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Who proved that smoking caused lung cancer?
Doll and Peto (epidemiologists) in the '50's, with the help of statistician Bradford Hill.
How much of lung cancer is preventable?
What may prevent cancer?
Chemopreventative agents, such as 'dietary fibre' and NSAIDs may induce apoptosis of tumours and inhibit hallmarks of cancer
non-steroidal anti-inflammatory drug e.g. aspirin
COX-2 is found in ____% of colon cancers
COX-2 leads to ____ prostaglandin E2 (PGE2) levels
What does high PGE2 do?
Promotes many hall marks of cancer (e.g. growth, survival, angiogenesis, invasion)
Why is COX-2 a good target for cancer?
No COX-2->no prostaglandins->apoptosis
can reduce the risk of colorectal cancer by inhibiting COX-1 and/or COX-2, reducing prostagladins --> apoptosis.
is an example of how one deregulated gene can affect many hallmarks of cancer
Researchers are looking for chemopreventive/therapuetic targets up and downstream of COX-2.
new biomarker for screening for cancer?
MANY CANCERS CAN BE
How can lung cancer be prevented?
How can liver cancer be prevented?
Hep-B virus vaccination/stop drinking alcohol
How can cervical/oral cancer be prevented?
How can Burkitt's lymphoma be prevented?
EBV vaccination/eradicate malaria
How can stomach cancer be prevented?
Helicobacter pylori eradication (by taking antibiotics)
How can mesothelioma/lung cancer be prevented?
Eliminate asbestos exposure/radon
a rare form of carcinoma of the mesothelium lining lungs or abdomen or heart - usually associated with asbestos exposure.
How can colorectal cancer be prevented?
Diet (specific factors - high fibre, particular cereal grains and whole grains. Low fat?)
How can breast cancer be prevented?
Diet/hormonal (high fibre, low fat)
What cancers are obesity associated with?
Breast and colorectal - diet.
prevention of cancer recurrence i.e. once primary cancer has been removed
Arrest, regress or eliminate an existing cancer
Familial Adenomatous Polyposis - inherited form of cancer
Epidemiology of breast and colon cancer
High in westernized countries, e.g. Australia/NZ and Western Europe. Lowest in Africa and Asia, where they eat a high fibre diet.
European Prospective Investigation into Cancer
Research study across Europe involving 400,000 healthy people in 7 countries. Designed to investigate why Northern European countries have higher rates of cancers (as well as autoimmune disease!) than Southern European countries
EPIC study showed a ___% reduction in risk of colorectal cancer per ___g of fibre consumed a day
How does high dietary fibre protect against bowel cancer?
Butyrate, a short chain fatty acid, is produced after fermentation of fibre by bacteria in the gut. Butyrate induces apoptosis in colonic tumour cell cultures - so may play a role in inducing in vivo colorectal cancer death.
EPIC showed in particular that _____ fibre and ______ _______ are associated with a reduction in colorectal cancer rates
cereal, whole grains
Butyrate induces _________ in colorectal adenoma and carcinoma cells
regulates apoptotic activity of Apfaf1 and caspase, controls release of cytochrome C from mitochondria
-inhibit apoptosis and are therefore protooncogenes
-inhibited by BAD
-others in family promote apoptosis Bax/Bak and Bid/Bim allow cyt-C release
What effect does butyrate have on bcl-2?
Downregulates bcl-2 -> apoptosis can be activated (not a hallmark of cancer)
CELL SURFACE, Cell Adhesion, Carcinoma of Stomach, Associated w/ Familial Gastric Cancer
What effect does butyrate have on E-cadherin?
Upregulates E-cadherin -> adhesion (cancer - anchorage independent)
A pro-apoptotic factor that cause the mitochondria to lose cytochrome c. Opposes effect of bcl-2.
What effect does butyrate have on Bax?
Upregulates bax -> induces apoptosis.
injection of a liquid through the anus to stimulate evacuation
Butyrate enema _____ IBD symptoms
Pertaining to any new and abnormal growth, specifically a new growth of tissue which is progressive and uncontrolled. These growths are generally called tumors. A neoplasm can be either benign or malignant. Malignant means tending to become progressively worse, resulting in death. Benign is simply the opposite of malignant. Cancer is a neoplastic disease.
