Cancer Bio (Michaelis Lecture 3 - Drug resistance in cancer) Flashcards
What is the most effective anti cancer therapy?
Surgery
- if cancer is detected early enough/localised tumour
What is a good therapeutic approach for preventing metastasis?
Surgery in addition to chemo/radiotherapy
What therapy is used for cancers that have metastasized?
Systemic therapies
- chemotherapy
What % of cancer cures are achieved by which therapy?
- Surgery 49%
- Local radiotherapy 40%
- Systemic therapy 11%
Give an example of a cancer for which systemic therapy is effective?
Testicular cancer
- Virtually non treatable until 1970s
- Current cure rates of about 95% in the UK
- Cisplatin commonly used
What are the 5 main reasons that cancer is so hard to cure with systemic therapy?
1) Medication adherence (whether patients take their drugs as prescribed)
2) Small therapeutic window due to similarity to normal cells
3) Lack of understanding of anti-cancer drugs
4) Each cancer disease is a very complex individual disease
5) Drug resistance
A study of drug adherence in patients with breast cancer (2013) followed how many people over how many years taking what drug?
1200 breast cancer patients
Taking tamoxifen for 5 years
What percentage of patients showed low adherence?
38%
Low adherence reduced time to recurrence by what %?
52%
Low adherence was associated with a loss of how many years of life?
1.43 years
Why is the therapeutic window so small for systemic cancer therapies?
Because cancer cells and normal diploid non-malignant cells are so similar
Normal and cancer cells only differ in what ways?
- Genetic stability
- Gene expression
- Activity/proliferation
How are bacteria targeted by therapy?
- Antibiotics target bacterial metabolism
- Distinct from eukaryotic metabolism
- penicillin inhibits cell wall synthesis
How are bacteria targeted by therapy?
- Antivirals target virus-specific structures
How are tumour cells targeted by therapy? Why does this show that the therapeutic window is small?
- Tumour cells and normal cells so similar
- Anti-cancer drugs mostly target both cancer and normal cells
e. g targetting of DNA integrity or cell division in unspecific manner
How do alkylating agents act as anti-cancer drugs? Give an example of a drug
- Alkylate guanine of DNA, preventing DNA replication - subsequent apoptosis
- ‘Nitrogen mustards’ e.g HN2 (mustine)
How do platinum drugs act as anti-cancer drugs? Give an example drug
- Pt reacts with DNA bases (preferentially guanine) resulting in intra and inter DNA cross linking
- Inhibits mitosis
- Causes apoptosis if DNA cannot be repaired
- Cisplatin, carboplatin
What are the 2 types of tubulin-binding agents?
1) Vinca alkaloids
2) Taxanes
How do Vinca alkaloids work? Give an example drug
- Bind to tubulin dimers and inhibit microtubule assembly
- Vincristine
How to Taxanes work? Give an example drug
- Stabilise microtubule polymers, prevent microtubule disassembly, block mitosis
- Paclitaxel
If cancer drugs kill normal cells, why are cancer therapies effective in some patients?
Because in most cases cancer cells are more sensitive to cytotoxic insult than normal diploid cells
What is it that mean cancer cells are more likely to be resistant to drugs?
- Heterogeneity
- Cancer cells highly adaptable: Genetically and epigenetically unstable
- Large variation
- More variation increases likelihood of drug resistance
What is the pharmacological factor for drug resistance in cancer?
- Normal therapeutic plasma level of drug cannot be achieved
What are some reasons why sometimes effective drug plasma levels cannot be achieved?
- Low pro-drug activation in liver
- High metabolism of drug or high excretion
- Tumour microenvironment (lack of vascularisation, hypoxia, diffusion)
- Physiological barriers e.g. blood-brain barrier, intestines
