CANCER Flashcards
Is a collection of related diseases
cancer
In ALL type of cancer, some of the body’s cells begin to divide without stopping and spread into surrounding tissues
cancer
Characteristics of cancer
- Self- sufficiency in growth signals
- Sustained angiogenesis
- Tissue invasion and metastasis
- Limitless replicative potential
- Evasion of apoptosis
- Insensitivity to antigrowth signals
Features of Genotoxic Carninogens
- Mutagenic
- Can be complete carcinogens
- Tumorigenicity is dose responsive
- No theoretical threshold
Features of Non-genotoxic carcinogens
- Nonmutagenic
-Threshold, reversible - Tumorigenicity is dose responsive
- May function at tumor promotion stage
- No direct DNA damage
- Species, stain, tissue specificity
Stages of carcinogenesis
initiation, promotion, and progression
Once a ________ is formed, additional intracellular and extracellular changes occur in the process of the development of a malignant cancer
neoplasm
Under initiation stage:
- DNA modification
- Mutation
- Genotoxic
- One cell division necessary to lock-in mutation
- Modification is not enough to produce cancer
- Non-reversible
- Single treatment can induce mutation
Once initiated cells are formed:
can remain in static non-dividing state through influences by growth control either via normal surrounding cells or through endocrine influence
Once initiated cells are formed:
may posses mutations incompatible with viability or normal function and be deleted through apoptotic mechanisms
Once initiated cells are formed:
the cell, through stimuli such as intrinsic factors or from chemical exposure, may undergo cell division resulting in the proliferation of the initiated cell
First step of carcinogenesis
initiation
Caused by irreversible genetic changes which predispose susceptible normal cells to malign evolution and immortality
initiation
the initiated cell is not a neoplastic cell (t or f)
T - has taken its first step towards this state
Under Promotion:
- No direct DNA modification
- non-genotoxic
- no direct mutation
- multiple cell divisions necessary
- clonal expansion of the initiated cell population
- increase in cell proliferation where decrease in cell death (apoptosis)
- reversible
- multiple treatments (prolonged treatment) necessary
- threshold
(under promotion) Involves the _________________ of initiated cells to produce a preneoplastic lesion
Selective clonal expansion
(under promotion) ______________ is a dose-dependent and _______________ process; with removal of the promotional agent, focal cells cease proliferation and may return to single initiated cells.
Tumor promotion; reversible
(under promotion) Carcinogens that function at the tumor promotion stage in general are organ specific. For example, phenobarbital functions at the tumor promotion stage selectively in _________
Liver
(under promotion) exogenous and endogenous agents that function at this stage are frequently referred to as __________ , which are not mutagenic and generally are not able to induce tumors by themselves.
tumor promoters
Under progression:
- DNA modification
- Genotoxic event
- Mutation chromosome disarrangement
- Changes from preneoplasia to neoplasia benign/malignant
- Irreversible
- Number of treatments needed with compound unknown may require only single treatment
Involves conversion of preneoplastic lesion into a neoplasm
Progression
Additional genotoxic events may further DNA damage including chromosomal damage such as aberrations and translocations.
