The molecular pathology of newer anti-cancer agents Flashcards
What are examples of conventional chemotherapies?
- Vinblastine
- Etoposide
- Ifosamide
- Cisplatin
What are examples of conventional chemotherapies that stop DNA replication?
- Vinblastine: antimicrotubule agent
- Etoposide: inhibits topoisomerase 2
What are examples of conventional chemotherapies that bind directly to DNA?
- Ifosamide
- Cisplatin
Both inhibit DNA synthesis by cross linking
What are cons of conventional chemotherapy?
- Not selective for tumour cells
- Usually hits cells that are dividing
What can conventional chemotherapy lead to?
- myelosuppression - a decrease in bone marrow activity that results in reduced production of blood cells
- hair loss
- diarrhoea
What are reasons for increase in tumour size?
- Cell division
- Lack of cell death (apoptosis)
What type of tumour is conventional chemotherapy good for?
- Good for fast dividing tumours
What are some examples of fast dividing tumours?
- germ cell tumours of testis
- acute leukaemias
- lymphomas
- embryonal paediatric tumours
- choriocarcinoma
What is targeted chemotherapy?
Exploits some difference between cancer cells and normal cells to target drugs to the cancer cells
What are some advantages of targeted chemotherapy?
- more effective
- less side effects
How can you differentiate between normal cells and cancer cells?
- Gene arrays
- Proteomics
- Tissue microarrays
What are examples of monoclonal antibodies that target growth factor receptors?
- Cetuximab
- Herceptin
What is cetuximab?
Monoclonal antibody inhibiting epidermal growth factor receptor (EGFR)
How does cetuximab work?
- chimeric IgG humanised monoclonal antibody
- binds competitively to extracellular domain of EGFR
- antitumour activity in xenograft models
- blocks production of VEGF, interleukin 8, bFGF
How do we select patients for Cetuximab therapy?
Immunohistochemistry
What is herceptin?
Monoclonal antibody against human epidermal growth factor receptor 2: Her-2
What is seen in Her-2 in breast cancer?
Overexpression
How does herceptin work?
- Removal of Her-2 by endocytosis
- Or lymphocytes can bind to herceptin then kill Her-2
What is her-2 associated with?
- large size
- high grade
- aneuploidy
- negative oestrogen receptor status
- independent adverse prognostic factor
How do we detect HER-2 amplification?
- Fluorescent in situ hybridisation (FISH)
- Chr 17 are green dots where Her-2
genes are - Timeconsuming
- Chr 17 are green dots where Her-2
- Immunohistochemistry
What is another example of monoclonal antibody therapy?
- Anti-PD1 (programmed cell death protein 1)
- Pembrolizumab
- Nivolumab
What is programmed cell death protein 1?
- Immune checkpoint
- Inhibits T cell response
- In normal physiology prevents auto-immunity
- PD1 over-expression in tumours
What are examples of small molecular inhibitors?
- Gleevec
- Gefitinib
How does gleevec work?
- Tablet that can shrink tumour, not totally cure
- Small molecular inhibitor of c-kit (tyrosine kinase)
- Mutation in c-kit protein meaning its always on
