Week 4 Flashcards
(120 cards)
1
Q
What % of mutations are acquired?
A
90%
2
Q
What causes DNA mutations?
A
Chemicals, radiation, viruses
3
Q
3 different types of cancer causing somatic cell mutations?
A
- Activation of growth promoting oncogenes
- Inactivation of tumor suppressor genes
- Alterations in genes that regulate apoptosis
4
Q
What is angiogenesis?
A
The development of new blood supply from preexisting vessels to an area that need more O2
Early stages of vascular-genesis
5
Q
General steps of cancer?
A
Mutation Clonal expansion Angiogenesis More mutations Escape from immunity Tumor progression Malignant neoplasm Invasion and metastasis
6
Q
Neoplastic progression?
A
A. Tumor growth B. Angiogenesis C. Invasion and metastasis D Evasion of immune system E. Evasion of Senescence (aging of cell line aka shortening telomeres)
7
Q
7 hallmarks or cancer?
A
Limitless replicative potential Sustained angiogenesis Evading Apoptosis Self-sufficiency in growth signals Insensitivity to antigrowth signals Evading immune surveillance Tissue invasion and metastasis disease
8
Q
Are tumors always one mutated cell line?
A
No they are often and mix of or variety of different mutated cell lines stemming from one mutation.
9
Q
What is the strongest most powerful carcinogen? Aka what causes most cancers?
A
Inflammation
10
Q
When does a tumor need to start angiogenesis aka develop its own blood supply?
A
When it gets bigger than 2 microns
11
Q
Is doubling time for a tumor cell shorter or longer than a normal cell?
A
Longer due to the DNA damage usually making them inefficient at replication
12
Q
If doubling time is longer then why do tumors grow so quickly sometimes?
A
More cancer cells are in replication cycle
Cancer cells are shed at a lower rate aka they dies less
Limitless replication potential
13
Q
Normal cell cycle versus tumor?
A
Normal- Division, acquires mutation, apoptosis
Cancer- division, acquire mutation, division, acquire another mutation, division etc usually by 4th mutation there is uncontrollable growth
14
Q
3 things that happen in tumors?
A
- Activation of oncogenes
- Inactivation of tumor suppressor genes
- Alterations in gene that code for apoptosis
15
Q
What is a oncogene?
A
Gene that codes a protein that causes transformation to a neoplastic phenotypes when activated or over expressed. Mutations in oncogenes are dominant on a cell level ie one mutation over expresses enough protein to cause uncontrolled cell proliferation
16
Q
Names 4 examples of Oncogenes?
A
erb-B2- amplification of growth factor receptors, Breast and ovarian
ras- signal transduction due to point mutations, lung colon and pancreatic
myc- nuclear regulatory proteins are translocated, Burkett lymphoma
cyclin D- cell cycle regulators that are amplified or translocated, Mantle cell lymphoma breast and esophageal
17
Q
What are tumor suppressor genes?
A
Genes that encode a protein that causes a transformation to a neoplastic phenotype when inactivated or under-expressed.
Mutations are recessive on a cell level one normal genes makes enough protein to keep things in check.
18
Q
Name 6 examples of tumor suppressor genes?
A
APC- in cytosol inhibition of signal transduction
Rb-cell cycle regulation in nucleus
P53- response to DNA damage work in nucleus regulating cell cycle and apoptosis
BRCA-1- in nucleus regulation DNA repair
p16- CDK inhibitors
p21- CDK inhibitors
19
Q
What do oncogenes and tumor suppressors do to cell cycle pathways?
A
Oncogenes- turn on
Tumor suppressors- turn off
20
Q
What part of the cell cycle is not involved in cancer proliferation?
A
G-naught- that is a holding pattern not in active replication
21
Q
What happens when a CDK (cyclin dependent kinase) and a cyclin bind together?
A
The make an active cyclin/CDK complex that phosphorylates target proteins and drives cell proliferation
22
Q
Describe levels of cyclin and CDK and CDK inhibitors during cell cycle?
A
CDKs are stable in the amount but activity goes up and down due to associations with cyclones and inhibitors
CDK inhibitors vary due to environmental signals
Cyclin varies according to cell cycle progression- higher at restriction points to drive them past…
Both cyclin and CDK are only active when associated with each other.
23
Q
What does the CDK/cyclin complex do?
A
Regulates transcription factors and replication factors by phosphorylation
24
Q
What happens in cyclin over expression and how does it fit into pathway with tumor suppressor genes Rb, p21 and p16?
