Cancer I Flashcards
Cancer is a ____ disease, but other ____ changes also occur; what is it characterized by?
genetic; epigenetic; abnormal cellular growth and reduced cell death
How can cells accumulate DNA damage (2 ways)? List four targets of genetic damage
- Acquired (chemicals, radiation, viruses)
- Inherited in germ line;
- Growth promoting protooncogenes
- Tumor suppressor genes
- Genes regulating apoptosis or cell death
- Genes that repair damaged DNA
List the steps in which you can go from a normal colon to carcinoma?
- Germline or somatic mutations of cancer suppressor genes (first hit)
- Methylation abnormalities or inactivation of normal alleles (second hit)
- Protooncogene mutation
- Homozygous loss of additional cancer suppressor genes
- Additional mutations; gross chromosomal alterations
Where do tumors arise from? What else arises from original clone during continuous growth? How do these descendants differ from the original clone?
Single transformed clone;
new subclones arise from the original clone’s descendants;
Can be more aggressive, metastatic, and have ability to evade host defense
How many doublings are needed to get to 10^9 cells? What is the smallest clinically detectable mass? What is the max solid tumor mass that is compatible with life? How long woul it take to get a mass of 1 gm given this knowledge and the assumption that the cell cycle lasts 3 days?
30; 1 gm; 1 kg; 90 days (1 gm felt with 30 population doublings and 3 day cell cycle)
What are the two approaches to cancer treatment?
- Conventional chemo
2. Molecular Targeted Therapy
How do anticancer agents mediate their effects? How can these drugs act?
Induce cell cycle arrest and/or cell death; act in specific phase of cell cycle while others are phase nonspecific;
What is the cell cycle made up of (4 phases)? How much time could cells spend in these phases? What is Go?
G1, S, G2, M; 6-12 hr, 6-8 hr, 3-4 hr, 1 hr respectively; G0 has postmitotic cells exiting the cell cycle to enter a non-prolif phase (nerve cells) or some enter G0 temporarily and later re-enter the cycle
What proteins control the cell cycle progression (2)? What do these two combined help do? T/F: cdk’s can act on their own.
What does a cyclin determine?
- Cyclins (reg proteins, like A, B, D, E)
- Cdk’s (catalytic proteins, like 1, 2, 4, 6);
heterodimers that phosphorylate target proteins;
false: needs a cyclin associated to phosphorylate;
which proteins to be phosphorylated by cyclin-cdk complex
What are the cyclin-cdk complexes for G1, S, and G2/M phases?
Cdk4-cyclin D, Cdk2-cyclin A, Cdk1-cyclin B, respectively
What phosphorylates Rb? If it’s not phosphorylated, what happens with the thing it should be holding? What do progerssion from S to G2, and G2 to M involve?
Cyclin D/Cdk4, Cyclin D/Cdk6, Cyclin E/Cdk2; E2F is released and activates transcription of genes whose products control progression from G1 to S; cyclin A/Cdk2 and cyclin B/Cdk1
What are the four checkpoints in the cell cycle?
- G1 arrest: DNA damage, no progression to S (same with G2 going to M
- S-phase arrest: if DNA replication errors, no G2
- M arrest: If improper spindle formation, no division
What is a possible cause of breast cancer related to cdk/cyclin?
If cdks or cyclins overexpressed, cdks are hyperactivated (e.g. cyclin D and breast cancer)
How can a cell undergo apoptosis (two ways)?
Physiological process but can be induced
Morphological exam for apoptosis?
- cell shrinkage
- cell shape changes
- cytoplasmic condensation
- altered nuclear envelope, nuclear shrinkage
- chromatin condensation and fragmentation
- cell membrane blebbing
- formation of apoptotic bodies
- cell detachment
- phagocytosis of apoptotic bodies
What are the biochemical and molecular changes for apoptosis?
- Capses and serine proteases activated
- Proteolysis of important proteins
- Nucleases
- Loss of mito membrane potential
- Cyt c release from mito
- Other changes
What are characteristics of caspases (5)?
- Huge part of apoptotic machinery
- 14 identified, 11 well-studied
- CYSTEINE PROTEASES and exist as inactive pro-caspases
- Activated in response to apoptotic insults
- Recognize specific protein cleavage sites
What two pathways are responsible for the caspase cascade activation? What caspases go off first? Followed by which ones? What are ligands for one of the pathways
- Death receptor-dependent pathway
- Mito pathway;
Caspase 8 or 9, then capases 3, 6, and 7;
TNF, TRAIL, FAS
How can there be anticancer drug resistance?
- Intrinsic (inactivation of apoptosis promoting genes/proteins; hyperactivity of survival or anti-apoptotic genes; low serum levels due to absorption issues or rapid metabolism; delivery failure)
- Acquired (reduced apoptosis since cancer cels can repair DNA damage; gene amplification to overproduce proteins, like DHFR amp and methotrexate resistance; energy-dependent efflux pumps like p-glycoprotein, MRP1-MRP6, and other transporters; decreased drug uptake because transporters for drug aren’t working like cisplatin; cancer cells can block metabolism of drug into active metabolite; mech’s acquired by cancer cells to inactivate drugs)
What are the toxic effects that anticancer drugs could bring about? List also the consequences
- Hematopoietic system: Bone marrow suppression (myelosuppression leads to leukokemia; give G-CSF to shorten period of leukopenia)
- Dividing Mucosal Cells (oral mucosal ulceration and intestinal denudation)
- Hair follicles (alopecia)
- Repro system (permanent amenorrhea in women, azoospermia in men)
What are delayed toxic effects brought about by anticancer drugs?
Organ damage
- liver: endothelial damage leading to venoocclusive disease
- kidneys: neurotoxicities lead to renal failure
- lung: pulmonary fibrosis
- Heart
- Also seizures, paralysis, coma
What is an example of secondary neoplasia (ie a toxic effect brought about by anti-cancer drugs?
Most alkylating agents are leukemogenic
