Biological Basis Of Treatment Flashcards
What is implantation of tumours? Where are implants commonly found?
Mechanical spread of detached clumps of tumour cells, commonly found in peritoneum, ureters and CSF
List all the treatment options of cancer
Surgery Radiotherapy Chemotherapy Hormones Biologically targeted therapy
What are the different forms of chemotherapy?
Primary treatment
Adjuvant - after an operation
Neoadjuvant
Palliative
What is neoadjuvant therapy?
Primary treatment with chemotherapy for patients with a localised tumour. Can be used to assess biological responsiveness of tumours and before surgery to reduce tumour size
Why must chemo be administered in pulses?
Chemo depletes bone marrow as well
Bone marrow cells can recover to a higher level than cancer cells between doses so needs to be given in pulses
When would chemotherapy be given continuously?
If the patient is to have a bone marrow transplant
What are the different types of chemotherapies and what are their sites of action?
Antimetabolites stop DNA synthesis
Alkylating agents bind to DNA and fix it so it cannot be unwound
Intercalating agents affect DNA transcription and duplication
Spindle poisons stop mitosis
What do platinum compounds do?
Form platinated inter- and intra-strand adducts leading to inhibition of DNA synthesis
What is the overall aim of chemotherapy?
To cause DNA damage so that apoptosis is induced
What do topoisomerase-1 inhibitors do?
Inhibit topoisomerase-1
Topoisomerase-1 cleaves a strand of DNA transiently so that the other strand when tightly wound up in supercoiling can be unwound. The strand is then religated and can have normal replication
Inhibits the rejoining of strands causing single and double strand breaks - apoptosis
What does methotrexate do?
Targets the folate cycle which is needed to produce purines for DNA synthesis
What does 5-fluorouracil do?
Inhibits thymidilate synthase which is required for pyrimidine and purine synthesis and the folate cycle
Why are microtubule dynamics critical for mitosis?
They polymerise to attach to the chromosomes
They depolymerise to move sister chromatids away from the metaphase plate during anaphase
What do microtubule binding agents do?
Disrupt microtubule dynamics
- inhibit polymerisation
- stimulate polymerisation and prevent depolymerisation, so that chromatids cannot be pulled apart
What is the aim of combination therapy?
Increased efficacy by
-activity - different mechanisms of action
Problems with combination therapy?
Different mechanisms of action can cause different mechanisms of resistance
Need to consider side effects - safety
List some types of endocrine therapies for breast cancer
Anti-oestrogens eg tamoxifen
Aromatase inhibitors
Progesterones eg megestrol
LHRH agonists eg goserelin
How do aromatase inhibitors work?
Aromatase converts compounds to oestrogens and is located in ovaries and fat
Have less oestrogen if aromatase is inhibited
What are some current endocrine therapies for prostate cancer?
LHRH antagonists eg goserelin Anti-androgens eg flutamide Oestrogen Castration CYP17A1 inhibitor
What are some side effects of anti-androgens?
Less facial hair
Gynaecomastia
Loss of libido
How does a CYP17A1 inhibitor work?
This enzyme is crucial for conversion of pregnenolone and progesterone to testosterone, therefore have less testosterone production
What differences between cancer cells and normal cells can be exploited by biologically targeted therapy?
Cancer cells
- loss of contact inhibition
- increase in growth factor secretion
- increase in oncogene expression
- loss of tumour suppressor genes
Normal cells
- oncogene expression rare
- intermittent or coordinated growth factor secretion
- presence of tumour suppressor genes
What mutation is seen in myeloid leukaemia?
Philadelphia chromosome - a translocation between 9 and 22
- leads to transcription of a protein and leukaemic transformation
- activation of oncogene
What is imatinib?
A Bcr-Abl tyrosine kinase inhibitor
What happens if tyrosine kinase is switched on permanently?
Can cause unregulated cell growth
Tyrosine kinase is an enzyme which can transfer a phosphate group from ATP to a protein in a cell
What do all the therapies ending in ‘nib’ do?
Inhibit tyrosine kinase
What are signal transduction pathways?
Biochemical pathways that communicate to the nucleus
What is Herceptin?
A recombinant humanised IgG1 monoclonal antibody against human epidural growth factor receptor 2 (HER-2)
How does Herceptin work?
Binds to HER2+ cells and flags them for immune destruction
Blocks downstream HER2 signalling to inhibit proliferation of cells
What is high expression of EGFR in cancer cells associated with?
Invasion Metastasis Late-stage disease Chemotherapy resistance Hormone therapy resistance Bad prognosis
What does erbitux do?
Targets EGFR - it is an IgG1 monoclonal antibody
Inhibits EGFRs, altering the signalling cascade leading to multiple effects
Side effect of erbitux?
Can cause bad acne
What is panitumumab?
An anti-EGFR monoclonal antibody
What is panitumumab used for?
Commonly used in EGFR-expressing metastasis colon cancer with wild type K-Ras
However being phased out due to cost
How does VEGF promote angiogenesis?
Induces endothelial cells to invade collagen gels and proliferate to form capillary-like structures to form new blood vessels
Give the steps of angiogenesis
Endothelial cells migrate into the perivascular space towards angiogenic stimuli
They proliferate and adhere to create a lumen
Blood vessel spouts fuse to build new circulatory systems
List some therapies that target VEGF
Bevacizumab
Abflibercept
How does bevacizumab work?
It is a VEGF antibody
Binds to it, preventing it from interacting with its receptor
How does Abflibercept work?
An antibody which binds to VEGF so that VEGF cannot bind to its receptor
What are the different ways that rumours can spread?
Local
Lymphatic
Blood
Implantation
Give an example of an intercalating agent
Topoisomerase-1 inhibitor
Give an example of an alkylating agent and how it works
Cyclophosphamide
Adds an alkyl group to DNA causing the two strands to cross-link. The strands cannot be separated and replicated
Give an example of an anti-metabolite
Methotrexate
5-flurouracil