A
Cyclin is an oncogene and over expression means high levels of cyclin protein which is now around to bind to CDK and make a complex that separates a tumor suppressor Rb from E2F gene that drive cell cycle and replication aka
Increases transcription DNA synthesis genes such a EF2
Example-
- Rb tumor suppressor gene is bound to E2F protein which helps with DNA synthesis and…
- p16 or P21 hold CDK complex in check until it is time to move forward in cell cycle when they are inactivated.
If they are mutated or turned off then CDK complex is free.
- Free CDK/cyclin complex phosphorylates Rb releasing E2F to help with DNA synthesis is cell replication
25
Describe where the 4 oncogenes she wants us to know fit into the growth factor signal transduction pathway?
1. erb-B2 a receptor tyrosine kinase is phosphorylated when receives signal
2. Ras is activated by erb-B2 and then it travels through cytoplasm to nuclear wall
2. Myc receives signal from Ras and translocates to nucleus and activated Cyclin D which is made and then complexes with CDK which activates growth.
If any part of the pathway is mutation to being always on then unregulated tumor cell proliferation happens
26
What gene is implicated in 50% of cancers?
p53
27
Quick description of what p53 does?
It receives the DNA damage signal from a complex pathway and depending on level of damage that signals triggers p53 increase transcription of one of 2 choices:
1. Apoptosis genes if damage is bad via Bax activation which activates Cytc or
2. Activate p21 to freeze cell cycle and initiate DNA repair
28
Two p53 pathways and genes in them.
DNA repair p53 to p21
| Apoptosis p53 to Bax
29
What is chromosomal translocation?
When one part of the tip of a chromosome switches with another chromosome tip
30
How can chromosomal translocation affect cancer?
A oncogene can get placed next to an enhancer or activator or the translocation can makes new oncogene that is the result of the fusion of two separate genes.
Alone they are harmless but together they code for a cancer causing protein
31
How are translocations noted?
Small t and parentheses with each chromosome number ie
t(14,18) or t(9,22)
32
Name the two translocations she wants us to know?
t(14,18) and
| t(9,22)
33
What happens in t(14,18) ie what genes, what do they do, and what cancer?
The anti apoptosis oncogene bc12 on 18 is relocated to 14 next to the IgH enhancer. This results in over expression of bc12 causing Follicular Lymphoma
34
What does bc12 do?
Stops apoptosis signal to Bax in the case of DNA damage
The cell doesn’t die when it should but continues to live
35
What happens in t(9,22) ie what genes, what do they do, and what cancer?
The Philadelphia Chromosome
The 5’ Bcr gene from chromosome 22 relocates to chromosome 9 right next to the 3’ end of the Abl gene.
The two genes fuse and create an oncogenic tyrosine kinase that phosphorylated P13K creating a cascade that activates cell cycle progression, growth and proliferation
This is tied to CML aka Chronic Myelogenous Leukemia
36
What is the Philadelphia Chromosome and what cancer?
t(9,22)
| CML Chronic Myelogenous Leukemia
37
How can tumor suppressor genes be recessive at the cell level and dominant at the organismal level?
1 copy is enough to suppress the cancers but often in the life of an organism the one remaining copy is mutated and inactivated
So at some point the organism carrying the 1 copy will lose it and get cancer.
So if a kid inherited the broken gene from one parent and a working copy from the parent 2 when parent 2’s breaks they get cancer
38
What is Knudsen’s hypothesis?
The “two hit hypothesis”
1. One Hit is inherited ie 50% get a broken gene and heterozygous and phenotypically normal
2. Second hit is when the one working copy breaks and they become homozygous for the mutant
3. Inheritance pattern is dominant because the chance at least one cell will mutate and lose heterozygosity is really really high- everyone with the one broken gene with eventually break the 2nd working gene.
4. Non inherited tumor suppressor associated cancers the person has to break both genes.
39
What is the APC gene?
Adenomatous Polyposis Coli
| It is a tumor suppressor that leads to FAP- Familia Adenomatous Polyposis aka colon polyps and cancer
40
How does the APC gene work?
APC tags beta-catenins for degradation when they a released from keeping cell to cell contacts when the cell is getting ready to divide
If there is no APC to suppress the beta-catenins and tag them for destruction then they go on to change gene expression to cause cancer then there is proto-oncogene mutations then other cancer mutations and carcinoma
41
What angiogenic signals do tumor sub clones produce?
