Cancer I Flashcards
1
Q
cancer overview
A
- group of more than 100 diseases
- second leading cause of death
- more than 1 million new cases each year
- responsible for more deaths than heart disease in population younger than 85
2
Q
molecular basis of cancer
A
- cancer is a genetic disease, but other epigenetic changes occur
- characterized by abnormal cellular growth and reduced cell death
3
Q
non lethal genetic damage
A
- mutations
- acquired-chemicals, radiation, viruses
- inherited in germ line
4
Q
targets of genetic damage
A
- growth promoting oncogenes
- growth inhibiting tumor suppressor genes
- genes that regulate apoptosis or cell death
- genes that repair damaged DNA
5
Q
adenoma-carcinoma sequence in colorectal cancer
A
- germline (inherited) or somatic (acquired) mutations of cancer suppressor genes- 1st hit. APC at 5q21, mismatch repair genes
- methylation abnormalities, inactivation of normal alleles- second hit. APC, beta-catenin, MSH2
- protooncogene mutation- k ras
- homozygous loss of additional cancer suppressor genes- p53
- additional mutations, gross chromosomal abnomalities
6
Q
clonal evolution and tumor heterogenity
A
- all tumors arise from a single transformed clone
- new subclones arise from the descendants of the original clone during continuous growth
- new subclones differ from the original clone- more aggressive, metastatic, and acquire ability to evade host defense
7
Q
cancer stem cells
A
- a sub population of cells with ability to self renew and differentiate- have cancer initiating potential
- origin?
8
Q
rate of tumor growth
A
- 30 doublings to get 10^9 cells
- in solid tumor, these cells weigh 1 gram, which would be smallest clinically detected mass
- ten more doublings give 10^12 and a mass of 1 kg
- one kg is maximal solid tumor mass compatible with life
- 90 days to generate a mass of 1 gram if 30 doublings and a cell cycle time of 3 days
- in reality, long latent period before a tumor is detected in clinic- if detected, already completed a major portion of its life cycle
- average volume doubling time could be 2-3 months for some tumors- lung and colon
9
Q
approaches to cancer treatment
A
- conventional- alkylating, antimetabolites, natural products, miscellaneous, hormones and antagonists
- molecular targeted therapy- investigational anti cancer agents-rational molecular based approaches in the discovery, design, and utility of anticancer drugs
10
Q
cell cycle and apoptosis
A
- anticancer agents mediate their effects by inducing cell cycle arrest and/or cell death
- certain drugs act in specific phase of cell cycle while others do not
- a better understanding of cell cycle kinetics and apoptosis is essential for effective utility of anticancer agents
11
Q
cell cycle control
A
- G1, S, G2, M
- 6-12 hrs in G1,
- 6-8 in G2
- 3-4 in S
- 1 in M
- Go- postmitotic cells exit cell cycle and enter into a non-proliferative phase- terminally differentiated new cells
12
Q
cyclins
A
-regulatory protein- A, B, D, E
13
Q
cyclin dependent kinases
A
- Cdks
- 1, 2, 4, 6
14
Q
cyclins and cdks
A
- heterodimers that phosphorylate target proteins
- Cdks have no kinase activity unless associated with a cyclin
- cyclin determines which proteins to be phosphorylated by cyclin-cdk complex
15
Q
G1 cyclins
A
-Cdk 4, cyclin D
16
Q
S cyclins
A
-cdk 2, cyclin A
17
Q
G2/M cyclins
A
-cdk 1 cyclin B
18
Q
Rb-E2F pathway
A
- cyclinD/cdk 4, D6, E2, phosphorylate Rb protein
- hypoP Rb is bound to E2F
- hyper P Rb releases E2F
- E2F activates transcription of genes whose products control the progression from G1-S–> proliferation
19
Q
progression S-G2
A
- A2
- targets unknowns
20
Q
progression G2-M
A
- B1
- several target proteins
21
Q
checkpoints
A
- four key checkpoints- G1 arrest, S phase arrest, G2 arrest, M arrest
- implemented to ensure each stage of the cell cycle is properly completed before the next stage is initiated
22
Q
DNA damage
A
- stops in G1 or G2, no progress to S or M
- if DNA isn’t properly replicated- S phase arrest and no progress to G2
- if improper spindle formation- M phase arrest
23
Q
why learn all this?
