Unit 1 - Cancer Cherapeutics Flashcards Preview

MSII Pharmacology > Unit 1 - Cancer Cherapeutics > Flashcards

Flashcards in Unit 1 - Cancer Cherapeutics Deck (27):

what are the 5 general steps in cancer sequence?

1. germline (inherited) or somatic (acquired) mutations of cancer suppressor genes (first hit)
-APC at 5q21, mismatch repair genes
2. methylation abnormalities and inactivation of normal alleles (second hit)
-APC, B-catenin, MSH2
3. protooncogene mutation
-K-ras at 12p12
4. homozygous loss of additional cancer suppressor genes
-p53 at 17p13, LOH at 18q21
5. additional mutations and gross chromosomal alterations (in many genes)


clonal evolution of tumors and its relation to tumor heterogeneity

all tumors are believed to arise from a single transformed clone
-new subclones arise from descendants of original clone during continuous growth
-new subclones differ from original clone in many respects (aggressiveness, metastatic, defense evasion)


why is the rate of tumor growth important?

-at 10^9 cells (30 population doublings), a solid tumor weighs 1 g and is smallest clinically detectable mass and has already completed a major part of its life cycle
-at 10^12 cells (10 more population doublings), it weighs 1 kg and is the max mass compatible with life
-but there are usually latent periods so it's not this fast


what is the average volume-doubling time for tumors once clinically detectable?

2-3 months


what are the 2 approaches to cancer treatment?

1. conventional chemotherapy - currently in use
2. molecular targeted therapy - investigational anticancer agents


what is the normal somatic timing in each of the 4 cell phase cycles?

G1: 6-12 h
S: 6-8 h
G2: 3-4 h
M: 1 h


what are the important cyclin-CDK complexes that function in G1, S, and G2/M phase?

G1: Cdk4-cyclin D
S: Cdk2-cyclin A
G2/M: Cdk1-cyclin B


relationship between cyclins and Cdks

function as heterodimers that phosphorylate target proteins
-Cdks have no kinase activity unless associated with cyclin
-each Fdk can associate with different cyclins
-the cyclin determines which proteins would get phosphorylated by cyclin-Cdk complex


explain the Rb-E2F pathway

progression from G1 to S phase
-cyclin D/Cdk4/6 and cyclin E/Cdk2 phosphorylate Rb
-hypophosphorylated Rb is bound to E2F, but if hyperphosphorylated, will release E2F
-released E2F activates transcription of genes whose products control progression from G1 to S phase


what are the 4 key checkpoints?

G1 arrest
S arrest
G2 arrest
M arrest


how can anticancer drugs cause G1/2 arrest?

activate p53
-activate p21 --> G1/2 arrest
-activate 14-3-3 --> G2 arrest


what are morphological changes associated with apoptosis?

1. cell shrinkage and shape changes
2. cytoplasmic condensation
3. alterations in nuclear envelope and nuclear shirnkage
4. nuclear chromatin condensation and fragmentation
5. cell membrane blebbing
6. cell detachment
7. phagocytosis of apoptotic bodies


early VS late apoptosis

Early in apoptosis
-dense chromosome condensation occurs along the nuclear periphery; cell body shrinks although most organelles remain intact

Later in apoptosis:
-both the nucleus and cytoplasm fragment, forming apoptotic bodies. These are phagocytosed by the surrounding cells.


what are molecular and biochemical changes involved in apoptosis?

1. activation of proteases: caspases and serine proteases
2. proteolysis: cleavage of important PRO involved in cell structure and function
3. DNA fragmentation: nucleases
4. loss of mitochondrial membrane potential
5. cytochrome C release from mitochondria into cytosol


what are caspases?

integral component of apoptotic machinery (11/14 well-studied)
-cystein proteases that exist as pro-caspases, and are activated in response to apoptotic insults
-recognize specific cleavage sites within proteins (including caspases)
-used in "caspase cascade"


explain the caspase cascade

upstream initiator caspases (caspase 8/9) cleave and activate downstream effector (executioner) caspases 3/6/7


what are the 2 major apoptotic pathways responsible for activation of caspase cascade?

1. death receptor-dependent pathway
2. mitochondrial pathway


explain intrinsic resistance

1. dysregulation of one/both apoptotic pathways are common in many types of cancer due to inactivation of apoptosis promoting genes/proteins (mutations, deletions, epigenetic mechanisms)
2. hyperactivity of survival or anti-apoptotic genes/proteins
-confers cancer cells survival advantage and drug resistance (double whammy)
3. host factors (poor absorption or rapid metabolism or excretion of drugs; delivery failure)


explain acquired resistance

j1. due to dysregulation of one/both apoptotic pathways during chemotherapy
2. anticancer drugs that induce DNA damage --> cancer cells rapidly and efficiently repair DNA damage --> reduced apoptosis
3. gene amplification --> overproduction of genes that make anticancer drugs ineffective
4. increasex expression of E-dependent efflux pumps to confer multidrug resistance by ejecting drugs out of cells
5. decreased drug uptake b/c protein molecules stop working
6. dysregulation in drug metabolism (blocked within cells)
7. acquisition of mechanisms by cancer cells to inactivate drugs


what are toxic effects on the hematopoietic system? what is given to treat it?

suppression of all blood (marrow) elements
-myelosuppression - leukopenia
-G-CSF is given to shorten the period of leukopenia


what are toxic effects on dividing mucosal cells?

-oral mucosal ulceration
-intestinal denudation


what are toxic effects on hair follicles?



are acute toxicities dose-limiting?

yes, generally


what are toxic effects on reproductive systems?

-permanent amenorrhea for females
-azoospermia for males


what are possible delayed toxicities of chemotherapy?

1. organ damage (heart, lungs, kidney, liver)
-pulmonary fibrosis
-endothelial damage giving rise to veno-occlusive disease of liver
-nephrotoxicity giving rise to renal failure
-neurotoxicity giving rise to seizures, paralysis, and coma
-major organ damage can be avoided by strict adherence to treatment protocols
2. secondary neoplasia (since most alkylating agents are leukomogenic)
3. some drugs have specific acute effect on major organs


how is cyclophopshamide toxic?

releases nephrotoxic and urotoxic metabolite that causes hemorrhagic cystitis?


how are anthracycline antibiotics toxic?

cause dose-related cardiac toxicity