VEGF
42
What does VEGF do and how is it regulated?
In hypoxia conditions and when growth factors are around VEGF is made in cancer cells.
VEGF stimulates endothelial cell proliferation, migration and maturation aka new blood vessels made from EPCs from bone marrow, ECM remodeling, vascular permeability and new capillary sprouting
In short new blood supply of O2 to tumors
43
True or false
| Cancer need to create new blood vessels to get big ie undergo angiogenic switch
True
44
What need to happens for tumors to invade new spaces?
They need to go through the basement membrane and into the stroma.
45
What are the 4 steps of invasion?
1. Detach from neighboring cells
2. Bind tighter to basement membrane via receptors such as laminin and fibronectin receptors
3. Release MMPs aka metalomatrix proteases such as Type IV collagenase to cleave collagen in basement membrane
4. Migration and invasion using fibronection interactions and autocrine motility factors
46
Do our immune systems recognize tumor cells?
Yes they can and if they do the patient has a better chance but tumors can hide from immune system by:
1. not making antigens
2. Not displaying them since they don’t have the genes
3. Producing immune cell cytokines that suppress t-cells
47
What sites metastasize most commonly?
Liver, brain, bone, lungs
| Then breast, prostate, colon, pancreatic
48
What cancers don’t metastasize easily?
Basal cell carcinoma and squamous cell carcinoma aka skin cancers
49
What is cell senescence?
The phenomenon that normal cells telomeres shorten each division and limit cell division to approximately 50 times
50
Major causes of chronic inflammation that cause cancer?
```
Obesity
Smoking
Alcoholism
Gastric reflux disease
Inflammatory Bowel disease
Chronic pancreatitis
Gastric/peptic ulcer disease ie h-pylori
Steroids
Diabetes
High blood pressure
```
51
What is the only carcinogenic bacteria? What cancers is it linked to?
H-pylori
Gastric Adenocarcinoma
And low and high grade lymphoma aka Gastric MALT Lymphoma
If h-pylori infection is treated then it can clear up and not develop into cancer
52
What else other that inflammation can cause cancer?
Infections and genetic instability
53
What cancers are associated with inherited familial cancer syndromes?
Lynch syndrome- a gene that codes for mismatch DNA repair- colon cancer right side, endometrial cancer, and ovarian cancers- can present with two primary cancers at once that aren’t metastasized
Familial Adenomatous Polyposis- APC gene loss leads to colon cancer
54
Pharmacology is divided into what 2 main categories?
Pharmodynamics
And
Pharmokinetics
55
What is the study of pharmodynamics?
What a drug does to an organism
| Molecular, cellular, and physiological effects that are determined by the pharmacological properties of a drug
56
What is the study of pharmacokinetics?
The study of what an organism does to a drug ie absorption, distribution, metabolism and clearance which are determined by the chemical properties of a drug.
57
What are key areas for pharmacodynamics (7 of them)?
```
Receptors/effectors,
affinity,
efficacy,
potency,
agonists/antagonists
Allosteric modulators
Toxicity
```
58
What are receptors and how do they interact with drugs?
Proteins that are selectively bound by drugs that either turn them off or on, ie activated or inactivated by drug.
59
For the purpose of this class what are the 3 types of receptors?
Membrane receptors
Intracellular Enzymes
Nuclear Receptors
60
Basics of membrane receptors and some major types?
```
Receptors with a hydrophobic region imbedded in the cell membrane than receives a signal from outside the cell and transmits it through the cell wall.
G protein coupled receptors
Tyrosine kinase receptors
Ion channels
And others
```
61
What are intracellular enzymes?
Proteins that are in the cytoplasm of a cell that activate reactions
62
Name 3 examples of intracellular enzymes?
Cyclooxygenase
HMG-CoA reductase
Phosphodiesterases
63
How do drugs reach target enzymes in the cytosol?
Passive or active diffusion usually
64
What drugs target cyclooxygenase?
NSAIDS- aspirin, ibuprofen, naproxen, paracetamol
65
What drugs target HMG-CoA reductase?
Statins which treat high LDL cholesterol and heart diseases
66
What drugs target phosphodiesterases?
Sildenafil- erectile disfunction or pulmonary hypertension
| Milrinone- cardiac arrest
67
What are nuclear receptors?
Intracellular proteins that when activated go into the nucleus, bind DNA and start transcription, translation and protein synthesis.
