43.4 Cancer Therapy Flashcards
What are major, therapies for cancer?
Surgery and radiotherapy
What is radiotherapy?
Mainstay, local, treatment (w/ surgery)
*For clearly delineated tumours (usually 1o).
*X-rays directed in narrow fields of radiation minimising damage to normal tissue.
What is the aim of chemotherapy?
Aim to kill neoplastic cells, often w/ toxic side-effects on normal cells
What are the different uses of cytotoxic/ chemotherapy drugs?
*Neoadjuvant → before surgery (↓ size/ micrometastases)
*Adjuvant → after surgery (kill remaining tumour cells/micrometastases)
*Palliative care → ↓ size/ bulk of tumour → relieve symptoms/ prolong survival/ delay new lesion dev.
What are the main categories of cytotoxic drugs used to treat cancers?
- Antimetabolites
- Alkylating agents and platinum drugs
- Topoisomerase inhibitors (a.k.a. anti-tumour antibiotics)
- Anti-mitotic agents (a.k.a. microtubule poisons)
Give an example of an antimetabolite and its mechanism of action.
Methotrexate - inhibits DNA synthesis.
*Methotrexate is a competitive inhibitor of dihydrofolate reductase -> inhibit RNA synthesis and DNA replication
Give examples of an alkylating agent and its mechanism of action.
Cisplatin/ Cyclophosphamide - chemically damages DNA
*Cisplatin allows cross-linking of DNA bases by platinum -> intra-strand DNA crosslinks account for cytotoxicity
Give an example of a topoisomerase inhibitor/ anti-tumour antibiotic and its mechanism of action.
Doxorubicin - Inhibition of topoisomerase causes DNA breaks
*Doxorubicin inhibits DNA topoisomerase II, stabilising an intermediate in which both DNA strands are broken. Recognition of this intermediate as dsDNA breaks -> cytotoxicity
Give an example of an antimitotic agent (microtubule poison) and its mechanism of action.
Vincristine - blocks mitosis
*Vincristine inhibits tubulin polymerisation -> prevents assembly of mitotic spindle -> arrests cells in metaphase -> prevent further proliferation
What are the main issues with chemotherapy?
Limited selectivity
Low therapeutic index
What are the reversible cytotoxic effects of chemotherapy on the body? (3)
*Damage to bone marrow and lymphoid tissues = leaves patient immunosuppressed and aneamic
*Damage to GI epithelium
*Alopecia (hair loss)
What are the irreversible cytotoxic effects of chemotherapy on the body?
Irreversible cytotoxicity to organs with little/ no cell growth (e.g. Kidney/ nerves/ heart/ lung)
What other antibiotic is doxorubicin similar to in its mechanism of action?
Fluroquinolones (inhibit topoisomerase)
What is the normal function of DNA gyrase?
(topoisomerase 2)
reversible swivelling needs to take place during DNA replication in order to prevent daughter DNA molecule becoming entangled
This is done by topoisomerase which ‘nicks’ the strands to reduce the tension and then reseales them
Doxorubicin inhibits the enzyme once it has nicked the DNA = causing DNA breaks
What side effect results in low adherence with chemotherapy?
Nausea and vomiting (given anti-emetics)
Which antibiotic has the same mechanism of action as methotrexate?
Inhibitor of DHFR (eukaryotic isoform as opposed to bacterial)
Trimethoprim
Which phase of mitosis do tumour cells arrest in when given vincristine?
Metaphase (prevents assembly of mitotic spindle)
Which phase of the cell cycle is Doxorubicin selectively toxic for?
G2 phase
What are the mechanisms of resistance to chemotherapy?
*↓ drug entry into cells.
*Altered expression or mutation of target enzymes.
*Improved DNA repair activity
*↓ likelihood of apoptosis.
*↑ detoxification.
*Drug extrusion (multi-drug resistance).
What is a mechanism of resistance that has developed against alkylating agents?
Improved DNA repair activity
What is a mechanism of resistance that has developed against doxorubicin?
Altered activity of the target (topoisomerase active site)
What is a mechanism of resistance that has developed against methotrexate?
Decreased drug entry into cell.
What are the ways in which resistance to anti-cancer drugs has been reduced? (3)
*Continue therapeutic process to completion so cancer is fully eliminated
*Use of maximum tolerated dose
*Combination therapies (multiple agents at one time)
What is important in the development of drug resistance?
Tumour progression
What is the mechanism of action of cisplatin?
Enters cells, Cl- dissociates leaving a reactive complex which causes cross linking of N7 and O6 in guanine molecules by platinum
What is the mechanism of action of cyclophosphamide?
Inactive until metabolised in the liver by P450 oxidase
Bifunctional (forms two carbonium ions which each bind to amide group (N7) in guanine bases)
Cross linking of guanine bases
What is the mechanism of action of doxorubicin?
Inhibits cellular enzyme DNA topoisomerase II (DNA gyrase) whose activity is increased in replicating cells
What is the mechanism of action of methotrexate?
FOLATE ANTAGONIST
(Folates are needed for the synthesis of purine nucleotides and dTMP- which are needed for RNA synthesis and DNA replication)
Methotrexate has a similar structure to folic acid and competitively inhibits DHFR which reduces FH2 to FH4
What is the mechanism of action of vincristine?
Binds to tubulin and inhibits its polymerisation into tubules, preventing spindle formation in dividing cells and causing arrest at metaphase
Effects only take place when the cell is undergoing mitosis
What are the different types of targeted cancer therapies?
*Endocrine
*Inhibitors of growth signal transduction
How does targeted cell therapy compare to cytotoxic drugs?
They have a lower toxicity due to a greater specificity compared to cytotoxic drugs.
How does tamoxifen work?
tamoxifen –met→ hydroxytamoxifen (ER antagonist) → inhibits ER-dependent transcription.
*Arrests growth of ER+ breast cancer.
How can prostatic tumours be treated using endocrine targeted therapy?
*Reduction of testosterone to treat prostatic tumours (orchidectomy, drugs to depress LH release, anti-androgens)
Give some examples of hormonal drugs for treatment of cancers.
- Tamoxifen
- Aromatase inhibitors
- Orchidectomy
- Drugs to depress LH release
- Anti-androgens
(These are the ones mentioned in the spec)
How do aromatase inhibitors work?
They are a hormonal therapy for breast cancer:
- Block peripheral estrogen synthesis in post-menopausal women
- Used in breast cancer
Name two types of inhibitors of growth signal transduction.
- Therapeutic antibodies against growth factor receptors (e.g. trastuzumab)
- Small molecule inhibitors of cell cycle enzymes (e.g. imatinib)
Describe chronic myeloid leukaemia and how it can be treated.
- Chronic myeloid leukaemia is caused by a translocation between chromosomes 9 and 22
- This generates a BCR-ABL fusion gene, which has deregulated tyrosine kinase activity -> This leads to the cancer
- It can be treated using imatinib
How does imatinib work?
It is a small molecule inhibitor used in targeted therapies:
- Inhibitor of tyrosine kinase activity
- This means it blocks the activity of the BCR-ABL seen in chronic myeloid leukaemia
- It is also effective against other tyrosine kinases, so it is effective against multiple types of cancer
How does trastuzumab work?
It is a therapeutic antibody:
- It binds to HER2 receptors on HER2+ breast cancer cells
- This down-regulates the growth factor signals that are mediated by the HER2 receptors and it also induces antibody-dependent cellular cytotoxicity (ADCC)
- This means it is useful in treating breast cancer
