Download CARCINOGENIC AGENTS AND THEIR CELLULAR

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CARCINOGENIC AGENTS AND THEIR CELLULAR INTERACTIONS
LEARNING OBJECTIVES
By the end of lecture the student should be able to know:
Different types of carcinogens
Mechanism of action of carcinogens
Therapeutic agents that also act as carcinogens
Skin cancer and radiation
Viral carcinogens and types
CARCINOGEN
A carcinogen is any substance or agent that, because of the way it
affects cell DNA, can cause cancer
Carcinogens may be chemical substances; physical agents, such as
asbestos dust; or biological agents, such as certain viruses and
bacteria
In the workplace, carcinogenic substances may be inhaled, absorbed
through the skin or even ingested in some cases
MECHANISM OF ACTION
initiator — mutagenic agent that damages DNA permanently.
Mechanism is rapid and irreversible
promoters — encouraging cell proliferation. Augmenting agent not
carcinogen by themselves. They do not affect the DNA directly and so
mechanism is reversible
TYPES OF CARCINOGENS
Three main types:
– Chemical
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Direct acting
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Indirect acting
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Physical (radiation)
Biological (especially virus)
CHEMICAL CARCINOGENS
Direct-acting
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Weak carcinogens
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Require no chemical transformation
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Alkylating agents
– Cyclophosphamide, chlorambucil, nitrosoureas
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Second malignancy decades later
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Acylating agents
- Acetyl-imidazole, Dimethylcarbamyl chloride
CHEMICAL CARCINOGENS
Indirect-acting
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Require metabolic conversion before they become active.
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Aromatic amines and azo dyes
• Beta-naphthylamine: Bladder CA in rubber factories
• Azo dyes used in food color
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Nitrosamines and amides
• Formed endogenously in acid environment of stomach: GI
cancer
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Aflatoxin B
• Aspergillus in grains: Hepatocellular cancer
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Polycyclic hydrocarbons: fossil fuels, active epoxides bind DNA
CHEMICAL CARCINOGENS
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DRUGS THAT ARE ALSO CARCINOGENS
Adriamycin (doxorubicin)
Androgenic steroids
Chlorambucil
Cisplatin
Cyclophosphamide
Cyclosporin A
Diethylstilbestrol
Ethylene oxide
Melphalan
Tamoxifen
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IONIZING RADIATION
Death of pioneer radiation researchers from neoplasms
High incidence of leukemia among radiologists recognized in 1940s
Osteosarcoma incidence in radium dial painters
MOLECULAR PROGRESSION
MUTATION ACCUMULATION
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SKIN CANCER
One of the most common human cancer and one of the most
preventable
~106 cases of BCC and SCC are diagnosed per year
This is more than all other types of cancer combined
Most of these will be caused by exposure to ultraviolet (UV) irradiation
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ASBESTOS
Widely used in construction, insulation, and manufacturing
Family of related fibrous silicates:
Chrysotile
Crocidolite
Causes malignant mesothelioma
Mainly occurs in pleural and peritoneal cavities
Rare in general population
RADIATION CARCINOGENESIS
Ionizing radiation: chromosome breakage, translocations and point
mutations
Types of radiation
– Ultraviolet rays of sunlight
• Melanoma, Squamous cell carcinoma, basal cell carcinoma
– X-rays
• Early developers: skin cancer
• ENT Ca with irradiation: thyroid cancer
– Nuclear fission
• Survivors of nuclear bomb: leukemia
– Radionuclides
• Miners: lung cancer
VIRAL CARCINOGENESIS
Viral infections account for an estimated one in seven human cancers
worldwide
Retroviral carcinogens:
– Only cancer causing RNA viruses
Prototype retrovirus:
– GAG (core proteins)
– POL (reverse transcriptase)
– ENV (envelope proteins)
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HUMAN T-CELL LEUKEMIA VIRUS TYPE 1
Common in Japan and Caribbean basin
Transmission: sexual, blood product, breastfeeding
CD4 T cell target for neoplastic transformation
TAX gene essential for cell proliferation
The proliferating T cells are at increased risk of mutations and genomic
instability induced also by TAX
Leukemia develops in infected person after latent period of 40-60 yrs
HTLV-1 and ATL
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DNA TUMOR VIRUSES ASSOCIATED WITH HUMAN CANCER
Human papilloma virus (HPV) and cervical cancer
Hepatitis b (HBV) and liver cancer (hepatoma)
Epstein-barr virus (EBV) and burkitt’s lymphoma
HUMAN PAPILLOMA VIRUS (HPV)
Over 70 subtypes
DNA virus with small double-stranded circular genome
Sexual transmission leading to cervical cancer
Co-factors include cigarette smoking, coexisting microbial infection,
hormonal changes
Subtypes possess varying degrees of low risk and high risk
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MECHANISM OF ACTION
Oncogenic potential related to two viral genes E6 and E7
Enhance p53 degradation causing block of apoptosis and decreased
activity of p21 cell cycle inhibitor
Also activates cyclins E and A
Thus restraints to cell proliferation is removed
LOW AND HIGH RISK HPV
HPV subtypes classified as low risk or high risk based on whether the
associated genital tract lesions are at significant risk for malignant
progression
High risk : HPV 16 and 18, cause squamous cell carcinoma of cervix
and anogenital region
Low risk: HPV 6 and 11, cause benign squamous papillomas warts
EPSTEIN BARR VIRUS (EBV)
Infects B cells and possibly epithelial cells of oropharynx
LMP1 acts as oncogene promotes B- cell survival and proliferation
Prevents apoptosis by activating BCL2
EBNA-2: activates cyclin D and src genes
Cytokine vIL-10 prevent macrophages and monocytes from activating
T cells and thus is required for EBV dependent transformation of B
cells
EPSTEIN-BARR VIRUS (EBV)
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Four cancers
– Burkitt’s lymphoma
– B-cell lymphoma in immunosupressed
– Nasopharyngeal carcinoma
– Hodgkin’s disease
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Association with Burkitt’s
– High antibody titer
– DNA clonally present in tumor cells
– EBV transforms cultured lymphocytes
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HELICOBACTER PYLORI
Increased epithelial cell proliferation in a background of chronic
inflammation
Gastric infection linked to gastric lymphomas and adenocarcinomas
Detection of H pylori in majority of cases of gastric lymphomas
Antibiotic treatment results in gastric lymphoma regression in most
cases
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HEPATITIS B AND C VIRUS
Cause hepatocellular carcinoma
HBV & HCV genomes do not encode any viral oncoproteins
Chronic heptaocellular injury leads to compensatory proliferation of
hepatocytes
Mediators such as reactive oxygen species are released which are
genotoxic and mutagenic
NF-kB pathway blocks apoptosis
Chromosome rearrangement and deletion occurs
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REFERENCES
Pathologic basis of disease
Robbins & Cotran
8th edition
Ch. 7, Neoplasia
Pgs. # 309-316
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