Progression
Cells accumulate mutations and epigenetic changes that cause cells to lose normal growth control
Neoplastic state
Progression is irreversible, whether the formed neoplasm is benign or malignant, and autonomous growth and/or lack of growth control is achieved (t or f)
T
Can occur from spontaneous karyotypic changes that occur in mitotically active initiated cells during promotion
Spontaneous progression
Hallmarks of progression
accumulation of nonrandom chromosomal aberrations and karyotypic instability
Characteristics of a Neoplasm as it progresses into malignant state
- sustaining cell proliferation
- resisting cell death (apoptosis)
- inducing angiogenesis
- enabling replicative immortality
- activating invasion and metastasis
- evading growth suppressors
- reprogramming of energy metabolism
- evading immune destruction
Is a multistage, multistep process that involves the ultimate release of the neoplastic cells from normal growth control processes and creating a tumor microenvironment
Formation of neoplasm
Normal stromal and inflammatory cells
contributes to the growth and development of neoplasm
Interacts with nuclear DNA of a target cell producing DNA damage that, if not repaired, is inherited in subsequent daughter cells
Genotoxic compounds
DNA-reactive carcinogens can be further subdivided according to:
Active in their parent form (direct-acting) or those that require metabolic activation (indirect-acting)
Relative carcinogenic strength depends in part of the relative rates of interactions between the chemical and genomic DNA, as well as competing reactions with chemical and other cellular nucleophiles
Direct-acting
Chemical stability, transport, and membrane permeability, determine the carcinogenic activity of the chemical. ______________are typically carcinogenic at multiple sites and in all species examined
Direct-acting
Majority of the DNA-reactive carcinogens are found as parent compounds, or procarcinogens that require subsequent metabolism to be carcinogenic
Indirect-acting
Procarcinogen
Parent compound
Proximate carcinogen
Intermediate
Ultimate carcinogen
Final
Most likely the chemical species that result in mutation and neoplastic transformation
Ultimate form
Usually produce their neoplastic effects at the target tissue where the metabolic activation of the chemical occurs
Indirect-acting genotoxic carcinogens
effects of mutation depend on when in the cell cycle the DNA adducts are formed, where the adducts are formed, and the type of repair process used in the response to the damage
Mutagenesis
Result from the misread DNA through transitions and transversions, frame-shifting or broken DNA strands
Mutagenesis
Most chemical carcinogens require ___________ to exert a carcinogenic effect (damage by alkylating electrophiles)
Metabolic activation
The ultimate carcinogenic forms of these chemical are frequently ______________ that can readily form covalent adducts with nucleophilic targets (damage by alkylating electrophiles)
strong electrophiles
_________________ display a greater range of nucleophilic target (attack weak and strong nucleophiles) ________________ whereas are only capable of alkylating strong nucleophiles (atoms in amino acids)
The stronger electrophiles; weak electrophiles
Relative rates or persistence of particular DNA adducts may bee an important determinant of carcinogenicity
DNA repair
DNA region containing the adduct is removed and a new patch of DNA is synthesized, using the opposite intact strand as a template
DNA repair
The new DNA segment is then spliced into the DNA molecule in place of the defective one. To be effective in restoring a cell to normal, repair of DNA must occur prior to cell division
DNA repair
Exposure to chemicals can increase the probability of acquiring mutations that ultimately lead to cancer development (t or f)
T
DNA repair mechanisms
- Mismatch repair of single-base mispairs
- Excision repair
- Homologous Recombination and Nonhomologous End-joining repair DNA
may occur through normal cellular DNA replication mistakes such as point mutations, a chance in a single base pair in the DNA sequence, or a small insertion or deletion or a frame shift mutation of some modest size (under mismatch repair of single-base mispairs)
Spontaneous mutation
Is a fairly common occurrence and spontaneous event in mammals, and results in the formation of apurinic sites (under mismatch repair of single-base mispairs)
Depurination
