Cancer - Signal Transduction in Wound Healing: Pharmacogenomicsl
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- What stage of wound healing do we see PDGF and TGF-ß1 (transforming growth factor)?
- Epithelialization
- Which stage of wound healing do we see VEGF ?
- angiogenesis
- Which stage of wound healing do we see Fibrinogen --> fibrinogen?
- Break in skin (clot formation)
- Which stage of wound healing to we see MMP and reorganization of the ECM?
- Wound closure
- Which cells produce TGFß1, TGF-∂ PDGF-AB, PDGF-BB, FGF and VEGF?
- Platelets: TGFß1, and PDGF-AB… 2) Macrophages: VEGF, TGF-ß1/∂, PDGF-BB, and FGF… 3) Endothelial cells: VEGF and FGF
- What is Avastin approved use in Rx? What does it also work on?
- CRC⬦ Macular degeneration
- What is avastin mechanism of action?
- Anti-VEGF mAB
- What is the difference between Avastin (Bevacizumab) and Lucentis?
- Lucentis is second generation Avastin⬦ both are mAb against VEGF, but Lucentis is humanized (thus produces less inflammatory reponse), and is affinity maturized
- Which, Avastin (Bevacizumab) and Lucentis, has the Fc region?
- Avastin
- what is the pathway for GF (mitogen) to activate Myc genes?
- Mitogen binds (TKR) --> RAS --> MAP kinase --> Myc gene transcription
- Name the 3 different ways, Myc can activate E2F.
-
1. Increased Cyclin-D activity --> G1/S-Cdk activation --> Rb phosphorylation --> increased E2F activity⬦
2. Increased p27 degradation --> G1/S-Cdk activation --> Rb phosphorylation --> increased E2F activity⬦
3. Increased E2F synthesis --> inceased E2F activity - What is p27?
- A Cdk inhibitor
- What does E2F activity lead to?
- entry of cells from G1 into S-phase
- Is Myc a tumor suppressor or pro-oncogene?
- pro-oncogene
- What is the mechanism of action of Becaplermin (Regranex gel)?
- since the PDGF-BB TKR crossphosphorylate by dimerization, Becaplermin is two ligands covalently bound and thus causes dimerization
- What does Becaplermin effective in binding and what is it used for?
- PDGF-BB.. Used for diabetic ulcer care
- what are the theoretical side effects of engineered growth factors used in wound healing?
- malignancy and hypertrophic scars
- What is an isozyme of an enzyme?
- polymorphisms for metabolizing drugs in different people.
- What two isozymes are of therapeutic value?
- 1. The enzyme the converts the prodrug into an active drug⬦ 2. The enzyme that converts an active drug into an inactive metabolic derivative.
- In CPT-11 (Irinotecan) which is a prodrug, certain patients have less activity in the enzyme that converts the active drug into an inactive metabolite, However, the metabolite (SN-38) is toxic at high dose and causes diarrhea and leukopenia. What do you
- Reduce the dosage
- Platinum compounds damage DNA. What mechanism repairs this damage?
- Nucleotide excision repair
- Which DNA repair mechanism is used to fix Xeroderma pigmentosum? (UV damage, oxidative damage and cross-links)
- Nucleotide excision repair
-
What polymorphism do people with group D protein XPD (Xeroderma pigmentosum-D) have?
What does this polymorphism cause?
What is the faulty repair mechanism associated with XP? -
1. polymorphism at 312 and 715⬦
2. Decreased response to 5-FU/oxaliplatin
3. Nucleotide Exclusion repair - What are the 4 stated steps of wound healing physiology, starting from and including a break in the skin?
- 1. Break in the skin (clot formation) ⬦ 2. Epithelialization⬦ 3. Neoangiogenesis⬦ 4. Wound closure
- Which step of wound healing includes metabolic signals (need for oxygen and nutrients) VEGF?
- Angiogenesis
- Which step of wound healing includes degradation of ECM, Proliferation of epidermal cells, and PDGF and TGF-ß1?
- Epithelialization
- What step of wound healing includes fibrinogen --> fibrin (fibrin clot), inflammation, and platelet infiltration?
- Break in skin barrier (clot formation)
- What step of wound healing includes Reorganization of the ECM, MMPs secreted by macrophages, endothelial cells, fibroblasts, and epithelial cells in the context of signal transduction?
- Wound closure