Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
78 Cards in this Set
- Front
- Back
What are various environmental and lifestyle factors causing human cancers?
|
-tobacco products (smoking, chewing tobacco, snuff)
-diet (natural ingredients,, contaminated food, preservatives, caloric restriction, how we cook it) -occurpation (dye industry, creosote, and asbestos) -reproductive and sexual behavior (viral infection of cervix, aids associated tumors) -geophysical (UV radiation, natural radiation, natural metals, asbestos) -medicines (anticancer drugs) -alcohol (increase drug absorption and metabolism) |
|
What is the pathway of multi-step carcinogenesis?
|
-normal epithelium--> hyperplasia--> metaplasia--> dysplasia-->carinoma in situ (CIS)--> invasive cancer
|
|
What is the carcinogenic process?
|
-initiation (generation of cells with DNA mutation)
-promotion (expansion of mutated cell population) -progression (continued mutation and expansion) |
|
What is the intiation step of carcinogenesis?
|
-A rapid and essentially irreversible alteration of cell genome by carcinogenic intiators
-most initiators are either electrophile or metabolically electrophile and able to bind to DNA to induce permanent DNA sequence change -they are mutagens |
|
What is the promotion step of carcinogenesis?
|
-expansion of initiated cell population by altering singal transduction, immune function etc
-considereed reversible, non-genetic -promoters themselves may not be carcinogenic and usually are not electrophiles, but they are able to increase the number of tumors or decrease the latency period. |
|
What is the progression step of carcinogenesis?
|
-continued mutation and expansion leading to an increased capability to survive, grow, and metastasize
|
|
What is the metabolism pathway of polycyclic aromatic hydrocarbons (PAHs)?
|
-benzo[a]pyrene (procarcinogen) gets metabolized by CYP1A1 with NADPH and oxygen
-then with water, then with same cofactors and enzymes as step 1 -to make benzo[a]pyrenediolepoxide (BPDE) (ultimate carcinogen) |
|
What is the mechanism of DNA adduct formation?
|
-benzo[a]pyrenediolepoxide binds covalently with deoxyribose irrevesibly
|
|
What is the mechanism of aflatoxin and liver carcinogenesis?
|
-aflatoxin B1 gets metabolized by cytochrome p-450 to aflatoxin B1-8,9-oxide
-goes through epoxide hydrase or glutathione S-transferase for detoxification -or covalently binds to DNA if no detox available |
|
What is the mechanism of heterocyclic amines and colon carcinogenesis?
|
-PhIP with exocyclic amine gets metabolized by CYP1A2 to N-OH-PhIP
-it then binds covalently to deoxyguanosine irreversibly |
|
What are UV-induced DNA adduct formation?
|
-forms pyrimidine dimers (major photoproduct) and pyrimidine pyrimidinone photoproduct
|
|
What are specific promotors in cancer generation?
|
-12-O-tetradeecanoylphorbol-13-acetate (TPA) or phorbol-12-myristate-13-acetate (PMA)
- isolated from croton plants, potent promotor in tumorigenesis and strong protein kinase C activator -bile acids for human colon cancers -estrogen for human breast cancers -chronic inflammation for majority human cancers |
|
What are oncogenes?
|
-function as growth factors, receptors, signal transducers, transcription factors, and cell cycle components
-similar to protooncogenes, but lack of regulation |
|
What are tumor suppressor genes?
|
-function as cell proliferation inhibitors
-involved as cell proliferation inhibitors -involved in cell cycle checking apoptosis pathways |
|
What is the association between inflammation and cancer?
|
-many inflammatory condituons predispose to cancer and arise at chronic sites
-functional polymorphisms of cytokine genes are associateed with cancer susceptibility and severity -distinct populations of inflammatory cells are detected in many cancers -chemokines are detected in many cancers, they are associated with inflammatory infiltrate and cell motility -deletion of cytokines and chemokines can protect against carcinogens |
|
What is the mechanism of inflammation as a tumor promotor?
|
-various types of inflammatory stimuli occur
-causes recruitment of inflammator cells, endothelial cells and stimulation of TNF-alpha transmitter -binds to TNF receptor -caused proliferation of tumor cells, more einflammation, or apoptosis based on chemical transmission -stimulated prostraglandin H2 pathway for loss of contact inhibition, achorage-independent proliferation, loss of E-cadherin, and increased proliferation with formation of prostaglandin E2 |
|
What is the length of multi-step carcinogenesis with colon cancer?
|
-takes 5-20 years to bcome an adenoma
-then 5-15 years to bcome cancer |
|
What is the length of multi-step carcinogenesis with head and neck cancer?