all mammalian cells prosses __________ that function to cut DNA near apurinic sites. Cut is extended by exonucleases, and the resulting gap repaired by DNA polymerases and ligase
apurinic endonucleases
DNA regions containing chemically modified bases, or DNA chemical adducts, are typically repaired by ____________ processes
Excision repair
Proteins that slide along the surface of a double-stranded DNA molecule recognize the irregularities in the shape of the double helix and affect the repair of the lesion
Excision repair
A cell that has double-stranded breaks can be repaired by _________________
joining the free DNA ends
The joining of broken ends from different chromosomes, however will lead to the _________________ pieces from one chromosome to another
translocation of DNA
Have the potential to enable abnormal cell growth by placing the proto-oncogene next to, and, therefore, under the control of another gene promoter
Translocations
Is one of two mechanisms responsible for the repair of double -strand break on one chromosome is repaired using the information on the homologous, intact chromosome
Homologous recombination
The predominant mechanism for double-stranded DNA repair in multicellular organisms is non-homologous repair and involves
rejoining the ends of the two DNA molecules
Although the process yields a continuous double-stranded molecules, ___________________ at the joining point. This type of deletion may _______________________
several base pairs are lost; produce a possible mutagenic coding change
Classes of Genotoxic Carcinogens
Polyaromatic Hydrocarbons (PAH), Alkylating agents, Aromatic amines and amides
Are found at high levels in charcoal-broiled foods, cigarettes, smoke, and in diesel exhaust
Polyaromatic Hydrocarbons (PAH)
Readily reacts with DNA at more than 12 sites. The N7 position of guanine and the N3 position of adenine are the most reactive sites for alkylating chemicals to bind to DNA
Alkylating agents
Encompass a class of chemical with varied structures. Exposure to these chemicals was through use in the dye industry. Today, exposure still occurs through cigarette smoke and environmental sources
Aromatic amines and amides
yield hydroxylated metabolites that are often associated with adduct formation in proteins and DNA and produce liver and bladder carcinogenicity
Phase I cytochrome P450-mediated reactions
Induced by non-genotoxic carcinogens are often in tissues where a significant incidence of background, spontaneous tumors is seen in the animal model
Organ and tissue targets
___________ to relatively high levels of chemicals is usually necessary for tumor production by this mechanism
Prolonged exposure
Proposed modes of action for selected non-genotoxic chemical carcinogens
- Cytotoxicity
- a2U-Globulin binding
- Receptor mediated
> CAR
> PPARa
> AHR - Hormonal
- Altered Methylation
- Immunosuppression
- Oxidative stress inducers
Cytotoxicity
- Chloroform
- Melamine
a2U-Globulin binding
- D-Limonene
- 1,4-Dichlorobenzene
CAR
- Phenobarbital
- Toxaphene
PPARa
- Trichloroethylene
- Perchloroethylene
- Diethylhexylphthalate
- Fibrates (e.g. clofibrate)
Hormonal
- Biogenic amines
- Phenobarbital
- Steroid and peptide hormones
- Diethylstilbestrol (DES)
- Phytoestrogens (Bisphenols-A)
- Tamoxifen
Altered methylation
- Phenobarbital
- Choline deficiency
- Diethanolamine
Immunosuppression
- Atrazine
- Bisphenol A
- Phthalates
Oxidative stress inducers
- Ethanol
- TCDD
- Lindane
- Dieldrin
- Acrylonitrile
Chemicals functions through this mechanism produce sustained cell death that is accompanied by persistent regenerative growth, resulting in the potential for the acquisition of spontaneous DNA mutations and allowing mutated cells to accumulate and proliferate
Cytotoxicity
This process gives rise to preneoplastic focal lesions that upon further expansion can lead to tumor formation
Cytotoxicity
Induction of cytotoxicity may be observed with many carcinogens both genotoxic and non-genotoxic when high toxic exposure occur (t or f)
T
Induction of cytotoxicity with compensatory hyperplasia may contribute to the observed tumorigenicity of many carcinogenic chemicals at high-dose levels (t or f)
T
Receptor mediated
CAR, PPARa, AHR
Is a commonly studied non-DNA-reactive compound that is known to cause tumors by a non-genotoxic mechanism involving liver hyperplasia
Phenobarbital
Induction of ___________ is mediated by activation of the constitutive androstane receptor (CAR), a member of the nuclear receptor family.
