Chapter 14 and 15 (exam 3) Flashcards
cancer
- uncontrolled cell growth producing a population of cells that can invade surrounding and distant tissues
- generally caused by successive mutations - change in genetic material that can be inherited during cell division
- placement on DNA matters -
–fatal mutation kills the cell (cannot become cancer)
–growth and identity
–codon redundancy
–intron/exon
proto-oncogenes
- regulatory genes
- mutation of genes associated with cell signaling, regulation of growth and cell identity are critical for initiation of cancer
- mutated proto-oncogene becomes an oncogene
- oncogenes - damaged gene that is characteristic of a tumor-forming cell population
tumor suppressor genes
- inhbit cell proliferation or help to eliminate mutated cells
- can disrupt apoptosis
- contact inhibition - cells will grow to the space provided
–regulatory process
–occurs in cell culture/dish
–receptors on cells that cause contact inhibition
Environmental causes
- 70-90% human cancers are related to environmental exposures
- diet, tobacco, infection, SDI, occupation
- as populations migrate, assume the cancer profile of the new population
–japanese men in CA follow CA trends, different than Japanese men in Japan
–attribute to environment
Dose Response for Cancer
-Generally follows the logarithmic model
-linear curve begins at the origin
–one molecule could effect a single cell that reproduces and the mutated gene is inherited
–very unlikely
–often need multiple mutations
–bypass many regulatory processes
–need to accumulate damage
DNA adduct
N-7 on guanine is the most nucleophilic on DNAm therefore most suseptible to reactive electrophiles
- effect the transcription proteins - mutation - potentially change codon - change AA - altered protein - impact the fucntion or tertiary structure
- effect is perminent when replicated w/o being repaired. larger effect
-DNA mutations
- insertion or deletion of a base pair
- grameshift mutation - effect all downstream codons
–nonsense protein which is completely different than the original
- change the reading frame
- may introduce a premature stop codon
PAH Carcinogen
-Acetulaminofluorene adducts onto guanine
–3 possible ways, various sterics
-Aflatoxin adducts - mycotoxin (produced by fungus) can grow on peanuts
–adducts onto N-7 og guanine via an epoxide.
–activated by phase I
-Benzo[a]pyrene - epoxide - diol epoxide - adduct to DNA - G to T mutation that is resistant to excision repair (due to sterics)
Initiators
provide genetic damge, physically or chemically interact with DNA
- change must be heritable and must impact a gene that is related to growth or identity of the cell
- generally reactive compounds (ROS, RNS, alkylating agents) or forms of radiation (UV, xray, gamma)
–UV - dimerization, cross linking of strands, energy impacts the bond
–Xray and gamma - can ionize an atom, change bonds
Promotion
- allows for proliferation of cells following initiation
- NOT mutagenic
- can be reversible, decrease exposure, decrease proliferation
- hormones, pharmaceuticals, natural products(mycotoxins)
- must occur AFTER initiation or there is no effect
–genetic damage leads to susceptibility, then promoter provides a signal that depends on susceptibility
Progression
-further accumulation of genetic damage decreases growth regulation and results in tumor formation
Carcinogen Classification
- indirect - parent compund does not directly interact with DNA ex (benzo[a]pyrene)
- proximate - result of metabolism, but not the form that reacts with DNA
- ultimate - final metabolite that reacts with DNA
example: B[a]p, B[a]p diol, B[a]p diol epoxide
Ames Test
- Salmonella typhimurium
- strain is histidine dependent, cannot synthesize it alone due ot point mutation in a single enzyme
- random mutation can reverse and make it histidine independent (revertant cell or reversion)
- grow in a histidine media, expose to potential mutagen, cells grown without histidine, cells that continue to grow have been mutated by the mutagen, compare to the control to account for spontaneous reversions
Ames Metabolic
- assay cannot detect mutagens that require metabolic activation
- conduct with external enzymes (liver S9 fraction)
- S9 contains microsomes and metabolic enzymes, P450
- metabolize the potential mutagen
- realistic conditions
Chronic 2 year Rodent Bioassay
- primary method to assess human risk
- covers lifespan of the animal
- uses 2-3 dosing levels
- high dose near the maximum tolerated dose
- dosing begins at 6 weeks through lifespan
- tumors are quantified in all organs
- 2 years needed to accumulate the mutations that will manifest into uncontrolled cell growth and a tumor
- max tolerated dose is just before death or other major negative effect
- max tolerated dose may be large difference from realistic exposure
- hard to generate a false negative, but increase chance of a false positive