|
-with tobacco use and 4-10 years to become dysplastic oral leukemia
-then 6-8 years to become cancer |
|
What is the length of multi-step carcinogenesis with cervical cancer?
|
-with CIN 1 and 9-13 years to become CIN-3/CIS
-then 10-20 years to bcome cancer |
|
What is the length of multi-step carcinogenesis with lung cancer?
|
-with smokers, 20-40 pack years to become cancer
|
|
What is the length of multi-step carcinogenesis with breast cancer?
|
-with atypical hyperplasia, becomes ductal carcinoma in situ
-then 6-10 years to become cancer |
|
What is the length of multi-step carcinogenesis with prostate cancer?
|
-takes 20 years to become prostatic intraepithelial neoplasia
-after at least 10 years, becomes latent cancer -then 3-15 years later, cancer |
|
What is the pathway of carcinogen activity to cancer growth?
|
-exposure leads to metabolism (which also can get excreted
-causes genotoxic mechanisms (DNA adducts, and chromosome breakage, fusion, deletion, mis-agregation, and non-disjunction) which can cause genomic damage -or non-gentoxic mechanisms (inflammation, immunosuppression, reactive oxygen species, receptor activation, and epigenetic silencing) which leads to altereed signal transduction -both lead to hypermutability, genomic instability, loss of proliferation control, and resistance to apoptosis -which lead to cancer |
|
What are the possible causes of prostate inflammation?
|
-infectious agents (viruses and bacteria)
-hormonal changes (estradiol-->estrogen) -physical trauma (corpora amylacea) -urine reflux (uric acid build up) -dietary habits (charred meat and PhIP) |
|
What is prostate neoplasia progression?
|
-normal-->proliferative inflammatoiry atrophy (PIA)--> low-grade PIN--> high-grade PIN--> invasive carcinoma
|
|
What is mutagenesis?
|
-the generation of genetic mutation
|
|
What is a mutation?
|
– Hereditary changes in the DNA molecules due to
either spontaneous DNA replication errors or mutagen-induced chemical alterations. |
|
What are mutagens?
|
– Chemical and physical agents (either endogenous or
exogeneous) that increase the frequency of mutations. |
|
What are consequences of mutations?
|
– No major changes in phenotype
– Could be harmful to the individual organisms, leading to fertility disorders, embryonic and prenatal death, malformations, hereditary diseases and cancers. – Offering advantages in survival |
|
What are types of DNA damage?
|
• Base alterations
– Point mutation by chemical modification (alkylation, deamination, oxidation) – insertion/deletion – cross-linking (intrastrand, interstrand) • Strand breaks – single strand vs. double strand • Chromosomal rearrangements (translocation) |
|
What is point mutation?
|
• Depurination
• Depyrimidination • Deamination -Oxidation -alkylation -DNA adducts |
|
What is depurination?
|
-loss of
purine bases |
|
What is depyrimidination?
|
-loss
of pyrimidine bases |
|
What i deanimation? What does it lead to?
|
-loss of amine groups
-Leading to transition mutation: one pyrimidine replaced by another, e.g.C to T |
|
What does oxidation lead to?
|
-Leading to transversion mutation: one pyrimidine replaced by a purine
(or the opposite), e.g. G:C to G:A |
|
What is alkylation?
|
-attaching alkyl groups covalently to
the DNA base |
|
What is DNA intrastrand cross-linking?
|
-cross-linking of 2 adjacent pyrimidine or purine bases
-caused by UV rays |
|
What is DNA intertran cross-linking?
|
-cross-linkign of a pyrimidine and purine that are diagonal to each other
-caused by nitrogen musturd |
|
What is DNA repair?
|
• Widespread in nature
– similar in prokaryotes and eukaryotes • Critical to survival of cells/organisms – mutations (spontaneous and induced) – errors in DNA replication • Direct vs. excision repair |
|
What is DNA repair by DNA photolyase?
|
-separates intrastrand cross-linking with a blue light
|
|
What is DNA repair by DNA methyltransferase?
|
-MGMT dealkylates DNA
|
|
What is DNA repair by nucleotide excision repair?
|
-DNA danamge rcognized by several proteins
-TFIIH complex binds to damaged DNA section -DNA helix is unwounds by helicase -endonuclease cuts segment of DNA -DNA polymerase fills in gap -DNA ligase seals strand |
|
What is DNA repair by base excision repair?
|
-DNA glycolyase removes damaged base
-AP endonuclease breaks strand and removes deoxyribose phosphate group -DNA polymerase replaces missign nucleotide -DNA ligase seals |
|
What is DNA repair by mismatch repair?