Cyp2b
Other CAR-dependent phenobarbital responses that are critical for tumor formation include
- increased cell proliferation
- inhibition of apoptosis
- inhibition of gap junctional communication
- hypertrophy
- development of preneoplastic focal lesions in the liver
CAR can be activated by both direct ligand binding and ligand-independent (indirect) mechanisms (t or f)
T
Phenobarbital activates CAR indirectly by inhibiting __________ binding to EGF and preventing downstream events leading to increased gene expression
epidermal growth factor receptor (EGFR)
A wide array of chemicals increase the number and volume of peroxisomes in the cytoplasm of cells
PPARa (peroxisome proliferator activator receptor a)
Peroxisome proliferators include
- lipid lowering fibrate drugs
- herbicides
- chlorinated solvents
- per fluorinated compounds
- plasticizers
- natural products
Lipid lowering fibrate drugs
ciprofibrate, clofibrate
Herbicides
2,4- dichlorophenoxyacetic acid
Chlorinated solvents
trichloroethylene and perchloroethylene
Perfluorinated compounds
perfluorooctane sulfonate and perfluorooctanoic acid
Plasticizers
diethylhexylphthalate and other phthalates
PPARa is highly expressed in cells that have active fatty acid oxidation capacity (site)
hepatocytes, cardiomyocytes, enterocytes
Plays a central role in lipid metabolism and acts as a transcription factor to modulate gene expression following ligand activation
PPARa
TCDD and selected polychlorinated and brominated-biphenyl (PCBs and PBBs0 compounds bind to the AhR, the ligand bound AHR translocate to the nucleus, dimerizes with the Ah receptor nuclear transporter (ARNT) and binds to aryl hydrocarbon response elements
Aryl Hydrocarbon Receptor activators
AREs are also known as
dioxin repsonse elements (DRE) and xenobiotic response elements (XRE)
AhR-ARNT-dependent genes
- cytochrome P450 family members
- NAD(P)H: quinone oxidoreductase
- cytosolic aldehyde dehydrogenase 3
- UDP-glucuronosyltransferase
- glutathione transferase
Hormonally active chemicals include _______________________ that produce tissue-specific changes through interaction with a receptor
steroids, peptide hormones
Induce cell proliferation at their target organs, which may lead to tumor development when the mechanisms of hormonal control are disrupted
Trophic hormones
Hormonal mode of action
- estrogenic agents
- thyroid hormone
Can induce tumors in estrogen-dependent tissues
Estrogen and estrogen-mimetic chemicals
Individuals with higher circulating estrogen levels and those with exposure to the potent estrogenic chemical diethylstilbestrol (DES) are at increased risk for cancer development (t or f)
T
DES has been causally associated with the higher incidence of
adenocarcinomas of the vagina and cervix in daughters of women treated with the hormone during pregnancy
Mechanism of DES
induce changes in the cell cycle and microtubule function, which may lead to an abnormal number of chromosomes in a cell
Estrogenic substances in plants (phytoestrogens)
genistein, daidzein, glycitein, equol, and their metabolites found in soy products, and various lignan derivatives
A ________ of thyroid hormone concentrations (T4 and /or T3) and _______ thyroid-stimulating hormone (TSH) have been shown to induce neoplasia in the rodent thyroid
reduction; increased
____ Increases proliferative activity in the thyroid. After chronic treatment chemical-induced increased in ____ lead to follicular cell hypertrophy, hyperplasia, and eventually neoplasia
TSH
_______ of the five position of cytosine (5-methylcytosine; 5mC) is a naturally occurring modification to DNA in higher eukaryotes that influence gene expression. Under normal conditions, DNA is methylated symmetrically on both strands
Post-DNA synthetic methylation
Immediately following DNA replication, the newly synthesized double-stranded DNA contains ____________________
Hemimethylated sites
Signals DNA maintenance methylases to transfer methyl groups from S-adenosylmethionine to cytosine residues on the new DNA strand
Hemimethylated sites
The degree of methylation within a gene __________ correlates with the expression of that gene
inversely
hypermethylation of genes is associated with _________, whereas hypomethylation results in ________________
gene silencing; enhanced expression of genes
During carcinogenesis, both hypomethylation and hypermethylation are observed (t or f)
T
Can also modify DNA methylation through interfering with the ability of methyltransferases to interact with DNA resulting in changes in DNA methylation profiles.
