Chemical Carcinogenesis Flashcards
Abnormal cell differentiation and growth
Cancer/Neoplasm
In all types of cancer, some of the body’s cells begin to ______ without stopping and ______ into surrounding tissues
Divide; spread
1 cm tumor (~1g) = _______ cancer cells
1 billion (10⁹)
1 kg = ______ cancer cells
10¹² (1 trillion)
Characteristics of Cancer:
- __________ in growth signals
- __________ to antigrowth signals
- __________ of apoptosis
- Limitless __________ potential
- Tissue _________ and _________
- Sustained ___________
- Self-sufficiency
- Insensitivity
- Evasion
- Replicative
- Invasion; metastasis
- Angiogenesis
One of the characteristics of cancer is the spread outside of its original location. What is that term?
Metastasis
In cancer, there is formation of new blood vessels. What is that term?
Angiogenesis
Reversible stage of carcinogenesis by stopping the tumor promoter of the one responsible of spreading the damaged cells but only until initiation
Promotion
Triggered by tumor promoter
Initiated cell
The first stage of carcinogenesis
Initiation
Irreversible stages of carcinogenesis
Initiation and progression
Abnormal tissue growth in mucosal surface of colon (most common), ear canal, cervix.
Benign Tumors / Polyp
Malignant tumor of epithelial origin
Carcinoma
Most common. Cancer of the skin or organ lining e.g., liver or kidneys
Carcinoma
Malignant tumor of mesenchymal origin
Sarcoma
Cancer of connective tissue e.g., bones, muscles, cartilage, & blood vessels
Sarcoma
Bone marrow cancer
Leukemia
Cancer of the immune system. There is a presence of Reed-Sternberg (giant cells)
Hodgkin or Non-Hodgkin Lymphoma, Multiple Myeloma
Agents that causes change in the gene structure. May result from misread DNA through transitions and transversions, frame-shifting or broken DNA stands
Mutagens
Example of mutagen
Genotoxic/ DNA-reactive Carcinogens
Carcinogen: Active parent. There is no metabolism
Direct-acting
Carcinogen: Metabolite. There is a presence of metabolism
Indirect-acting
Damages by alkylating electrophiles
Direct-acting Genotoxic Carcinogens
The development of cancer following exposure to chemical carcinogens is a relatively _____ event because of a cell’s ability to recognize and _____ DNA.
rare; repair
The DNA region containing the adduct is removed and a new patch of DNA is synthesized, using the opposite intact strand as a template.
Cut-and-Patch by Pol 1
In Cut-and-Patch by pol 1 DNA repair mechanism, the new DNA segment is then ______ into the DNA molecule in place of the defective one. To be effective in restoring a cell to normal, _______________ must occur prior to ____________.
spliced; repair of DNA; cell division
Typically repairs chemically modified nucleobases
Base Excision or Mismatch Repair of Single-base Mispairs
Components of Base Excision or Mismatch Repair of Single-base Mispairs
DNA Glycosylase and Apurinic endonucleases
Removes altered base; pol I fills the gap
DNA Glycosylase
Cut DNA near apurinic sites (the cut is then extended by exonucleases, and the resulting gap is repaired by DNA polymerase and ligase)
Apurinic endonucleases
Component of photoreactivation repair
Photolyase
Binds thymine-thymine cyclobutane dimer → Individual pyrimidine bases
Photolyase
The double-strand break on one chromosome is repaired using the information on the homologous, intact chromosome. The same chromosome was used.
Homologous recombination
The predominant mechanism for double-stranded DNA repair
Nonhomologous End-joining Repair of DNA
Disadvantage of Nonhomologous End-joining Repair of DNA: Several base pairs are ______ at the joining point. This type of deletion may produce a possible ______________________________
lost; mutagenic coding change
What are the 6 DNA Repair Mechanisms?
