Pregunta 1
Pregunta
Targeted cancer therapies are products of [blank_start]rational[blank_end] drug design, act on [blank_start]specific[blank_end] molecular targets, and are generally [blank_start]cytostatic[blank_end]. They interfere with specific molecules involved in cancer cell [blank_start]growth and survival[blank_end]. Can be:
1. [blank_start]Small molecule[blank_end] drugs, easily enter tumour cell
or
2. [blank_start]Moncolonal antibodies[blank_end], bind to specific targets on cell surface
Respuesta
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rational
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specific
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cytostatic
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growth and survival
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Small molecule
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Moncolonal antibodies
Pregunta 2
Pregunta
Tumour associated antigens (TIAs) are optimal blocking targets.
Pregunta 3
Pregunta
Products of activated oncogenes include cell surface receptors that [blank_start]activate[blank_end] tyrosine kinases. Tyrosine kinase [blank_start]autophosphorylates[blank_end] the receptors in the cell to make: [blank_start]vascular endothelium[blank_end] derived growth factor receptors, human [blank_start]epidermal[blank_end] growth factor, and [blank_start]platelet[blank_end]-derived growth factor receptors. These stimulate [blank_start]proliferation[blank_end] and block [blank_start]apoptosis[blank_end].
Chromosomal abnormalities are in cancer cells but not normal cells. [blank_start]Thee[blank_end] fusion gene which causes the abnormality makes fusion proteins that[blank_start]. drive[blank_end] cancer development. We can identify cancerous proteins and [blank_start]block[blank_end] their production. Example: Chronic [blank_start]myeloid leukaemia[blank_end] often have the Philadelphia chromosome, which creates a [blank_start]BCR-ABL[blank_end] fusion protein. In cancer it causes constitutively active [blank_start]tyrosine kinase[blank_end] activity.
Respuesta
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activate
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autophosphorylates
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vascular endothelium
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epidermal
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platelet
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proliferation
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apoptosis
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The
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drive
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block
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myeloid leukaemia
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BCR-ABL
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tyrosine kinase
Pregunta 4
Pregunta
Imatinib: First NIB approved by FDA. The suffix "nib" indicates a small-molecule [blank_start]inhibitor[blank_end] ("nib" is verbal shorthand for "inhibit") of kinase enzymes.
- A small molecule [blank_start]intracellular[blank_end] inhibitor of tyrosine kinase
- Treats chronic myeloid leukaemia; as it is selective for [blank_start]BCR-ABL[blank_end] TK fusion protein and competes with [blank_start]ATP[blank_end] for binding siten inhibiting phosphorylation (and [blank_start]proliferation[blank_end]).
Other NIBs in clinical use: gefitinib, erlotinib, sorafenib, sunitinib, and dasatinib.
- Share [blank_start]same[blank_end] mechanism of action (competitive ATP inhibition at catalytic binding site of TK) BUT difference is the [blank_start]spectrum[blank_end] of targeted kinases
e.g. [blank_start]sunitinib[blank_end] inhibits signals from several Rs including VEGF and PDGRF families.
NIBs are well tolerated but frequently cause [blank_start]myelosupression, rash, GI upset, fatigue[blank_end], arthralgia, & myalgia. Rarely
cumulative cardiotoxicity: [blank_start]monitoring[blank_end] needed.
Pregunta 5
Pregunta
Targeted therapy with monoclonal antibodies:
Target is angiogenesis, specifically the key targets [blank_start]VEGF-A and VEGFR2[blank_end].
Bevacizumab (brand name Avastin): [blank_start]recombinant humanized[blank_end] monoclonal v VEGF-A, given by [blank_start]intravenous[blank_end] infusion, first line for [blank_start]colorectal, lung, renal[blank_end] cancer.
Mode of action:
Prevents VEGF-A [blank_start]binding[blank_end] and so prevents tumour vascularisation and growth. Serious unwanted effects:, [blank_start]Hyper[blank_end]tension
• Infections (from [blank_start]neutropaenia[blank_end]), impaired [blank_start]would[blank_end] healing, bleeding, GI perforation, haemorrhage. [blank_start]DVT, PE[blank_end] in the elderly.
Pregunta 6
Pregunta
Target: Human epidermal growth factor 2 (HER-2)
Receptor coupled [blank_start]enzyme[blank_end], binds to EGF.
• Normally promotes growth and [blank_start]differentiation[blank_end]
• Integral [blank_start]tyrosine kinase[blank_end] activity inhibits p27 (cyclin dependent cell cycle [blank_start]regulator[blank_end])
• Stimulates [blank_start]proliferation[blank_end]
• HER2 is found in 20-30% of breast tumours.
Respuesta
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enzyme
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differentiation
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tyrosine kinase
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regulator
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proliferation
Pregunta 7
Pregunta
Trastuzumab (Herceptin):
[blank_start]Humanised mouse[blank_end] monoclonal of HER2, for [blank_start]metastatic[blank_end] breast cancer.
Mode of action: G1 [blank_start]arrest[blank_end] - less proliferation(no change in HER2 expression). Downregulates [blank_start]kinase[blank_end] activation, causing less [blank_start]PI3K, Akt[blank_end], which activates [blank_start]p27[blank_end] and halts cell cycle.
Pertuzumab:
inhibits HER2 [blank_start]dimerisation[blank_end].
Respuesta
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Humanised mouse
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metastatic
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arrest
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kinase
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PI3K, Akt
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p27
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dimerisation
Pregunta 8
Pregunta
Unwanted effects of monoclonal ABs:
Mechanism dependent.
Common:
• [blank_start]Infusion[blank_end] related SEs ([blank_start]cytokine[blank_end] release syndrome), 1st infusion
• [blank_start]Fever, chills,[blank_end] nausea and vomiting, hypersensitivity
More Serious
• [blank_start]Tumour Lysis Syndrome[blank_end] - release of cellular contents: high K+, P, uric acid, N, low Ca2+ = kidney [blank_start]failure[blank_end], seizures, [blank_start]cardiac[blank_end] arrhythmias, death.
• Increased [blank_start]infection[blank_end] risk (HepB/reactivation)
• Caution: autoimmune disease, HIV
Respuesta
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Infusion
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cytokine
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Fever, chills,
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Tumour Lysis Syndrome
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failure
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cardiac
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infection
Pregunta 9
Pregunta
Target: Cell surface glycoproteins.
[blank_start]CD20[blank_end] antigen found on the surface of normal and malignant B lymphocytes, function unknown. Can activate [blank_start]B[blank_end] cells.
Drug: Rituxumab.
Mediates B cell [blank_start]lysis[blank_end].
- [blank_start]Complement[blank_end] dependent cytotoxicity (CDCC)
- [blank_start]Antibody[blank_end] dependent cell-mediated cytotoxicity (ADCC)
- Apotosis
• [blank_start]Increases[blank_end] NK cell success from 40-80%
Unwanted effects, most serious:
• Cardiomyopathy
• [blank_start]Infusion[blank_end] related SEs
• Hypersensitivity ([blank_start]first[blank_end] infusion)
• Myelosupression
Respuesta
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CD20
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B
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lysis
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Complement
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Antibody
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Increases
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Infusion
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first