Reactive oxygen species
______________ of CpG sites allows the expression of normally quiescent genes. Also, the abnormal methylation pattern observed in cells transformed by chemical oxidants may contribute to an overall aberrant gene expression and promote the tumor process
Hypomethylation
Are small noncoding RNAs usually consisting of 21 to 25 nucleotides, that typically regulate gene expression through repression or degradation of targeted messenger RNAs (mRNAs) controlling gene involved in multiple cellular processes
MicroRNAs
Has been implicated in the development of initiation, promotion, and progression of cancer
dysregulation of mRNAs
Many _________ functions as anti tumor agents ( or tumor suppressor genes ), others behave as oncogenes, commonly known as onco _______
miRNAs
May potentially be used as indicators of the carcinogenic process, biomarkers for carcinogen exposure, and for the identification of potential chemical carcinogen
miRNA profiles and miRNAs specific to carcinogen exposure
Is an essential host protection mechanism that inhibits carcinogenesis by identifying and removing early preneoplastic cells from the body and to maintain cellular homeostasis
Cancer immune surveillance
is one hallmark of cancer
Evading immune recognition and destruction
Has also been proposed as a possible mode of action of non-genotoxic carcinogens
Immune suppression
can destroy immune cells leading to immune suppression
Prolonged inflammation
Immunosuppression is suggested to be involved in the carcinogenesis of environmental immune disruptors such as
bisphenol A, atrazine, phthalates, and PBDEs
includes superoxide anion (O2), hydroperoxyl radical (HO2), hydrogen peroxide (H2O2), the the hydroxyl radical (OH) produced from both endogenous and exogenous sources which are typically counterbalanced by antioxidants
Reactive oxygen species
Endogenous sources of ROS includes:
oxidative phosphorylation, P450 metabolism, peroxisomes, and inflammatory cell activation
An increase is H2O2 production often accompanies exposure to chemicals that stimulate the number and activity of peroxisomes (t or f)
T
left unbalanced by antioxidants can
result in damage to cellular macromolecules
ROS
can produce single or double-stranded
DNA breaks, purine, pyrimidine, or deoxyribose modifications, and DNA cross-links
ROS
can result in either arrest or induce
transcription, induce signal transduction pathways, replication errors, and genomic instability: these events are potentially involved in carcinogenesis.
Persistent DNA Damage
Reasons why mitochondrial genome is susceptible to oxidative base damage
- close proximity to the electron transport system, a major source of reactive oxygen species
- lack of mitochondrial DNA protection by histones
- limited DNA repair capacity in the mitochondria
High concentrations of reactive oxygen species can initiate apoptosis, whereas low levels influence signal transduction pathways and alter gene expression. (t or f)
T
Xenobiotics alter gene expression through activation of:
- cAMP-mediated cascades
- calcium-calmodulin pathways
- transcription factors such as AP-1, Nrf2, Hif1, and NF-κB
- mitogen-activated protein (MAP) kinases
- extracellular signal-regulated kinases [ERK]
- c-Jun N-terminal kinases [JNK], and the p38 kinases)
Cells within an organism communicate variously including through _________, which are aggregates of connexin proteins that form a conduit between two adjacent cells
gap junctions
communication is important in the regulation of cell growth and cell death, in part, through the ability to exchange small molecules (<1 kDa) between cells
Gap junctional intercellular
Inorganic carcinogens
Metals: arsenic, beryllium, cadmium, chromium, nickel, and lead.
Modifiers of Chemical Carcinogenic Effects: have a significant impact on the way in which individuals and/or organisms respond to carcinogen exposure
Genetic and environmental factors
As with most genes, enzymes that metabolize carcinogens are expressed in a ________ manner, and the enzymatic profile can vary with tissue or cell type or display differential localization within cells.
