Pharmacology - Cancer Flashcards
What is cancer?
Epigenetic disease resulting in the reprogramming of cancer cells so that they are growing in a no regulated manner and overcome physiological tissue and organ barriers (Invasive growth)
What are the main 2 causes of cancer?
1) Germline mutations/hereditary familil syndromes (5-10%)
2) Environmental factors/somatic mutations (90-95%)
What are the main risk factors of cancer?
1) Diet (35%) - (obesity (20%))
2) Smoking - 30%
3) Chronic infections (15-20%)
- Viruses 70%
What cancers have the highest and lowest 5 year relative survival for men and women?
Men: Highest > Testes 96% > Hodgkin lymphoma 84% Lowest > Pancreas 3% > Lung 6%
Women Highest > Melanoma 90% > Hodgkin lymphoma 83% Lowest > Pancreas 2% > Lung 6%`
What is the major cancer treatment?
Surgical removal of the tumour if detected early enough
What is radical mastectomy and when was it first indroduced?
surgical procedure in which the breast, underlying chest muscle (including pectoralis major and pectoralis minor), and lymph nodes of the axilla (armpit area) are removed as a treatment for breast cancer.
1894 to avoid cancer spread
For how long did radical mastectomy remain a standard procedure?
> 70 years
What therapy was introduced to replace radical mastectomy?
Removal of tumour mass plus chemo/radiotherapy
Equally effective but less morbidity
How does untreatable cancer kill patients?
Primary tumour and/or metastases destroy essential tissue and organs
- wasting syndrome (20%): appetite loss, weight loss, weakness, fatigue, muscle atrophy
- Only 1 in 5 patients with metastasised disease will survive >5 years
What percentage of cancer cures are achieved by which therapy?
- Systemic therapy (most common is chemotherapy) - 11%
- Local radiotherapy - 40%
- Surgery - 49%
What limits the efficacy of anti-cancer therapies?
1) Drug concordance (patients need to take their drugs)
2) The therapeutic window is very small
3) Do not fully understand the action of anti cancer drugs
4) Complicated disease
5) Cancer cell populations are highly adaptable
Why is the cancer therapeutic window so small?
Because cancer cells and normal diploid non maligant cells are so similar
- differences are in expression levels of genes but limited number of cancer specific mutations
- Result is that anti cancer drugs also have some non specific activity on normal cells
Describe some factors that contribute to cancer complexity?
Every cancer is its own unique disease:
- Genetic factors differ
- Time point of cancer formation
- Time point of diagnosis
- The therapy
Metastases may require different treatment than the primary tumour
AND
Different cells from the same tumour may require different treatment
How are cancer cells so highly adaptable?
They undergo clonal evolution by natural selection
Selection pressures include:
- hypoxia (oxygen deficiency)
- starvation
- Anti-cancer therapy
- different microenvironments (invasion of other tissues)
What is the result of cancer cell adaptability?
Initially respond to treatment but eventually mutant resistant cells emerge and proliferate
Name 7 common anti-cancer drug types
- Alkylating agents
- Platinum drugs
- Tubulin-binding agents
- Antimetabolites
- Topoisomerase inhibitors
- Cytotoxic antibiotics (extra reading)
- Monoclonal antibiotics (ER)
What are akylating agents, how do they act and what are they used to treat? Give an example
Drugs regularly used in chemotherapy
React bases in DNA, and prevent cell division by cross linking the 2 strands on the double helix with an alkyl group
Used to treat Hodgkins lymphoma and other lymphoma laukaemias
Example drug: cyclophosphamide
chlorambucil
What are platinum drugs, how do they act and what are they used to treat? Give examples
Platinum reacts with DNA bases (mainly guanine) resulting in intra and inter DNA strand cross linking
- Inhibits mitosis
- Induces DNA repair and subsequently cell death if the DNA damage is too severe
Examples:
- Cisplatin
- Carboplatin
- Oxaliplatin
What are the 2 types of tubulin binding agents and what is their basic function?
Destabilising agents: bind to tubulin dimers and inhibit microtubule assembly
Stabilising agents: prevent microtubule disassembly , block mitosis
What are the 2 types of destabilising tubulin-binding agents and what are they used to treat?
1) Vinca domain binders
- Vinca alkaloids (e.g vincristine, vinblastine) and Eribulin
- Used in chemotherapy to treat cancers by preventing mitosis
2) Colchicine domain binders
- Colchicine
- Used to treat gout
What is the 1 type of stabilising tubulin-binding agent? Name the classes of drugs and individual examples?
Taxoid domain binders
- Drug classes: Taxanes (paclitaxel, docetaxel)
Epothilones (ixabepilone)
What do antimetabolites do broadly?
Inhibit purine and pyrimidine synthesis, affecting DNA synthesis and therefore preventing DNA replication
What is methotrexate and how does it function?
Antimetabolite - folic acid antagonist
Inhibits dihydrofolate resuctase in folate metabolism - folic acid needed for DNA synthesis
What are nucleoside analogues and how do they work?
Antimetabolite
Contain nucleotide analogue, a sugar and 3 phosphates
Faulty nucleotides incorporated into chain, causing termination
e.g deoxycytidine
What does topoisomerase I do?
Creates a single strand break during DNA replication, to relieve tension in the double stranded region to prevent supercoiling
- Also reseals the break
What do topoisomerase I inhibitors do?
Inhibit topoisomerase I function resulting in inhibition of DNA replication
e.g topotecan
What does topoisomerase II do?
Involved in reversing supercoiled DNA
- causes a double stranded break to allow another strand to pass through it, then reseals
What do topoisomerase II inhibitors do?
Inhibit topoisomerase II, resulting in double stand breakages
e.g etoposide
What are the 3 main types of targeted anti cancer drugs?
- Hormone therapy
- Kinase inhibitors
- Antibodies
What is oestrogen receptor (ER) positive breast cancer
Breast cancers that rely on oestrogen to grow
How is tamoxifen used to treat ER positive breast cancer?
Oestrogen receptor antagonist
- metabolised by cytochrome P450 in liver into active metabolites such as afimoxifen and endoxifen
- These have a much higher affinity for oestrogen receptors
- Competitive inhibition of oestrogen
- Tumour grows slows or stops due to lack of oestrogen
What are the 3 main types of monoclonal antibodies used in cancer treatment?
Trastuzumab
Rituximab
Bevacizumab
What does trastuzumab do and what cancer is it used to treat?
Targets human epidermal growth factor receptor 2 (HER2)
Used in treatment of breast cancer where there is overexpression of HER2
what does rituximab do and what cancers is it used to treat?
Lyses B cell lymphocytes by attatching to a surface protein (CD20)
- used to treat B cell lymphomas
What does Bevacizumab do and what cancer is it used to treat?
Inhibitor of vascular endothelial growth factor
Improves survival of patients with colorectal cancers