A
- a large number of cancers with abnormalities in some component of cell cycle
- hyperactivation of cdks due to cyclin and/or cdk expression- cyclin D overexpression in cancer
24
Q
anticancer drugs
A
- activate p53, which activates p21 and 14-3-3- G1, G2 arrest or just G2 arrest
- tumors with p53 mutations will not respond to this
25
Q
pathways of cell death
A
- apoptosis
- physiologic process but can be induced
26
Q
morphological changes in apoptosis
A
- cell shrinkage
- cell shape changes
- cytoplasmic condensation
- alterations in nuclear envelope and nuclear shrinkage
- nuclear chromatin condensation and fragmentation
- cell membrane blebbing
- formation of apoptotic bodies
- phagocytosis of apoptotic bodies
27
Q
molecular and biochemical changes in apoptosis
A
- activation of proteases- caspases and serine proteases
- proteolysis- cleavage of important proteins involved in cell structure and function
- DNA fragmentation- nucleases
- loss of mitochondrial membrane potential
- cytochrome C release from mito into cytosol
- other changes
28
Q
caspases
A
- integral component of apoptotic machinery
- 14 caspases have been identified by 11 are well studied
- they are cystein proteases and exist as inactive proenzymes named procaspases
- activated in response to apoptotic insults- anticancer treatment
- recognize specific cleavage sites within proteins (including caspases)
29
Q
how caspases are used
A
- they are utilized in a cascade known as the caspase cascade
- upstream initiator caspases (8 or 9) cleave and activate downstream effector (executioner) caspases, like 3, 6, 7
30
Q
two major apoptotic pathways
A
- responsible for activation of caspase cascade
- death receptor dependent pathway- through caspase 8 to 3
- mitochondrial pathway - 9 to 3
31
Q
anticancer drug resistance
A
-intrinsic or acquired
32
Q
intrinsic resistance
A
- dysregulation of one or both apoptotic pathways due to inactivation of apoptosis promoting genes and proteins- mutations, deletions, epigenetic mechanisms
- hyperactivity of survival or anti-apoptotic genes
- confers intrinsic survival advantage and resistance to drugs- double whammy
- host factors- poor absorption, rapid metabolism or excretion of drugs–> low serum levels
- delivery failure- bulky tumors or high molecular mass of drugs- monoclonal antibodies
33
Q
acquired resistance
A
- dysregulation of 1 or both apoptotic pathways during chemo
- many anticancer drugs induce DNA damage, cells acquire ability to repair DNA quickly- less apoptosis
- gene amplification-amp of genes triggering overproduction of proteins that make the drugs ineffective
- increased expression of energy dependent efflux pumps-eject drugs- ABC (ATP binding cassette) family, MRP1 through MRP6
- decreased drug uptake because protein molecules that facilitate transport into cells stops working
- dysreg of metabolism of drug- some are metabolized into active forms but cancer cells can block that (def in deoxycytidine kinase, no active drug)
- acquisition of mechanisms to inactivate drugs (overexpression of cytidine deaminase)
- both 6 and 7 refer to AraC
34
Q
anticancer drug tox
A
- drugs affect rapidly dividing normal and malignant cells
- tox with bone marrow, intestinal epithelium
- acute tox usually dose limiting
35
Q
toxic effect on hematopoietic system
A
- bone marrow suppression
- suppression of all blood elements can occur
- myelosuppression- leukopenia
- G-CSF- granulocyte colony stim factor- now given to shorten period of leukopenia
36
Q
toxic effect on dividing mucosal cells
A
- oral mucosal ulceration
- intestinal denudation
37
Q
toxic effects on hair follicles
A
-alopecia
38
Q
toxic effect on repro system
A
-permanent amenrrhea, azoospermia
39
Q
delayed toxicities
A
- organ damage- heart, lungs, kidney, liver
- pulm fibrosis
- endothelial damage giving rise to venoocclusive disease of liver
- nephrotoxicity giving rise to renal failure
- neurotox giving rise to seizures, paralysis, coma
- major organ damage can be avoided by strict adherence to treatment protocols
40
Q
secondary neoplasia
A
-most alkylating agents are leukemogenic
41
Q
specific acute effects
A
- cyclophosphamide- nephrotoxic and urotoxic metabolite-hemorrhagic cystitis
- anthracycline antibiotics- doxorubicin- dose related cardiac tox