tissue-specific
Polymorphisms in Carcinogen Metabolism and DNA Repair: where a gene has more than one allele arise from human genetic variability
Genetic polymorphism
Base variations occurred approximately once in every ________base pairs
1000
is a variant in DNA sequence found in greater than 1% of the population
single nucleotide polymorphism (SNP)
encode a wide array of proteins that function to control cell growth and proliferation
Proto-oncogenes and tumor-suppressor genes
Proto-oncogenes
- dominant
- Broad tissue specificity for cancer development
- germline inheritance rarely involved in cancer
developmen - Analogous to certain viral oncogenes
- Somatic mutations activated during all stages of carcinogenesis
Oncogenes
- dominant
- broadspecificity for cancer development
- Germline inheritance rarely involved in cancer
development - No known analogues in oncogenic viruses
- Somatic mutations activated during all stages of carcinogenesis
Tumor suppressor genes
- Recessive
- Considerable tissue specificity for cancer development
- Germline inheritance frequently involved in cancer development
- No known analogues in oncogenic viruses
- Germline mutations may initiate, but mutation to neoplasia occurs only during progression stage
RSV can produce sarcomas
Rous sarcoma virus
The genome of RSV and other retroviruses consists of:
two identical copies of mRNA, which is then reverse transcribed into DNA and incorporated into the host-cell genome
Oncogenic transforming viruses such as RSV contain the_______, a gene required for cancer induction.
v-src gene
_________ contains a gene closely related to v-src in RSV
Normal cells
This discovery highlighted that cancer may be induced by the action of normal, or nearly normal, genes. (T or F)
T
Six major classes of DNA tumor viruses have been identified:
- simian virus 40 SV40
- polyoma virus
- hepatitis B virus
- papilloma viruses
- adenoviruses
- herpes viruses
- poxviruses
Retroviral oncogenes are derived from normal cellular genes and have no functions for the virus (t or f)
T
encodes a protein that is capable of transforming cells in culture or inducing cancer in animals
Oncogene
the majority appear to have been derived from normal genes and are involved in cell signaling cascades.
proto-oncogenes
Activation arises through mutational events occurring within proto-oncogenes
Proto-oncogenes
In contrast to oncogenes, the proteins encoded by most tumor- suppressor genes act as inhibitors of cell proliferation or cell survival
Tumor-suppressor genes
Prototype tumor-suppressor gene
Rb gene
Loss or mutational inactivation of Rb contributes to the development of many human cancers (t or f)
T
In its unphosphorylated form, Rb binds to the ___________ preventing E2F-mediated transcriptional activation of several genes whose products are required for DNA synthesis.
E2 factor (E2F) transcription factor
When Rb becomes phosphorylated during late ______ and dissociates from E2F, E2F induces synthesis of DNA replication enzymes resulting in a commitment into the cell cycle
G1
Tumor suppressors
- Rb1
- p53
- BRCA1
- WT-1
- p16
Rb1 disorder
Retinoblastoma
Rb1 neoplasm
Small-cell lung carcinoma
p53 disorder
Li-Fraumeni syndrome
p53 neoplasm
Breast, colon, lung cancers
BRCA1 disorder
Unknown
BRCA1 neoplasm
Breast carcinoma
WT-1 disorder
Wilms tumor
WT-1 neoplasm
Lung cancer
p16 disorder
Unknown
p16 neoplasm
Melanoma
is a tumor-suppressor that is essential for
checkpoint control and arrests the cell cycle in cells with damaged DNA in G1
p53
Cells with __________ arrest in G1 when exposed to DNA-damaging agents such as irradiation
functional p53
whereas cells lacking
functional p53 are unable to block the cell cycle. (T or f)
T
p53 is activated by a wide array of stressors including
UV light, γ-irradiation, heat, and many carcinogens
In most cells, accumulation of p53 also leads to induction of proteins that promote__________, thereby preventing proliferation of cells that are likely to accumulate multiple mutations
apoptosis
Genetic analysis of breast tumors has revealed a hereditary predisposition for breast cancer linked to…
BRCA1
Mutation of a single BRCA1 allele results in a % probability of developing breast cancer by age 50
60% probability
lead to loss of function of the BRCA1 gene,
perhaps by acting as a transcription factor through binding at a zinc finger domain. However, no mutations have been observed in sporadic breast cancers, suggesting that BRCA1 gene silencing may occur through non-mutational mechanisms
Germ-line mutations
occurs in the developing kidney at a rate of
approximately one per 10,000 children
WT-1 gene
The proteins that function as cyclin-kinase inhibitors are important in cell cycle regulation
p16
would mimic cyclin D1 overexpression, leading to Rb hyperphosphorylation and release of active E2F transcription factor
Loss of p16
is a U, J, or inverted U-shaped dose–response with low-dose exposures often resulting in beneficial rather than harmful effects
Hormesis
usually involve actions of the chemical on cellular signaling pathways that lead to changes in gene expression, resulting in enhanced detoxification and excretion of the chemical as well as preserving the cell cycle and programmed cell death
Adaptive response
A common feature of chemical carcinogens for which hormetic effects have been proposed is the formation of
ROS and induction of cytochrome P450 isoenzyme
The study of chemicals that prevent, inhibit, or slow down the process of cancer is referred to as
Chemoprevention
are typically of the duration of days to a few weeks, intermediate-term tests last from weeks up to a year, whereas chronic long-term tests usually encompass 6 months to 2 years.
