.  Susceptibility - polymorphisms in the genes.  Age, sex, nutritional status determine the internal dose of toxicants produced.

MOLECULAR TARGETS OF CHEMICAL CARCINOGENS
 DNA is the primary target  Majority of carcinogens are mutagenic  For initiation to occur, carcinogen-altered cells must undergo at least 1 cycle of proliferation so that the change in the DNA becomes fixed or permanent.

 Stimulus to proliferate in quiescent cells is given by:
 Carcinogen itself  Concurrent exposure to : viruses, parasites, dietary

factors and hormonal influences.

PROMOTION OF CHEMICAL CARCINOGNESIS
 Promoters – hormones, phenols, drugs.  Cause proliferation and clonal expansion of initiated cells.  Initiated cells respond differently to promoters than normal cells Reduced GF requirements Less responsive to growth inhibitory signals
Cell proliferation

Additional mutations Malignancy

CARCINOGENIC CHEMICALS
Direct acting Alkylating agents  Activation independent, weak carcinogens  Interact with and damage DNA  Used as anticancer and immunosuppressive drugs Polycyclic aromatic hydrocarbons  Most potent carcinogens  Induce tumors in variety of tissues : Bladder, skin, lungs  Produced in : Combustion of tobacco Animal fats in process of broiling and smoked meats and fish

Aromatic amines and dyes  Effect exerted mainly in the liver  ß naphthylamine – bladder cancer Naturally occurring carcinogens  Aflatoxin B1 : Hepatocellular Ca  Nitrosamines and amides : Gastric Ca Others  Asbestos : Mesothelioma, lung cancer, GI cancers  Vinyl chloride : Angiosarcoma of the liver  Chromium, nickel : Lung cancers  Arsenic : Skin cancers Promoters  Diethylstilbestrol : Postmenopausal : Endometrial Ca, Children exposed in utero : Vaginal Ca.  High dietary fat intake : Colon Ca  Alcohol : Ca of mouth, pharynx, larynx

RADIATION CARCINOGENESIS

Long periods of observation required, due to :  Latency of radiant energy  Cumulative effect  Additive or synergistic effect with other potential carcinogens Of 2 types:  Ionizing radiation Electromagnetic  UV rays
 UVA : 320-400nm,

 UVB** : 280-320nm,  UVC : 200-280nm : filtered by ozone layer

Ultraviolet rays
 Cutaneous Ca : BCC, SCC, Melanoma  Effects on cell :

Inhibit cell division Inactivate enzymes Induce mutations ( RAS, p53 ) Sufficient dosage : Cell death  Carcinogenicity of UVB : Formation of pyrimidine dimers in DNA. Excess sun exposure
Capacity of Nucleotide Excision Repair pathway overwhelmed

Some DNA damage unrepaired Cancer

Ionizing radiation
 Electromagnetic X rays Gamma rays  Particulate

Alpha particles ß particles Protons Neutrons  Most frequent carcinomas Leukemias Thyroid carcinomas  Intermediate risk – breast, lung, salivary glands  Resistant to radiation induced neoplasia – GIT, bone, skin


								
To top