|
-complex of proteins binds to mismatch pair
-Exonuclease activity removes 100-1000 nucleotides from strand with mismatched base -DNA polymerase fills in gap using other strand as a template -DNA ligase seals it |
|
What is teratogenesis?
|
– Production of developmental malformations. Greek terato
means a monster. – Teratology: the study of malformations. |
|
How are genetic factors a general principle of teratology?
|
– Susceptibility to teratogens depends on the genotype
of the organisms – Due to differences in the distribution, metabolism, transplacental passage of teratogens, tolerance to teratogens… in different organisms. – E.g. humans, monkeys and certain strains of rabbit and rat are very sensitive to Thalidomide whereas most other mammals are quite resistant |
|
How are critical periods a general principle of teratology?
|
-The type of malformation is determined by the developmental
stage of the fetus at the time of exposure |
|
How are intiating mechanisms a general principle of teratology?
|
– Different initiating mechanisms often lead to similar
abnormalities |
|
What are various intiatial changes for defect pathway of teratology?
|
-Gene mutation
-Chromosomal abnormality -Mitotic interference -Lack of nutrients -Lack of key proteins -Enzyme inhibition -Membrane abnormality -Osmolar imbalance -Inhibition of angiogenesis |
|
What are examplees of pathogenesis?
|
Excessive cell death
Reduced cell death Reduced biosynthesis Impeded cell migration Mechanic tissue disruption |
|
What are consequences of deformed developement as a general princicplee of teratology?
|
– Death
• Damages during the implantation period, rarely occurs. • Often requires high doses. • Embryotoxic agents are not teratogens. – Malformation • Damages during the organogenesis period. – Growth retardation • Damages during the fetal period. – Functional disorder • Damages during the fetal period |
|
How is access to the embryo and fetus a general principle of teratogenesis?
|
– Only some physical forces (e.g. radiation, ultrasound) can
penetrate directly through the maternal tissue. – Chemicals and their metabolites have to go through embryo fluid or placental blood barrier. – Generally, most unbound lipophilic compound with MW less than 600 can pass through placental blood barrier through passive diffusion. |
|
How is the dose-response relationship a general principle of teratology?
|
-higher doses lead to more damage
|
|
What is human teratogenesis?
|
• About 3-7% of human babies are born with malformations serious
enough to require treatment. • In most cases, the causes for these malformations are not known. |
|
What is thalidomide and how does it affect teratogenesis?
|
6
• Synthesized in Germany in 1953 as an antibiotics • No antibiotic or any other obvious effects found • 1955: free distribution to doctors as sedative without any experimental evidence • 1956: A first thalidomide-induced birth defect Thalidomide • 1957: Thalidomide was sold in Germany and more than 40 other countries as the first choice for pregnant women with morning sickness. • 1960: Thalidomide was submitted for FDA approval six times, which were all rejected by FDA’s newest reviewer Frances Kelsey who was in the agency for only one month. • 1959-1961: More and more birth defects were reported worldwide. • Nov 1961: German authority removed thalidomide from the market. • 2006: FDA approval of thalidomide for multiple myeloma. Thalidomide • One of the most potent human teratogens known • One tablet taken at any time from the third to the seventh week of pregnancy is effective in producing a teratogenic effect. • Thalidomide administration beyond embryonic period does not cause malformations. • The most pronounced defect is the shortening or missing of limbs. • Very species specific – Humans: as low as 0.5-1.0 mg/kg during the embryonic period – Most mouse or rat strains: more than 4000 mg/kg • Teratogenic mechanism is still controversial. – Intercalating into DNA G-C rich region – Antiangiogenesis |
|
How does alcohol cause teratogenesis?
|
-– Fetal alcohol syndrome (FAS): (1) prenatal or postnatal growth
retardation; (2) characteristic facial anomalies (microcephaly, small eye opening, thinned upper lip); (3) CNS dysfunction (mental retardation, developmental delays). – Teratogenic mechanism is still not clear. Hypoxia has been suggested to be involved in it. |
|
What are the untis of atomic energy?
|
Units:
Joule = kg m2/s2 (SI unit) Electron Volt = kinetic energy gained by an electron accelerated through 1Volt. 1 eV = 1.6 x 10-19 J |
|
What are energy calculations of atomic energy?
|
E = hν
h = Plank’s constant ν = photon frequency h = 6.626x10-34 J s = 4.135 x 10-15 eV s |
|
What is rest energy of a mass?
|
E = mc2
|
|
What is binding energy?