Short-term tests
tests for mutagenicity were developed to identify potentially carcinogenic chemicals based on their ability to induce mutations in DNA
Short-term
Therefore, although they are usually very predictive of indirect (if a metabolic source is provided) and direct acting agents, these tests routinely fail to detect non-genotoxic carcinogens.
Short-term tests
most widely used short-term test is:
Ames test
Salmonella typhimurium strains, deficient in DNA repair and unable to synthesize histidine, are treated with several doses of the test compound.
Ames test
is used to determine whether a chemical is capable of inducing mutation in eukaryotic cells. The ability of cells in culture to acquire resistance to trifluorothymidine (the result of forward mutation at the thymidine kinase locus) is quantified.
mouse lymphoma assay
is commonly used to assess the potential mutagenicity of chemicals with the hypoxanthine–guanine phosphoribosyltransferase (HGPRT) gene as the endpoint.
Chinese hamster ovary (CHO) test
In vitro gene mutation assays
- Ames test
- Mouse lymphoma assay
- Chinese hamster ovary (CHO) test
disadvantages over the in vitro test systems in
that they take into account whole animal processes such as absorption, tissue distribution, metabolism, and excretion of chemicals and their metabolites. (t or f)
F
commonly used in vivo models include
transgenic rodent mutation assay systems, base on genes of lac operon (MutaMouse, Big Blue, and Pig-a gene mutation assay)
is primarily performed in rats and is based on the X-linked ________ which is involved in the production of glycosylphosphatidylinositol (GPI) anchor
proteins on the cell surface.
Pig-a gene mutation assay
the assay is optimized for measuring the Pig-a
mutant phenotype in peripheral blood erythrocytes by
quantification of ______________________
CD59- negative reticulocytes and red blood cells
is highly conserved in humans, rats, mice, and
monkeys, allowing comparison of mutation induction across multiple species.
Pig-a gene
are quite common in malignant neoplasms. Both in vivo and in vitro assays are available.
Chromosomal alterations
To assess induction of chromosomal alterations, cells are
harvested in their ___________ after the initiation of
chemical exposure. Cells are stained with _______ and scored for completeness of karyotype (21 ± 2 chromosomes).
first mitotic division; Giemsa
represents possible pre-mutational events that can be detected, either directly or indirectly, using mammalian cells in culture or using rodent tissue.
Primary DNA damage
is a commonly used assay that measures the ability of a test article to induce DNA lesions by quantifying the increase in DNA repair.
Unscheduled DNA synthesis (UDS)
has been widely used for the transformation assay; It was originally derived from fibroblasts taken from the prostate of a C3H mouse embryo.
C3H/10T½ cell line
this assay assesses carcinogenic potential based on the percentage of colonies that are transformed.
transformation assays
a diploid cell transformation assay, measures carcinogenic potential of xenobiotics by assessing transformed colonies based on morphological criterion.
Syrian Hamster Embryo cell assay (SHE)
____________ studies in laboratory rodents remain the primary method by which chemicals or physical agents are identified as having the potential to be hazardous to humans.
