Term
| How does radiation therapy kill cells? |
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Definition
Creates oxygen radicals- these generate reactive compounds that damage DNA
Selectively kills proliferating cells in late G2/M. cells in earlier phases have time to repair their DNA
Hypoxic tumors are less sensative to radiation |
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Term
| How targeted cancer therapy exploits genetic difference to selectively kill cancer cells |
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Definition
Cancers are genetically different from normal tissues
Each tumor is unique, however, mutations in the same proteins are found in many different tumors
Targeting proteins that are overexpressed or overactive in cancer cells kills them with minimal damage to normal cells |
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Term
| Types or proteins that are potential anticancer drug targets |
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Definition
1) Cell cycle control and proliferation (kinases)
2) Protein degradation (ubiquitin pathway)
3) Angiogenesis - (Receptors/GF/ECM)
4) Apoptosis
5) Overexpressive cell surface antigens |
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Term
| Chronic Myelogenous leukemia |
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Definition
Occurs with a translocation between chromosome 9 and 22, where the N-abl from chromosome 9 fuses with the C-bcl.
abl is involved in cell proliferation.
bcr-abl is constitutively active
Increased tyr-kinase activity-overproliferation
Cells accumulate abnormalities. |
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Term
| Is Bcr-abl a good drug target |
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Definition
Key role of bcr-abl in CML suggested it was a good target for chemo
Kinase domains are usually highly conserved-inhibitors of ATP binding were considered non specific targets.
Specificity is crucial because there are many tys kinases in transduction
An inhibitor was found (STI 571) which binds with greater affinity to Bcr-Able tys kinase than ATP |
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Term
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Definition
Works for CML. Also binds to c-kit and Platelet derived growth factor receptor, and gastrointestinal stromal tumors.
Unfortunatly unlike GIST amd CML, most cancers have multiple singles that drive them |
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Term
| Developing resistance to Gleevec |
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Definition
Mutant bcr-abl can no longer bind to the drug
bcr-abl can be amplified means that not enough drug to block activity
Increased production of alpha1-acidic glycoprotein(plasma protein that binds drug)
Cancer stem cells are not killed |
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Term
| Ways to prevent or overcome drug resistance |
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Definition
Combination therapy
Switch to new inhibitor (BMS-354825 is analog)
Design additional therapies that target cancer stem cells |
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Term
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Definition
EGFR is a tyr-kinase.
GF binding (EGF, TGF) to exxtracellular receptors leads to activation of signal transduction
Signalling is involved in proliferation, apoptosis, angiogenesis, and metastasis
EGFR and TGF overexpression is common in nonsmall cell lung cancers. |
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Term
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Definition
Tarceva and Iressa inhibit ATP binding to EGFR.
Inhibit cancer cell proliferation
Induce apoptosis
Inhibit angiogenesis
Inhibit metastasis |
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Term
| Proteasome as a drug target |
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Definition
Proteasome controls protein degradation.
Poly-ubiquitination targets proteins to the proteasome.
Ubiquitination is carried out by the E1, E2, and E3 ligases. |
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Term
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Definition
E1 is ubiquitin activating enzyme
E2 is ubiquitin conjugating enzyme
E3 is substrate recognition and transfer of ubiquitin to protein
After poly-ubiquitination, the protein is escorted to proteasome by escort protein |
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Term
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Definition
E3 ligases - substrate specific
Proteases - some specificity
Proteasome inhibition stabilizes inhibitory factors to growth arrest and cell death |
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Term
| Proteins in the proteasomal system implicated in cancer |
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Definition
| Mdm2-E3 ligase overexpresse in some cancers, inhibits p53 function-BRCA1 |
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Term
| Proteins whose abnormal degradation contributes to cancer |
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Definition
| p53 transcription factor (loss of function) |
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Term
| Targeting the p53 pathway |
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Definition
p53 degradation regulated by polyubiquitination via mdm2
mdm2 is overexpressed in some cancers
Results in degradation of p53 and loss of function
In tumors with wildtype p53, inhibition of mdm2 restores p53 tumor suppression function |
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Term
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Definition
Nutlin 3 - Found by chemical library screen, small molecule inhibitor of E3 ligase mdm2
Binds in the p53 pocket of mdm2, displaces p53
p53 doesn't get ubiquinated
restores the p53 pathway |
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