Biological Basis of Cancer Therapy Flashcards
What are the four main anti-cancer modalities?
Radiotherapy
Chemotherapy
Surgery
Immunotherapy
List the different types of cytotoxic chemotherapy.
Alkylating agents Pseudoalkylating agents Antimetabolites Anthracyclines Vinca alkaloids and taxanes Topoisomerase inhibitors
What are the main types of targeted therapy for cancer?
Monoclonal antibodies
Small molecule inhibitors
What is the term used to describe chemotherapy that is given:
a. Following surgery
b. Before surgery
Adjuvant
Neoadjuvant
How do alkylating agents work?
They add an alkyl group to the guanine residues in DNA
This causes cross-linking of the DNA strands and prevents DNA from uncoiling at replication
This then triggers apoptosis (via a DNA checkpoint pathway)
How do pseudoalkylating agents work?
They have the same mechanism as alkylating agents but use platinum instead of alkyl groups
How do anti-metabolites work?
They masquerade as purine or pyrimidines leading to inhibition of DNA replication and transcription
They can also be folate antagonists (dihydrofolate reductase inhibitors)
This blocks DNA replication and transcription
How do anthracyclines work?
Insert between nucleotides in DNA/RNA so inhibits transcription and replication therefore BLOCKS DNA REPAIR creating FREE RADICALS that will damage the cells and cause APOPTOSIS
How do vinca alkaloids and taxanes work?
Vinca alkaloids inhibit assembly of microtubules
Taxanes inhibit disassembly of microtubules
This forces the cells into mitotic arrest
How do topoisomerase inhibitors work?
Topoisomerase is responsible for the unwinding of DNA and they induce temporary single and double strand breaks in the phosphodiester backbone
Topoisomerase inhibitors alter the binding of topoisomerase to DNA and allow permanent breaks in the DNA
What are the six hallmarks of cancer?
SPINAP Self-sufficient Pro-invasive and metastatic Insensitive to anti-growth signals Non-senescent Anti-apoptotic Pro-angiogenic
Give three examples of receptors that are over-expressed in cancer.
EGFR
HER2
PDGFR
Give an example of a ligand that is over-expressed in some cancers.
VEGF
Give two examples of constitutive (ligand independent) receptor activation in cancer.
EGFR
FGFR
How do small molecule inhibitors work?
They mimic ATP and bind to the kinase domain of tyrosine kinase receptors within the cytoplasm and block autophosphorylation and downstream signalling
State some resistance mechanisms to targeted therapies.
Mutations in ATP binding domain
Intrinsic resistance
Intragenic mutations
Upregulation of downstream signalling pathways
Side effects of all alkylating agents
Nephrotoxicity
Neurotoxicity
Side effects of antimetabolites
Palmar-plantar erythrodysesthesia
Side effects of anthracyclines
Cardiac toxicity
Red urine and red tears- Doxorubicin
Side effects of vinca alkaloids
Neuropathy
Arthralgia
Allergy
Side effects of taxanes
Neuropathy
Arthralgia
Allergy
What are 3 things monoclonal antibodies can do
Ligand neutralisation
Prevent receptor dimerisation
Cause receptor internalisation
What do small molecule inhibitors do
ATP-mimetics bind to kinase domains of tyrosine kinase in cytoplasm blocking the autophosphorylation therefore stop downstream kinase activation
Expensive alternate cancer therapy
Anti-sense oligonucleotides
RNA interference
b-RAF inhibitor
3 mechanisms of resistance to targeted therapy
DNA repair upregulated
ATP binding cassette transporters efflux drug
Altered target site
Drug classes affected by upregulated DNA repair
Alkylating agents
Antimetabolites
Topoisomerase inhibitors
Drug classes effluxed by ABC transporters
Pseudoalkylating agents
Vinca alkaloids
Drugs affected by altered target site
Anthracyclines