Chronic (Two Year) Bioassay Two-year
In the chronic bioassay, two or three dose levels of a test
chemical (up to the maximum tolerated dose) and a vehicle control are administered to _______________ , _______________, continuing throughout their lifespan.
50 males and 50 females (mice and rats); beginning at 8 weeks of age
During the study (chronic bioassay), ______________ 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.
food consumption and bodyweight gain
It has been estimated that nearly half of the
chemicals tested in the two-year chronic bioassay by the National Toxicology Program showed an increased incidence of liver cancer. (t or f)
T
have been developed to study and distinguish chemicals that affect the initiation or promotion stage of hepatocarcinogenesis.
Liver carcinogenesis assays
this model exploits many of the unique properties of mouse skin, one major advantage being that the development of neoplasia can be followed visually. In addition, the number and relative size of papillomas and carcinomas can be quantified as the tumors progress.
Carcinogenicity Testing in Skin: mouse skin model
In this model, carcinogenicity is typically assessed as an
acceleration of tumor development rather than an increase in tumor incidence.
Carcinogenicity Testing in Lung Strain: mouse lung tumor assay
mice are genetically susceptible to the development of lung tumors, with lung tumors being observed in control animals as _______________ with a steady increase to nearly 100% by _____________.
early as 3 to 4 weeks of age; 24 months of age
The strain A mouse lung tumor assay is sensitive to chemicals, such as.
PAHs, nitrosamines, nitrosoureas, carbamates, aflatoxin, certain metals, and hydrazines
the component that contributes the most to human
cancer induction and progression is:
lifestyle: tobacco use, alcohol use, and poor diet
is estimated to be responsible for 25% to 40% of all human cancers
tobacco usage
____________ consumption also contributes anywhere from 2% to 4% of cancers of the esophagus, liver, and larynx.
Alcohol
whether high-fat, low-protein, high-calories or diets
lacking in needed antioxidants and minerals account for
anywhere from 10% to 70% of human cancers.
poor diet
excess calories and/or high-fat diets contributes to breast,
colon, and liver cancer in humans
overnutrition
are formed during broiling and grilling of meat
carcinogenic heterocyclic amine and PAHs
a suspected human carcinogen, has been found in
fried foods at low concentrations.
Acrylamide
Carcinogenic factors associated with Lifestyle
chemicals:
- alcohol
- alfatoxins
- betel chewing
- dietary intake (fat, protein, calories)
- tobacco smoking
Neoplasm(s) from alcohol beverage
Esophagus, liver, oropharynx, and larynx
Neoplasm(s) from aflatoxins
liver
Neoplasm(s) from betel chewing
mouth
Neoplasm(s) from dietary intake
breast, colon, endometrium, gallbladder
Neoplasm(s) from tobacco smoking
Mouth, pharynx, larynx, lung, esophagus, bladder
Agent is carcinogenic to humans
- Evidence: Human data strong Animal data strong
IARC Classification of the Evaluation of Carcinogenicity for
Human Beings: GROUP 1
Agent is probably carcinogenic to humans
- Evidence: Human epidemiology data
suggestive Animal data positive
IARC Classification of the Evaluation of Carcinogenicity for
Human Beings: GROUP 2A
Agent is possibly carcinogenic to humans
- Evidence: Human epidemiology data weak Animal data positive
IARC Classification of the Evaluation of Carcinogenicity for
Human Beings: GROUP 2B
Agent is not classifiable as to carcinogenicity to humans
- Evidence: Human and animal data inadequate
IARC Classification of the Evaluation of Carcinogenicity for
Human Beings: GROUP 3
Agent is probably not carcinogenic to humans
- Evidence: Human and animal data negative
IARC Classification of the Evaluation of Carcinogenicity for
Human Beings: GROUP 4
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
appears to exhibit multiple characteristics including
increased selective lesion growth (through sustained cell
proliferation and/or resistance to apoptosis), the induction of angiogenesis, enabling replicative immortality, activation of factors that influence invasion and metastasis, evasion of normal growth suppression, modulation of energy metabolism, and the avoidance of attack by the immune system.
Neoplasia