|
-The energy required to remove an electron from the atom
-increases with proximity to the nucleus. -It also increases with increasing number of protons (Z) in the nucleus. |
|
What is radiation?
|
energy transmitted by electromagnetive wave or particles
through medium |
|
What is electromagnetic radiation?
|
-includes the normal spectum of light
-microwaves -x-rays -gamma rays -etc. |
|
What is non-electromagnetic radiation or particle radiation?
|
Alpha radiation: helium nuclei (2 protons and 2 neutrons), short traveling
path due to heavy weight and charges. • Beta radiation: electrons or positrons, longer path than Alpha, often followed by Gamma ray. • Neutron radiation: neutrons, longer than Beta, often inducing Gamma ray. |
|
What is ultraviolet radiation as non-ionizing radiation? sources? Classification? adverse effects? biological targets?
|
– natural (sunlight), artificial (tanning beds, etc.)
– UV-A (320-400 nm), UV-B (290-320 nm), UV-C (100- 290 nm) -– Eyes (cataract) – Skin (sunburn, premature aging, cancer) -T-T photodimers → DNA mutations →cancer – inflammation → sunburn |
|
What are micrwaves as non-ionizing radiation? sources? adverse effects? biological targets?
|
– Natural, artificial (microwave ovens, radar guns,
TV/radio broadcasts, etc.) – Thermal effects (major) – Non-thermal (not significant)– -thermal injury due to tissue heating – unknown for non-thermal injury |
|
What are electomagnetic fields as non-ionizing radiation? sources? adverse effects? biological targets?
|
– natural (Earth), artificial (cell phones, power
lines, electrical appliances, etc.) – reproductive effects (teratogenesis?, spontaneous abortions?, etc.) – other (cancer?) – ion fluxes – ↓ melatonin synthesis – immunosuppression – ↓ RNA/protein synthesis – altered metabolism |
|
How are x-ray or gamma rays ionized electromagentic radiation? sources? discovery?
|
– Natural (80%): cosmic rays, isotopes…
– artificial (20%): medical uses, occupational or accidental exposures. – 1895 German physicist Roentgen WK discovered X-ray |
|
What is the interaction of x-ray with matter?
|
Probability is low and decreases significantly with increasing energy
|
|
What is Reileigh scattering as interaction of x-rays with matter?
|
-scattered photon has same wavelength as incomign photon
|
|
What is compton scattering as an intereaction of x-rays with matter?
|
-scattered photon has a higher wavelength than the incoming photon
|
|
What is the photoelectric effect as an interaction of x-rays with matter?
|
-A photon of energy hν is absorbed and an electron of kinetic energy
EKE = hν - Eb is ejected. -As the energy of the electron decreases below the binding energy of a shell, then the contribution to the overall cross section drops to zero from that shell. |
|
What is pair production as an intereaction of x-rays with matter?
|
-incident photon produces a negatron an a positron (matter and anti-matter) as matter is scattered
|
|
What are basic cellular mechanisms of radiation damage?
|
-radiation forms free radicals for indirect damage or damages DNA directly (fast)
-which is then either repaired or causes a mutation which leads to a biological response (slow) |
|
What are basic DNA mechanisms of radiation damage?
|
-base deletion
-base substituition -hydrogen bond disruption -single strand or double strand break |
|
What are short term effects of radiation?
|
• Generally associated with acute exposure
• Clinical symptoms seen within hours to weeks • Cell cycle determines tissue sensitivity – Proportional to the number of cells in growth phase – Most sensitive: skin, GI tract, bone marrow – Least sensitive: muscle, CNS • Acute radiation effects – Hematopoietic syndrome due to the destruction of bone marrow stem cells – Gastrointestinal syndrome due to the destruction of epithelial cells in the GI tract – CNS syndrome due to the destruction of neurons |
|
What are the 3 kinds of acute radiation death?
|
1) cerebrovascular syndrome – 24-48 hrs, 100Gy
- neurologic and cardiovascular breakdown 2) gastrointestinal syndrome – days later, 5-12 Gy - diarrhea and destruction of gastrointestinal mucosa 3) bone marrow death (hematopoietic syndrome) – weeks later, 2.5 – 5 Gy - destruction of blood forming organs |
|
What are deterministic long term effects of radiation?
|
– above a threshold dose the effect increases linearly
with dose. - results from direct cell death effects (eg. radiation induced cataracts) |
|
What are probabilistic long-term effects of radiation?
|
– change in cell occurs, but does not induce death
- severity of condition is not increased with dose, but probability of occurrence increases. - assumption of no threshold dose (eg. Cancer, genetic mutation). |