Cut-and-Patch by pol 1, Nick Translation by pol 1, Base Excision or Mismatch Repair of Single-base Mispairs, Photoreactivation Repair, Homologous Recombination, and Nonhomologous End-joining Repair of DNA
Chemical mutagens
Polycyclic Aromatic Hydrocarbons (PAHs), Alkylating agents (electrophilic), Aromatic amines and amides, and Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT)
Classify the chemical mutagen: Benzopyrene in charcoal-broiled foods, tobacco, diesel exhaust
Polycyclic Aromatic Hydrocarbons (PAHs)
Classify the chemical mutagen: nitrosamines and alkyl sulfates
Alkylating agents (Electrophilic)
Classify the chemical mutagen: aflatoxin, and cytotoxic alkylating agents
Alkylating agents (electrophilic)
Classify the chemical mutagen: Dyes
Aromatic amines and amides
Physical mutagen found from sun exposure
Non-ionizing UV radiations (UVC, UVB, and UVA)
Physical mutagens found from X and Gamma rays
Ionizing radiations
This is contraindicated for vitiligo and psoriasis patients because this compound is a photosensitizing agent, creating higher risk for cancer
Furocoumarin (Psoralen)
It is a non-ionizing UV radiation that does not cross the ozone layer. It has a shorter wave
UVC
It is a non-ionizing UV radiation that causes tanning, burning, and skin cancer. It has longer waves than UVC. It penetrates until the epidermis layer of the skin.
UVB
It is a non-ionizing UV radiation that causes DNA damage, skin aging and skin cancer. It penetrates until the dermis layer of the skin because of its longer waves
UVA
Cancer in the glands, one of the most common
Adenocarcinoma
This toxin came from improper drying of nuts, and it is very hepatotoxic
Aflatoxin
Fragments of DNA are replaced
Nick Translation by pol 1
Mechanisms of actions of non-genotoxic carcinogens
sustained cytotoxicity, receptor mediated, hormonal perturbation, induction of oxidative stress, modulation/alteration of methylation status, and immunosuppression
Sustained toxicity leads to:
spontaneous DNA mutations, allowing it to mutate and accumulate. It has persistent regenerative growth
Example of non-genotoxic carcinogens that functions via sustained toxicity
chloroform
Receptors in receptor-mediated mechanisms of action of non-genotoxic carcinogens
Constitutive Androstane Receptor (CAR), Peroxisome proliferator-activated receptor alpha (PPARα), and Aryl hydrocarbon receptor (AhR)
It is a P450-related receptor. Its inducers would result in liver hyperplasia (preneoplastic focal lesion)
Constitutive Androstane Receptor (CAR)
example of inducer of Constitutive Androstane Receptor (CAR) and CYP2B
Phenobarbital
binding to this receptor leads to fatty acid oxidation, usually seen in lipids or fatty components
Peroxisome proliferator-activated receptor alpha (PPARα)
example of non-genotoxic carcinogens that bind to Peroxisome proliferator–activated receptor alpha (PPARα)
Fibrates
Effect of fibrates
lower cholesterol
this receptor leads to immunotoxicity
Aryl hydrocarbon receptor (AhR)
Can be found in carbon-less copy paper, contaminated food (fishes - remove skin or fats of the contaminated food since it accumulates in the skin and fatty areas.)