Neoplastic cells use _____ as an energy source
Accumulation of butyrate in tumorigenic environment, rather than glucose, induces _______
Normal colorectal epithelium uses _______ as an energy source
Bacterial fermentation product, ______, which can inhibit colorectal tumours, is an excellent example of the symbiosis between man and bacteria
may be targeting cancer stem cells to reduce incidence of colorectal cancer
NSAIDs, such as aspirin, _______ risk of colorectal cancer
Harold Elliott Varmus
1989 co-Nobel prize winner for discovery of the cellular origin of retroviral oncogenes.
Where can a natural drug related to aspirin be found?
Willow tree bark
Natural salicin (salicylic acid)
causes irritation - modified chemically to produce acetyl salicylic acid (aspirin)
anti-inflammatory drug that inhibits prostaglandins
aspirin, salicylic acid (salicylic), ibuprofen, sulindac, indomethacin, piroxicam
Natural salicylates induces ______ in plants
Elder et al. in 1996 suggested
aspirin induces apoptosis in colon tumour cells
inflammation, fever and pain
First clue that NSAIDs were effective against cancers...
Sulindac was given to relieve pain in FAP patients - dramatic regression of polyps also seen. Are NSAIDs targeting tumour stem cells to undergo apoptosis?
prostaglandin endoperoxide synthase
Two main isoforms of COX
COX-1 AND COX-2 (genes found on different chromosomes - 9 and 1 respectively)
Is there a COX-3 isoform?
Yes, but it is assumed to be non-functional in humans
COX-1 and -2 are involved in the conversion of ___________ acid to ______________ (e.g. PGE2)
constitutively expressed in most normal tissues (e.g. gastric mucosa/GI bleeding)
particularly important for the development of healthy mucosa in the stomach - protects the gastric lining from the action of gastric acid.
most normal tissues do not express COX-2
BUT COX-2 is constitutively expressed in...
the brain, pancreatic islet cels, ovary, uterus and kidney
COX-2 is _____________ in most bowel cancers (but not COX-1)
COX-1 gene found on chromosome
COX-2 gene found on chromosome
COX-2 is _____________ in most cancers
COX-2 expression is elevated in a number of tumours, including
colorectal carcinoma's, barrett's esophagus, bladder, breast, oesophageal adenocarcinoma, head and neck, kidney, lung, pancreas and prostate
Destruction of the esophagus due to reflux
Precursor to esophageal cancer
COX-2 may be a proto-________
Aspirin strongly inhibits _____
Aspirin weakly inhibits _____
Aspirin, although it does reduce the risk of colorectal cancer, it is not recommended for the general public due to its _______ side effects
Is aspirin a selective or non-selective NSAID?
Low dose aspirin is recommended in some cases
for high risk heart attack patients. Also, under trial in patients with, or at high risk of developing, hereditary bowel cancer.
Unwanted side effects of aspirin due, in part, to
inhibition of COX-1
Anti-cancer effects of NSAIDs act through
inhibition of COX-2 and prostaglandin production
COX-2 selective NSAIDs
celecoxib and rofecoxib
- produced by pharmaceutical companies in the hope that they would induce less GI bleeding. However, these drugs also have side effects e.g. increased risk of thrombosis
Prostaglandins increase _________ and decrease _________
block the action of COX-1 and -2 (no prostaglandins produced from arachidonic acid), and instead arachidonic acid remains in the cytoplasm. This causes sphingomyelin, a type of sphingolipid found in animal PMs, to be converted into ceramide. This acts as a signal for the cell to apoptose.
Traditional NSAIDs, sulindac, sulfone and COX-2 selective NSAIDs
also act on COX and non-cox targets to induce apoptosis.
Levels of PGE2 are controlled by 3 factors
COX (1 and 2)
Rate of uptake by the cell through its prostaglandin transporter
Enzymic degradation (by the TSG 15-PGDH)
- all are considered good targets for chemoprevention
COX-2 and PGE2 are ____-tumorigenic
Transfection of COX-2 into intestinal cells leads to:
COX-2 overexpression -> malignancy
Decreased expression of TGF beta receptor expression (normally sends growth, differentiation and apoptotic signals to the cell)
Increased bcl-2 expression and PGE2 -> protects from apoptosis
->Resistance to apoptosis induced by butyrate
Elevated matrix metalloproteinase secretion -> Increased cell migration and invasion
Celecoxib ______ the number of polyps in familial adenomatous polyposis (FAP)
COX-2 inhibitor, Celecoxib (400mg) given twice daily to FAP patients over six months
-> significant reduction in the number of colorectal polyps. (N. Engl. J. Med. 2000)
Sets with similar terms
Module 7 Patho