Cancer MCFM
Terms
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- caspases
- cysteine proteases cut after aspartic acid residues
- apoptosome
- made by activation of Apaf-1 which occurs after cytochome c release causes dATP->dADP. It forms a heptameric molecule that can then activated by procaspase 9
- Bcl-2/Bax
- modulate cytochrome c release from mitochondria
- Bcl-2
- possible family members are oncogenes that work by blocking apoptosis. Tere also proapoptotic proteins in this family
- DISC
- death inducing signalling complex, recruited after Fas/FasL binding. It consists of procaspase 8 or 10 and a death ligand that is a trimer and a death receptor that is also a trimer
- Bid
- proapoptotic protein BID interacts with another Bcl-2 family protein, Bax, leading to the insertion of Bax into organelle membranes, primarily the outer mitochondrial membrane
- Bcl-2 inhibition activity
- can also prevent apoptosis from occuring by blocking cytochrome c release
- CAK
- cyclin activating kinase. It is not enough for cyclin to bind the cdk. the complex must also be phosphorylated
- wee-1 kinase/Cdc25
- phosphorylates cdk/cyclin complex at an inhibitory site cdc25 is a phosphatase that increases Cdk activity
- CKI
- cyclin kinase inhibitor can bind tot he activated cyclin-Cdk complex inactivating it
- Rb
- active Rb protein binds to txn factor E2F to tell it that DNA synthesis shouldn't happen. RB associated with retinoblastoma. Rb can be inactivated by phosphorylation--> transcription occurs and eventually DNA synthesis
- Rb: HDAC
- active Rb complexes with HDAC and inactivated HDAC dissociates from HDAC
- APC
- anaphaase-promoting complex is a ubiquitin ligase--attches ubiquitin to a target protein
- p53
- "guardian of genome" in response to hyperproliferative signals, DNA damage, hypoxia, telomere shortening p53 can lead to cell cycle arrest, senescence, apoptosis
- p21
- inhibits G1/S progression. p21 is activated by p53. p21 is a Cdk inhibitor protein that binds to Cdk/cyclin complex to cause cell cycle arrest in response to DNA damage
- Mismatch repair
- involves enzymes MutS and MutL that excise newly synthesized strand and repair DNA break
- base excision repair
- an example is uracil DNA glycosylase which excises base and aP endonuclease and phosphodiesterase removes sugar phosphate then DNA polymerase and DNA ligase seals nick
- nucleotide excision repair
- removal of pyrimidine dimerss. First, excision nuclease removes region with dimer and then the correct nucleotides are added and strands are ligated
- Nonhomologous end joining
- after a double stranded break, ends are degraded and ends are joined without matching DNA
- homologous end joining
- repairing double stranded breaks using information from sister chromatid. Some nucleotides from ends are lost still
- XP (xeroderma pigmentosum)
- defective nucleotide excision repair, autosomal recessive, cells are hypersensitive to killing by UV
- PARP
- adds poly ADP-ribose groups to sites of DNA breaks in order to recruit enzymes of DNA repairs
- wound healing
- clot formation, inflammation, platelet infiltration, degradation of ECM, PDGF, TGFBeta1, neoangiogenesis cancer= wound that does not heal
- mitogen
- agent that stimulates entry into the cell cycle. Can activate Ras which activates MAP kinase and gene expression
- Myc
- a gene regulatory protein which increases expression of delayed-response genes including some that lead to G1-Cdk activity which triggers phosphorylation of Rb family of proteins, inactivating them and freeing E2F to activate txn of G1/S genes and promoting a positive feedback loop
- avastin
- a drug used to treat wet Age-related macular degeneration by targeting VEGF for destruction. It is whole ab that is humanized it has an FC portion so it can also activate complement (bad)
- lucentis
- another drug used to treat wet AMd but it is a humanized Ab that is affinity purified w/o Fc portion of ab
- pharmacokinetics
- determining what happens to substances that are administered to a person or animal
- pharmacogenetics
- anaylsis of variations in indvdl genes for differences related to drug responses
- genetic heterogeneity
- mutations in different genes cause the same disease
- allelic heterogeneity
- different mutations int he same gene cause disease
- 2 Hit hypothesis