polychlorinated biphenyls
non-genotoxic carcinogens that function via hormonal perturbation
biogenic amines, steroid hormones, tamoxifen, and peptide hormones
Examples of non-genotoxic carcinogens under steroid hormones
Phytoestrogens (Bisphenol A), Diethylstilbestrol
morning after pill that can cause vaginal/uterine cancers and cervical cancers (may also be inherited by their daughters)
Diethylstilbestrol
induce decrease in T3/ T4 levels and/ or increase in TSH levels
peptide hormones
Chemicals that function via oxidative stress
ROS formers [superoxide anion (O2-), hydroperoxyl radical (HO2), hydrogen peroxide (H2O2 ), and the hydroxyl radical (OH)]: Ethanol, Lindane, Dieldrin, Acrylonitrile
This causes modulation/ Alteration of methylation status
choline deficiency
this methylation status is negative, promoting tumor regenesis; associated with/ mutation rates (oncogenes are hypomethylated)
hypomethylation
this methylation status can be reversed
hypermethylation
these are examples of non-genotoxic carcinogens that function via immunosuppression
Phthalates, atrazine
These inorganic carcinogens create carcinogenic manifestations that vary and include increased risk for skin, lung, and liver tumors
Metals (As, Be, Cd, Cr, Ni, Pb)
These metals increase lung/respiratory tumors
Be, Ni, Cr
Metal that causes kidney tumors
Cd
Metal that causes mouth, larynx, esophagus tumors
As
Other factors affecting carcinogenesis
Genes, Viral infection (Oncogenic viruses), and Environmental factors
genetic factors affecting carcinogenesis
genetic polymorphism and mutations
Gene has more than one allele
genetic polymorphism
This gene encodes a protein capable of transforming cells in culture or inducing cancer in animals; involved in cell signaling cascades. Once it is altered, it will cause cancer (pro-cancer)
proto-oncogenes
Retinoblastoma Gene (Rb1), Breast CA Gene 1 (BRCA1), Wilms Tumor Gene (WT-1), p16, and p53 are classified as:
Tumor-suppressor genes
T/F: Risk of breast cancer, may be passed on if not manifested to the person
True
This tumor suppressor gene is associated with retinoblastoma (disorder) and small-cell lung carcinoma
Rb1
This tumor suppressor gene is associated with Li-Fraumeni syndrome (disorder) and breast, colon, lung cancers
p53
This tumor suppressor gene is associated with breast carcinoma
BRCA1
This tumor suppressor gene is associated with Wilms tumor (disorder) and lung cancer
WT-1
This tumor suppressor gene is associated with melanoma
p16
Oncogenic viruses
Retroviruses and the 7 DNA Tumor Viruses
A retrovirus that leads to sarcoma, which is found in chickens
Rous Sarcoma Virus (RSV)
What are the 7 DNA Tumor Viruses?
Simian virus 40 (SV40), Polyoma virus, Hepatitis B virus, Human Papilloma viruses (HPV), adenoviruses, herpes viruses, and Poxviruses
This oncogenic virus attacks the liver, and is transmissible
Hepatitis B Virus
This oncogenic virus is involved in brain and bone cancer induction
Simian virus 40 (SV40)
This oncogenic virus is involved in genital warts
Human Papilloma viruses (HPV)
In vitro assessment of carcinogenicity of chemicals
Ames test, mouse lymphoma assay, chinese hamster ovary (CHO) test, syrian hamster embryo (SHE), and C3H/10T½ Cell Line Transformation Assay
In vitro test that uses Salmonella typhimurium strains, deficient in DNA repair and unable to synthesize histidine, are treated with several doses of the test compound.
Ames Test
Ames Test: In the presence of a mutagenic chemical, the defective histidine gene can be mutated back to ____________ (back mutation), resulting in a restoration of bacterial growth in medium lacking histidine
Functional state
Used to determine whether a chemical is capable of inducing mutation in eukaryotic cells
mouse lymphoma assay
mouse lymphoma assay: The ability of cells in culture to acquire resistance to _________ (result of forward mutation at the thymidine kinase locus) is quantified
trifluorothymidine
Commonly used to assess the potential mutagenicity of chemicals with the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) gene as the endpoint
Chinese Hamster Ovary (CHO) Test
Diploid cell transformation assay, measures carcinogenic potential of xenobiotics by assessing transformed colonies based on morphological criterion
Syrian Hamster Embryo (SHE)
Originally derived from fibroblasts taken from the prostate of a C3H mouse embryo
C3H/10T½ Cell Line
Most frequently used endpoint (after exposure to carcinogen) in C3H/10T½ Cell Line Transformation Assay
Morphological transformation of mammalian cell fibroblasts in culture
What are the In vivo tests for assessing carcinogenicity of chemicals?
Transgenic rodent mutation assay systems and Chronic (Two Year) Bioassay Two-year
Advantages of In vivo over the In vitro test systems
Take into account whole animal processes such as ADME of chemicals and their metabolites.