68
Name 4 nuclear receptors and what drugs target them?
PPar-alpha Receptors- fribrates (gemfibrozil)
Glucocorticoid Receptors- Cortisol and other glucocorticoid steroids
Estrogen Receptors- estrogen and progesterone
Aldosterone Receptors- aldosterone and spironolactone
69
What type of receptor do most drugs target and what is second and 3rd?
1. Enzymes 47%
2. GPCRs 30%
3. Ion Channels 7%
70
Name 4 essential properties of drugs?
Affinity
Potency
Efficacy
Toxicity
71
What is affinity and how is it quantified?
A measure or how strongly and tightly a drug binds to its target
Quantified as a Equilibrium disassociation constant- Kd
Higher affinity equals a low Kd
72
What is Kd?
Affinity- concentration of drug needed to bind to half (50%) of target receptors
Smaller Kd has higher affinity
High Kd doesn’t bind as well
73
What is potency and how is it quantified?
The dose of a drug that causes 50% of a desirable effect.
Quantified by ED50 or EC50 for effective dose and effective concentration 50%.
Low EC50 or ED50 (same thing) means higher potency
High ED50 means low potency- more drug needed to see the effect
74
How is potency and ED50 determined and plotted?
They are figured out experimentally by plotting log dose and response to drugs.
By plotting them using logs the Drug Response Curves are sigmoidal
75
What else other than potency can DRCs (Drug Response Curves) plot?
Efficacy, affinity and toxicity
76
What is efficacy and how it it measured?
The max response that a drug can get. There comes a point where no matter how much more drug given there is no more response
Also called intrinsic activity
Measures amount versus response makes a %
77
What does a higher percent efficacy mean?
Higher percent is more efficacious.
Many natural ligands are 100%
Drugs are usual lower than 100% meaning that they don’t work all the time in everyone.
78
What is toxicity and how is it measured?
How much of the drug it takes to produce a negative effect usually death (LD)
Measured as Lethal Dose 50 or LD50
What dose in log scale causes 50% of people to respond with the negative effect of death
LD50 is the dose in log scale on the X-axis where 50% die…
79
What is the Therapeutic Index?
It is used to quantify the ratio of desired effect and to the undesired effect death.
Toxicity LD50 / Potency ED50
The further apart they are on the chart the higher the TI (therapeutic index) number the safer they are.
Ie 100 is pretty safe
80
Name 3 groups that drugs can be categorized based on how they work aka pharmacological categories?
Agonists
Antagonists
Allosteric Modulators
81
What are agonists?
Drugs that activate receptors
There are partial and full agonists
82
What are antagonists?
Drugs that block the action of agonists at receptors ie do NOT activate receptors
83
What are allosteric modulators and how do they work?
Drugs that enhance or diminish the actions of agonists
They bind to different sites than where the agonists binds and cause a conformational change that either increases or decreases binding ability.
84
What is pharmacokinetics?
The science of understanding what a body does to a drug.
85
Why are pharmacokinetics important?
Optimizing clinical doses to be safe and effective
Minimize toxicity
Prevent drug interactions
Drive new drug development such as delivery modules
86
What are some key things that are studied?
Absorption
Metabolism
Distribution
Excretion
Interactions
Pharmacogenomics
87
What are the 5 most common chemical groups of drugs and an example?
1. Basic elements- lithium
2. Peptides- insulin, vasopressin
3. Small molecules (most drugs)- opioids, antihistamines
4. Nucleic Acids- nucleoside inhibitors/mRNA
5. Antibodies- Adalimumab
88
What is the molecular weight range and most common?
Broad from 7 to 60K
| Most common are small molecules from 100-500 g/mol
89
What 3 major things affect Fl drug absorption?
Route of administration
Bioavailability
Drug permeation
90
Name 5 routes of administration and what are two main ones?
Main:
1. Parenteral- not by Gi tract, injection either IV, IM or SC
2. Enteral- through the GI tract ie oral, sublingual/buccal or anal
Others:
3. Inhalation
4. Topical
5. Transdermal
91
What is bioavailability?
Amount of drug circulating in the body versus the time since it was administered
92
What affects bioavailability?
Molecule type
Blood flow
Lipophilicity and hydrophobicity
Membrane transport vs passive diffusion
93
What factors affect drug distribution?
