Cancer 3 Flashcards
benign tumour characteristics
Generally self contained and localised
well defined periphery
slow growing
expands outwards from central mass
Malignant tumour characteristics
Not self contained or localised
presence of invading cells at periphery
able to spread
have capacity for rapid growth
metastic tumors
Hard to treat surgically
impair organ function
chemo resistant
How do cancer metastases
Lymphatic system is a common pathway for the initial spread of solid tumour
pattern of lymph nodes involvement follows natural route of drainage
can also spread through the body wall into abdominal and chest cavities
involvement of lining of cavities results in inflammatory response, accumulation of fluid and inflammatory cells
Metastasis: Cell-cell adhesion
E-cadherin plays a critical role and functions as a tumour suppressor
Reduced expression of E-cadherin increases invasiveness of Tumour cells
E-cadherin loss enables disaggregation of cancer cells
Loss of E-cadherin expression correlates with poor prognosis
Metastasis: Invasion into surrounding tissue
Malignant tumour secrete proteases that target the basement membrane
Facilitates local tissue penetration and entry into circulatory system
metastasis: Angiogenesis
Formation of new blood vessels from pre-existing ones
Blood supply needed for tumour growth
Facilitates tumour metastasis
Angiogenesis
- Release of angiogenic factors and proteases by tumour cells
- Degradation of basement membrane and proliferation of endothelial cells
- Migration of endothelial cells in direction of tumour
- Formation of tubular structures which anastomose with existing vasculature
sustained proliferative signaling
- Normal tissue carefully controls the production and release of growth promoting signals that instruct entry/progression through the cycle
- Cancer cells dysregulate these signals to become masters of their own destiny
- Cancer cells acquire capability for sustained proliferation in many ways
- They produce growth factor ligands themselves and respond via expression of cognate receptors
- They send signals to stimulate normal cells within the tumour associated stroma -> which then deliver various growth factors to the cancer cells
- Receptor signalling can also be dysregulated by elevating the number of protein receptors on the cancer cell surface -> rendering cells hype responsive to limiting amounts of growth factor
- Growth factor independent can also be derived from constitute activation of components of signalling pathway operating downstream of receptors -> no need for ligand mediated activation
Disruptions of Negative Feedback mechanisms
- Negative Feedback loops normally dampen down activity and regulate proliferative signals
- Defects in feedback can enhance proliferative signals -> RAS mutation
- Oncogenic effects of RAS are not seen in the hyperactivation of signalling, instead it affects RAS GTPASE activity which normally ensures the active signal transmission is transitory
EGFR inhbitors
When EGFR is active it triggers a cascade of signalling events that promotes proliferation
Sustained proliferative signalling occurs when aberrantly activated EGFR continuously stimulates cell proliferation (even in absence of GF)
EGFR inhibitors disrupts sustained proliferative signalling, slowing down cell division and potentially reducing tumour growth
Small molecule tyrosine kinase inhibitors (gefitinib) block the ATP binding site of the EGFR tyrosine kinase domain, inhibiting enzymatic activity and downstream signalling
Epidermal growth factor receptor
Inhibitors target the hallmark sustained proliferative signalling
EFGR is overexpressed in cancer cells -> uncontrolled proliferation and tumour development
the 4-Aniloquinazoline is important pharmacophore for EFGR tyrosine kinase inhibition
SAR shows electron groups are needed at the 6,7 positions and a small lipophilic group at 3’
Gefitnib
Pharmacophore
The portion of a molecule that determines the biological effects of a drug
Enediynes
Calicheamicin
- Targets DNA by binding to the major groove
- Polysaccharide chain containing aromatic ring and iodine atom binds to TCCT. TCTC, TTT regions
- Cellular activation produces a nucleophilic S
- Formation of new S ring causes the enediyne ring to shrink
- Cycloaromatization generates reactive benzene diradical
- Diradical cleaves both strands of DNA = CELL DEATH
DNA Repair - PARP
- Many enzymes repair DNA including PARP and BRCA1/2
- Ovarian and breast cancers are often deficient in BRCA1/2 which are the tumour supressors
- If PARP is inhibited in the cells, DNA repair is not possible and the cancer cells die
- PARP uses NAD+, nicotinamide region binds to the active site
- The adenine dinucleotide portion forms protein bound polymer - cellular signals for repair
