Cancer - malignant disease & cytotoxic chemotherapy Flashcards
tania webb
What are the causes of cancer?
Driven by mutated genes and their encoded proteins.
Mutations can be caused by:
Damage to DNA caused by oxygen free radicals.
Errors introduced during DNA replication or ineffective DNA repair.
Errors introduced during cell division.
Environmental factors.
Inflammation.
If they are introduced into the germline cells they can be inherited and have the potential to cause cancer in future generations.
How can viruses cause cancer?
Viruses with oncogenic potential require cofactors for cancer progression - typically including inflammation and imbalance of normal microflora (dysbiosis).
Give an example of one bacteria with a class 1 carcinogen status:
Helicobacter pylori.
What viruses are able to activate cell division (oncogenic)?
Hepatitis B virus and hepatitis C virus (HBV and HCV), are associated with hepatocellular carcinoma.
The Herpes viruses - Epstein-Barr virus is associated with Burkitt’s lymphoma, nasopharyngeal carcinoma, and a subset of gastric carcinoma.
Papillomaviruses (HPV) strains are associated with anogenital cancers, some head and neck cancers and skin cancers.
How does injury cause chronic inflammation and cancer?
Tumour formation has also been linked to chronic inflammation caused by injury:
Mechanical.
Chemical.
Due to inherited mutations.
How can chronic inflammation result in cancer?
Proposed mechanism 1:
Production of reactive oxygen and nitrogen species that induce the formation of DNA cross-links, single- or double-strand breaks that can drive:
Genomic instability.
Mutations within oncogenes and tumour suppressor genes.
Proposed mechanism 2:
Cancer-associated inflammation leads to immunosuppression of an anti-cancer immune response.
Proposed mechanism 3:
Macrophages and monocytes cause remodelling of tissue promoting proliferation - changes in gene expression mediated by transcription factors e.g. NF-κB which induces the expression of:
Bcl-2 and Bcl-xL (anti-apoptosis).
Cyclin D (cell proliferation).
VEGF (angiogenesis / cell invasion).
What is the tumour classification of leukaemia?
Production of blasts / leukaemia cells (undifferentiated white blood cells).
What is the tumour classification of a solid tumour?
An abnormal mass of tissue that usually does not contain cysts or liquid areas.
Benign - usually encapsulated.
Malignant - has ability to invade tissue and undergo metastasis.
What are the characteristics of malignant solid tumour cells?
Lack differentiation - are not specialised
Have abnormal nuclei - enlarged, number of chromosomes may be increased or decreased, chromosomes may have deletions, duplicated portions.
Form tumours - loss of contact inhibition, grow in multiple layers, uncontrolled growth i.e have reduced need for stimulatory growth factors, don’t respond to inhibitory growth factors, are immortal.
Undergo metasis - the development of secondary malignant growths at a distance from a primary site of cancer.
Undergo angiogenesis - formation of new blood vessels necessary for nutrients and oxygen to reach the tumour.
What is the rationale for using cytotoxic chemotherapy?
Cancer chemotherapy aims to induce apoptosis or senescence.
Often targeted at proteins overexpressed in the cancer.
Affects cell division by targeting:
DNA replication.
DNA transcription.
DNA repair.
What are the different cytotoxic classes?
Topoisomerase inhibitors.
Alkylating agents.
Antimetabolites.
Antibiotics.
Microtubule inhibitors.
What are topoisomerases?
Topoisomerases are enzymes that participate in the overwinding or underwinding of DNA.
DNA topoisomerase I cleaves one strand of DNA which it later reseals.
DNA topoisomerase II first cleaves both strands of DNA before it reseals.
Topoisomerases are over-expressed in many cancers.
What are the 4 possible mechamisms of action of topoisomerase inhibitors?
1) Stabilization / inhibition of enzyme/DNA complex.
2) Binding of Drug to DNA totally preventing enzyme action.
3) Binding of Drug cleaves DNA in the presence of enzyme but resealing by the enzyme is prevented.
4) Intercalation: The planar ring structure of anthracyclines intercalates between DNA strands, causing structural distortion of the DNA and preventing polymerase progression therefore inhibiting both DNA and RNA synthesis.
Explain the metabolism of irinotecan?
Irinotecan is a prodrug.
SN-38 is the active metabolite.
SN-38 is inactivated by glucuronidation, the addition of glucuronic acid by uridine diphosphoglucyronyl transferase (UGT1A1).
Effect of genotype:
UGT1A1 is a phase II enzyme with >60 alleles.
Some alleles, eg UGT1A1*28 allele (TA)7 repeat in TATA box of its promoter has a low activity phenotype leading to adverse reactions.
Could be addressed by genotyping or monitoring WBC.
This genotype does not have an impact on the efficacy of irinotecan.
Effect of the environment:
After inactivation SN-38-glucuronide is secreted via bile into the intestines.
There it can be re-activated through hydrolysis by an enzyme produced by gut microflora causing severe diarrhoea.
Could be addressed by inhibiting the bacterial enzyme to prevent the intestinal metabolism of irinotecan.
Monitoring the phenotype to take into account these genetic and environmental factors could reduce adverse effects of the drug, potentially allowing dose escalation that will enhance the drug’s efficacy.
What are alkylating agents?
Common features:
Form covalent bonds with DNA via the production of a reactive species.
Bivalent therefore bonds are formed across or within stands of DNA.
They are effective cytotoxics because they crosslink DNA causing:
DNA strand denaturing or breakage. DNA repair. Replication inhibition. Transcription inhibition. Cell cycle arrest. Cellular stress. Cell death.
