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Name the pro-apoptotic and anti-apoptotic BCL2 proteins involved in mitochondrial apoptosis signaling.
- • Pro-apoptotic BCL2
- proteins – BAD, BID, BAX, BIM
- • Anti-apoptotic BCL2 proteins – BCL2,
- BCL-XL
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This pro-angiogenic factor diffuses into nearby tissues and activates receptors on the endothelial cells of pre-existing blood vessels.
VEGF
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DNA Crosslinking agents.
- Nitrogen mustards
- nitrosoureas
- hydrazines and triazines ( do not form crosslinking)
- platinum compounds
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How to identify platinum compounds.
Pt.
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classes of antimetaolites
- purine analogs
- pyrimidine analogs
- antifolates
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Purine analog (6-mercaptopurine)
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- antifolate (methotrexate)
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How could cancer be cured by 2015?
•Screening for early detection of malignancies
•
•Chemoprevention
•
- •Three potential therapeutic strategies to
- improve selectivity:
Cancer-specific targets
- Universally-vital target
- with selective protection of normal cells
Tissue-selective therapy
•Change of lifestyle
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Why target DNA?
- DNA sequence information is pivotal to transcription, replication and recombination. DNA structure is dependent upon intracellular conditions such as ion concentration and the presence of proteins that may bind to DNA to facilitate the interconversion between different
- forms and to stabilize specific secondary structures
- 1.Genetic information
- 2.High rate of proliferation of cancer cells
- 3.Well defined structures
- 4.Enough complexity to achieve selectivity/specificity
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6 Classes of DNA Interactive Agents
- 1. DNA-DNA crosslinkers
- 2. DNA intercalators
- 3.Double stranded break
- 4. code reading
- 5. protein-DNA complex
- 6. Agents which react with secondary DNA structures, such as guanine tetrad (no drug for this class)
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4 different forms of cisplatine-DNA adducts
- interstrand crosslinking
- 1,2-intrastrand crosslinking
- 1,3-intrastrand crosslinking
- DNA protein crosslinking
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Mechanisms of resistance to Cisplatin
- decrease the effective concentration in the cell by:
- 1. Reduction of intracellular drug accumulation (increasing deactivation of Cisplatin by Glutithione or hydrolysis and/or efflux increase
- 2. increased inactivation by thiol-containing molecules (see above)
- 3. increase of DNA damage repair
- 4. increase tolerance
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Distinguishing characteristic of DNA intercalator molecules
- must be flat
- usually aromatic system
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Two types of tubulin-binding agents
Polymerization inhibitors – block addition of dimers to growing + end, continue to dissociate from – end
Depolymerization inhibitors – block the dissociation and promote and stabilize the formation of microtubules
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4 MOA of RB protein deactivation.
- viral inactivation
- gene mutation
- phosphorylation (endogenous mech)
- degradation
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