Unit 1 - Cancer Cherapeutics Flashcards
what are the 5 general steps in cancer sequence?
- germline (inherited) or somatic (acquired) mutations of cancer suppressor genes (first hit)
- APC at 5q21, mismatch repair genes - methylation abnormalities and inactivation of normal alleles (second hit)
- APC, B-catenin, MSH2 - protooncogene mutation
- K-ras at 12p12 - homozygous loss of additional cancer suppressor genes
- p53 at 17p13, LOH at 18q21 - 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?
- 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?
- cell shrinkage and shape changes
- cytoplasmic condensation
- alterations in nuclear envelope and nuclear shirnkage
- nuclear chromatin condensation and fragmentation
- cell membrane blebbing
- cell detachment
- 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?
- activation of proteases: caspases and serine proteases
- proteolysis: cleavage of important PRO involved in cell structure and function
- DNA fragmentation: nucleases
- loss of mitochondrial membrane potential
- 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”