1. Blood perfusion ie rate of blood flow
2. Tissue/blood partition ratio
3. Drug depots- off target places the drug binds and builds up, plasma proteins, bones, fats, tissues
4. Blood brain barrier- passive versus active Pglycoprotein pumps
94
What is Volume of distribution or Vd?
Theoretical estimation of whole body drug distribution- define as volume of fluid in which a drug would need to be diluted to achieve measured plasma concentration
Vd= amount of drug in body / drug in plasma
95
How is Vd calculated?
Using tables that estimate volume of what in each compartment such as ECM, blood, plasma, fat and bone to get total volume divided by measured drug plasma levels
96
What are Vd levels used for?
To help predict duration of action and time to clearance of drug
97
What does a high versus low Vd level mean?
High Vd greater than 100 means it is distributed throughout the body and can be stored in fat bone and tissues. 4K such as propofol crosses blood brain barrier
Low Vd less than 8 have high plasma binding but can’t cross plasma membranes
Medium Vd 8-100 are distributed throughout the body but not stored
98
How and where are drugs metabolized?
Mostly in liver
| The liver breaks them down for excretion, transforms them from lipids to water soluble compounds or activates them
99
What is first pass metabolism?
Especially drugs from small intestine are first passed through liver and what is left after “first pass metabolism” is what is bioavailable
100
Where are the enzymes in the liver and which ones are responsible for which phases of metabolism?
They are located in microsomes
Phase 1- cytochrome P450s
Phase 2- transferases
101
What do cytochrome p450s do?
Phase 1
They are oxidases that comprise 20% of all microsomal proteins and humans make ~60 different ones
There are drug to drug interactions when they are metabolized by the same one
102
What do transferases do?
Phase II
| They make drugs water soluble for excretion
103
What are some factors that affect metabolism of drugs in the liver?
CYP450 modulation- inhibition of or induction of them that affect drug plasma concentration- major drug interaction cause
Plasma protein binding- when bound to plasma proteins drugs can be metabolism resistant
Genetic factors
Liver disease can impair metabolism resulting in high levels of drugs in system
104
What are the ways drugs are excreted?
Renal- urine pH can effect drug reabsorption and excretion
Biliary- drugs in feces regulated by enterohepatic circulation
Saliva, sweat or exhaled
105
Simple way to calculate drug clearance?
Drug elimination rate over drug plasma level equals clearance rate
106
What is drug half life?
Time required for plasma drug levels to reduce by 1/2
t1/2 = .693 x Vd (volume distribution) divided by CL(clearance rate)
107
What are the two main times of elimination kinetics?
Zero order- elimination rate is constant
First order- rate is proportional to drug plasma concentration ie more drug higher elim (most drug do this
108
What can happen in zero order elimination?
Body can reach saturation point and elimination gets “backed up”
Examples- ethanol, aspirin, IV infusions, topical patches
109
Name 3 commons ways drugs interact with each other?
Metabolism-most common
Increase or decrease expression of p450s or compete for the same p450 enzyme which slows rate of metabolism and increases drug plasma levels
Change each other’s rate of absorption
Effect each other’s rate of excretion
110
Names some drugs that increase p450 expression?
Carbamazepine, phenobarbital, rifampicin
111
Names some drugs that Decrease p450 expression?
Ritonavir, clarithromycin, ketoconazole, verapamil
112
Names some drugs that use the same p450 CYP3A4?
Tamoxifen,cyclosporine, amitryptaline, venlaxafine, haloperidol
113
What is pharmacogenetics?
Understanding how different genes and mutations react to different drugs in both the pharmacokinetic and pharmacodynamic areas
Mutations includes point mutation to deletions, insertions and improper splicing
114
Name the genetic example he pointed out and what is does?
A mutation in the CYP2C9 which effects how warfarin (anticoagulant) is metabolized.
68% of population has wild type
32% have one of two mutant alelles that decrease metabolism of it by either 30 or 80%
This means elevated levels of the drug in a patients system. So they need to take a smaller dose. It also increases a patients chance Pof side affects such as excess bleeding including life threatening bleeding.
115
What are the DEA drug schedule categories?
I-V
| With I being the worst to V being the safest
116
Schedule V
Low abuse potential, medicinal use
117
Schedule IV drugs?
Low abuse potential
118
Schedule III drugs?
Moderate to low abuse potential
119
Schedule II drugs?
High abuse potential, use leads to psychological and physical dependence
120
Schedule I drugs?
No accepted medical use potential with high abuse potential
