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Pharmacology Unit 1 > Cancer I > Flashcards

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
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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
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3
Q

non lethal genetic damage

A
  • mutations
  • acquired-chemicals, radiation, viruses
  • inherited in germ line
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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
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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
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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
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7
Q

cancer stem cells

A
  • a sub population of cells with ability to self renew and differentiate- have cancer initiating potential
  • origin?
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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
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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
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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
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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
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12
Q

cyclins

A

-regulatory protein- A, B, D, E

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13
Q

cyclin dependent kinases

A
  • Cdks

- 1, 2, 4, 6

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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
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15
Q

G1 cyclins

A

-Cdk 4, cyclin D

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16
Q

S cyclins

A

-cdk 2, cyclin A

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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
  1. dysregulation of 1 or both apoptotic pathways during chemo
  2. many anticancer drugs induce DNA damage, cells acquire ability to repair DNA quickly- less apoptosis
  3. gene amplification-amp of genes triggering overproduction of proteins that make the drugs ineffective
  4. increased expression of energy dependent efflux pumps-eject drugs- ABC (ATP binding cassette) family, MRP1 through MRP6
  5. decreased drug uptake because protein molecules that facilitate transport into cells stops working
  6. dysreg of metabolism of drug- some are metabolized into active forms but cancer cells can block that (def in deoxycytidine kinase, no active drug)
  7. 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

Pharmacology Unit 1 (10 decks)

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