- first hit can occur in the germline of the child (one chromosome) and the second hit can occur at another time in the lifetime of the person at the 2nd chromosome resulting in a loss of heterozygosity
- 6 features of cancer cells
- 1)unrestrained proliferation 2) avoid programmed cell death 3) avoid senescence or differentiation 4) genetically unstable 5) able to invade 6) they grow in foreign sites
- proto-oncogene
- a normal gene involved in regulating/performing critical cellular processes such as growth survival. Only one copy mutated can cause oncogenic effect
- oncogene
- when a proto-oncogene is mis-expressed, over-expressed, or abnormally activated. It can act dominantly to deregulate cells
- tumor suppressor gene
- when inactivated causes cancer by promoting cell proliferation. These loss of function mutations can cause release of cells from growth control, lose apoptosis pathways, result in genomic instability
- Rous sarcoma virus
- a retrovirus that contains a mutation in the gene encoding Src
- activation of oncogenes (methods)
- point mutation leading to hyperactive protein made in normal amt or regulatory mutation, gene amplification or chromosome rearrangment leading to protein being overproduced. chromosome rearrangment can also lead to hyperactive protein being produced
- inactivation of tumor suppressor genes
- nondisjunction leading to chromosome loss, chromosome loss then chromosome duplication, gene conversion, deletion, point mutation, epigenetic modification can also inactivate a gene through methylation-->heterochromatin
- gatekeeper tumor suppressor genes
- directly regulate cell proliferation by regulating cell cycle checkpoints or promoting apoptosis
- caretaker Tumor suppressor genes
- protect the integrity of the genome. Loss of function of these genes promotes accumulation of mutations in oncogenes and gatekeeper TSG's. Thus they indirectly control cell proliferation
- Basal Cell Nevus Syndrome
- germline mutations in Patched gatekeeper tumor suppressor gene. PTCh1 involved in nucleotide excision repair
- Her-2
- an oncogene involved in breast cancer. It is a target for breast cancer therapeutics because ab against Her-2 improve survival
- gleevac
- used as a treatment for chronic myelogenous leukemia. It blocks the catalytic activity of Bcr-Abl
- other cells in tumor microenvironment
- mast cells, fibroblasts, myofibroblasts, macrophages Growth factors: epidermal growth factors (EGF) survival factors: insulin-like growth factor (IGF) Angiogenic factors- Vascular Endothelial Growth Factor (VEGF) proteases: MMP's
- EMT (epithelial to mesenchymal transition)
- a method by which cells escape from the tumor. It results in loss of cell adhesion(down regulation of E-cadherin)
- tumor associated macrophages
- assist tumor cells in migrating along collagen fibers to blood vessels
- sentinel node biopsy
- blue or radioactive dye is injected into a tumor and the first lymph node the tumor cells migrate to is removed
- circulating tumor cells
- predict tumor progression. They are detected by RT-PCR for epithelium-specific transcripts or by immunopurification from blood. Different CTC's have different abilities to invade particular organs
- prostrate cancer (nuclear hormone receptor)
- can measure PSA (prostrate specific antigen) Treatment: can target androgen receptors you can also use an LHRH agonist to block LH production and thus testosterone production
- breast cancer (nuclear hormone receptor)
- treatment: control estrogen synthesis by 1) removing ovaries 2) tamoxifen-blocks estrogen receptor 3) aromatase inhibitors which block androgen conversion to progesterone
- Kaposi's Sarcoma
- caused by Human Herpesvirus with a G protein coupled receptor domain that can induce secretion of VEGF. Thus KSHV GPCR is a viral oncogene
- erbB2 (HER2)
- epidermal growth factor receptor family of receptor tyrosine kinases. Overexpressed in some breast cancers. Erb2 dimerizes and signals
- Herceptin
- anti-erbB2 antibody it's mechanism is unclear but causes tumor loss in breast cancer
- Iressa
- treatment for lung cancer. epidermal growth factor blocker by blocking to EGF receptor side effects: rash, diarrhea (areas of epidermal growth) Some don't respond to drug; those who respond best are people with mutated receptor that overactivates the receptor
- chemotherapy steps