An In vivo test primarily performed in rats and is based on the X-linked phosphatidylinositol N-aceylglucosaminyltransferase subunit A
Pig-a gene mutation assay
__________ is involved in the production of glycosylphosphatidylinositol (GPI) anchor proteins on the cell surface.
Pig-a gene
Pig-a mutation assay: the assay is optimized for measuring the Pig-a mutant phenotype in peripheral blood erythrocytes by quantification of ___________ reticulocytes and red blood vessels
CD59-negative
During the study, food consumption and bodyweight gain are monitored and the animals are observed clinically on a regular basis; at necropsy, the tumor number, location, and diagnosis for each animal are thoroughly assessed
Chronic (Two Year) Bioassay
Chronic (Two Year) Bioassay Two-year procedure: 2-3 dose levels of a test chemical (up to the maximum tolerated dose) and a vehicle control are administered to 50 males and 50 females (mice and rats), beginning at _________ of age, continuing throughout their lifespan
8 weeks
A carcinogenic factor associated with lifestyle, a chemical whose neoplasms can be found on the esophagus, liver, oropharynx and larynx
Alcohol beverage
A carcinogenic factor associated with lifestyle, a chemical whose neoplasms can be found on the liver
Clue: this is from the improper drying of peanuts
aflatoxins
A carcinogenic factor associated with lifestyle, a chemical whose neoplasms can be found on the mouth
betel chewing
A carcinogenic factor associated with lifestyle, a chemical whose neoplasms can be found on the breast, colon, endometrium, and gallbladder
dietary intake (fat, protein, calories)
A carcinogenic factor associated with lifestyle, a chemical whose neoplasms can be found on the mouth, pharynx, larynx, lung, esophagus, and bladder
tobacco smoking
Occupational human carcinogens that causes neoplasms on the bronchus
Asbestos, arsenic, alkylating agents, chromium and chromates, nickel, polynuclear aromatic hydrocarbons, beryllium, cadmium, and formaldehyde
Occupational human carcinogens that causes neoplasms on the bone marrow
Benzene, and ethylene oxide
Occupational human carcinogens that causes neoplasms on the nasal sinus
chromium and chromates, nickel, wood dust, and formaldehyde
Occupational human carcinogens that causes neoplasms on the liver
arsenic, vinyl chloride monomer, and polychlorinated biphenyls
Occupational human carcinogens that causes neoplasms on the scrotum
polynuclear aromatic hydrocarbons
Occupational human carcinogens that causes neoplasms on the peritoneum
asbestos
Occupational human carcinogens that causes neoplasms on the skin
arsenic, and polynuclear aromatic hydrocarbons
Occupational human carcinogens that causes neoplasms on the urinary bladder
benzidine and B-naphthylamine
A human carcinogenic chemical associated with medical therapy and diagnosis, whose neoplasms are associated with the bladder and leukemia
alkylating agents (cyclophosphamide, melphalan)
A human carcinogenic chemical associated with medical therapy and diagnosis, whose neoplasms are associated with the lymphoma, reticulum cell sarcoma, skin, Kaposi sarcoma
Azathioprine
A human carcinogenic chemical associated with medical therapy and diagnosis, whose neoplasms are associated with leukemia
chloramphenicol
A human carcinogenic chemical associated with medical therapy and diagnosis, whose neoplasms are associated with the vagina (clear cell carcinoma)
Diethylstilbestrol
A human carcinogenic chemical associated with medical therapy and diagnosis, whose neoplasms are associated with the liver cell adenoma, endometrium, skin
estrogens
A human carcinogenic chemical associated with medical therapy and diagnosis, whose neoplasms are associated with the renal pelvis (carcinoma)
phenacetin
A human carcinogenic chemical associated with medical therapy and diagnosis, whose neoplasms are associated with the lymphoma and neuroblastoma
phenytoin
A human carcinogenic chemical associated with medical therapy and diagnosis, whose neoplasms are associated with the liver (angiosarcoma)
thorotrast
is a multistage process that involves initial mutational events followed by changes in gene expression leading to the selected clonal proliferation of the precancerous cell.
Cancer
Who is the prettiest poison you’ve ever seen?
Andre Martin E. Marapao