- induction-initial high dose consolidation=repetition of induction intensification-higher doses of induction regiment maintenace-long term, low dose regimen
- adjuvant
- after eradication of tumor by surgery/other treatments, short course of high dose chemo to remove residual tumor cells
- neoadjuvant
- chemotherapy given in pre- or perioperative period to downstage tumor before surgery
- primary chemotherapy
- like neoadjuvant but also describes chemo given in absence of surgery or radiation
- methotrexate
- an antimetabolite that blocks DNA replication
- alkylators
- crosslink DNA like nitrogen mustards, hydrazine, aziridines, epoxides, etc
- platinum derivatives
- prevent DNA replication so cell can't divide anymore includes cisplatin, carboplatin, oxaliplatin
- Topoisomerase interactive agents
- prevents resealing of SS or DS DNA after nicks made by Topo
- Anthracyclines
- come from streptomyces They inhibit topoisomerase, intercalate DNA or cause free radical damage
- Taxol
- microtubule disruptors so they affect G2/M phase. Vinca alkaloids are also microtuble disruptors
- Gompertzian growth of tumor
- the larger the tumor, the smaller the percentage of cells dividing making it resistant to drugs
- CD20 antigen
- expressed in normal pre-B and mature cells as well as malignant B lymphocytes. It is not found in stem cells, pro-B cells, plasma cells
- phases of clinical trials
- 1) determine dosage 2) drug activity in specific tumors 3) compare to standard therapy 4)role of drug in curative setting
- acute promyelocytic leukemia
- low platelet, low RBC's, high WBC's Translocation between chromosomes 17 and 15.It involves PML and RAR (retonoic acid receptors) Treatment: high doses of retinoic acid
- chronic myelogenous leukemia
- see many neutrophil precursors in blood, low platelets, high WBC's Caused by Philadelphia chromosome-trnaslocation between chromosome 9 and 22 to create Bcr/ABL fusion protein ( a tyrosine kinase) which is constitutively active (doesn't need a ligand)
- thrombocytosis
- increase in platelet number
- polycythemia
- increase in blood volume can be due to a malignancy
- Myeloproliferative disease
- overactive Jak in stem cells of bone marrow of patients leading to thrombocytosis and myelofibrosis
- Apaf-1
- cytochrome c released from mitochondria binds to Apaf1 causing it to oligmerize into apoptosome
- Bak
- found on the mitochondrial membrane, helps induce release of cytochrome c
- death receptor/death ligand
- extracellular signal proteins that trigger extrinsic pathway of apoptosis. An example is the Fas receptor/Fas ligand
- FADD
- fas associated death domain--it is an adaptor protein recurited by Fas which then recurits initiator procaspases to form DISC complex
- TNF-RIP pathway
- for NF-kB activation via TNF. This occurs in response to DNA damage.
- cyclophilin D/mitochondrial permeability transition pore
- cyclophilin D is a component of the transition pore involved in apoptosis
- CPT11
- works along with p53 to promote apoptosis of cancer cells. It is used in chemotherapy. If p53 is mutated it reduces its efficacy
- Flavopiridol
- promotes apoptosis. it is used in conjunction with CPT11 to treat cancer. p53 mutations reduce its efficacy
- p27
- CKI that binds to cyclin-cdk complex
- G1-Cdk complex
- it makes sure there is a favorable extracellular environment
- E2F
- txn control of s-phase gene transcription that leads to DNA synthesis of S phase
- Mut L/ Mut S
- mismatch repair proteins that identify newly synthesized strand and excise bad part
- uracil DNA glycosylase
- base excision repair enzyme
- age related macular degeneration
- related to neovascularization so can treat with Lucentis or Avastin
- SN-38/ SN-38 conjugate
- CPT 11 is the inactive drug that gets converted to SN 38. SN-38 gets converted to SN-38 conjugate (inactive by-product). The conversion to an inactive metabolite is dependent on a mutant or wild type promoter
- xeroderma pigmentosum (XP)
- caused by a defect in nucleotide excision repair. It is an autosomal recessive disorder that leads to increased risk of cancer
- Ras
- activates MAP kinase eventually resulting in gene expression in the nucleus
- cyclin D/Cdk4 complex
- in a proliferating cell this complex is active; overactivity of this complex encourages cell division by phosphorylating Rb
- ALL (acute lymphocytic leukemia)
- also indicated by the presence of a philadelphia chromosome