Cancer Therapy Flashcards
What is the meaning of adjuvant therapy?
Treatment given in addition to the primary therapy, eg. chemo, radio, hormone treatment
What is the meaning of neoadjuvant therapy?
Treatment given to shrink the tumour before the primary treatment
What are the functions of surgery in cancer treatment?
Prevention, diagnosis, staging, primary treatment, debulking, relieving symptoms/side effects
When is and when isn’t surgery appropriate for treatment of cancer?
Surgery is most often used when tumours are at their early stage, or are localised and solid. Surgery is not suitable for systemic cancers or those that have metastasised to risky areas such as major blood vessels
What usually happens in surgery?
The main aim of surgery is to remove the whole tumour/host organ. The surrounding healthy tissue is also removed to reduce the chance of recurrence. Some lymphatic system may also be removed. Surgery if often used in combination with other modalities of treatment. Can also be used to alleviate symptoms
What are the risks of surgery?
Bleeding, blood clots, damage to nearby tissues and nerves, adverse reactions to surgery drugs, damage to other organs, pain, infections, slow recovery of other body functions
What are the main types of surgery?
Debulking - before chemo or radio, removes most of tumour, improving chances
Laparoscopic - “keyhole”, uses laparascope (small tube) with camera and light source to guide the surgery
Radical - Removes all nearby tissues eg. nerves, lymph nodes, muscles
Preventative (prophylactic) - Removes non cancerous tissues in high risk patients eg. with BRCA1/2 mutations
How does radiotherapy work?
Uses ionising radiation, usually delivered by linear accelerator, to kill malignant cells via DNA damage. Can be curative when the tumour is localised. The radiation is delivered to match the 3D shape of the tumour so that healthy cells are not affected. Renal cell carcinoma is radioresistant, and can’t be used in metastatic cancers. Radio usually given over time to allow the cells to recover.
What are the different types of radiotherapy?
3D conformal radiotherapy - Use computer programmes to analyse tumour and design radiowaves in that shape
Intensity modulated radiotherapy - 3D shape divided into segments and different intensities used for different segments
Image guided radiotherapy - Used to treat tumours in areas that move eg. lungs. Frequent images taken before and during surgery to assist in precise delivery to the tumour
Stereotactic body radiation - Use imaging and computer modulation to deliver high intensity doses of radio. Given in single/few treatments as an alternative to surgery in small tumours
Brachytherapy - Radioisotope source placed in sealed container inside the body near the tumour
What is the mechanism of action of radiotherapy?
Ionising radiation has enough energy to knock the electron off of an atom, forming an ion. This can directly damage DNA, or form free radicals from H2O which damage DNA. DNA repair mechanisms often significantly disrupted in cancer cells, so this can lead to apoptosis. Also, the sheer amount of damage can overwhelm these mechanisms. Mitotic catastrophe, IR-induced senescence, necrosis, and autophagy can happen. When dsbreaks occur, sensor proteins (PARP, MRN) recruit transducer proteins ATM/ATR which phosphorylate H2AX which is maintained by mediator proteins, effector proteins are signalled to which lead to apoptosis
What is mitotic catastrophe?
Mitotic catastrophe is when cells enter mitosis prematurely or inappropriately.
What are the side effects of radiotherapy?
The healthy cells receive some radiation, however they repair much more effectively due to their intact repair mechanisms. They’re still able to be damaged.
Sore red skin, fatigue (low rbc, energy used for repair), hair loss, nausea, loss of appetite, sore mouth, diarrhoea, lymphedema (damaged lymphatic system -> swelling)
What is chemotherapy?
Chemotherapy uses cytotoxic drugs to kill cancer cells. It is systemic, given orally or via IV, and given in cycles with recovery periods inbetween. It targets dividing cells at various stages of the cell cycle. The fact that it targets rapidly dividing cells means that it can also affect normal cells ie. digestive tract, reproductive system, hair
How can chemotherapy be used?
It can be adjuvant, neo-adjuvant, or solo. Mitomycin, Ifosfamide, Cisplatin (MIC) is used for non small cell lung, and oesophageal cancer
Cyclophosphamide, Doxorubicin, Oncovin (Vincristine), Prednisolone (CHOP) used for Non H lymphoma and chronic lymphocytic leukaemia
What are alkylating agents and how do they work?
Alkylating agents add an alkyl group to G in the DNA, crosslinking the strands so that the DNA can’t unwind during replication, stalling replication at the DNA checkpoint, leading to apoptosis. They also encourage mispairing during DNA repair. Toxic to normal cells, especially fast dividing ones.
What are the side effects of alkylating agents?
Hair loss (carboplatin), nephrotoxicity, neurotoxicity, ototoxicity (ear, platinums), nausea, vomiting, diarrhoea, immunosuppression, tiredness
What are antimetabolites and how do they work?
They interfere with DNA synthesis enzymes. They masquerade as purine/pyramidine residues, inhibiting replication and transcription. Can be folate antagonists, inhibiting dihydrofolate reductase which produces folic acid, a DNA building block. They induce apoptosis in S phase when DNA is being synthesised
What are the side effects of anti-metabolites?
Fatigue, alopecia, BM suppression -> anemia, low wbc & platelet, increased risk of neutropaenic sepsis (inflammatory response to infection) or bleeding, nausea and vomiting, mucositis, diarrhoea, palmar-plantar erythrodysesthesia (red, swell, numb, skin sloughing off palms and soles)
What are anti-microtubule agents and how do they work?
They inhibit cell proliferation by binding to and suppressing microtubule dynamics in the mitotic stage. Vinca alkaloids and taxanes inhibit assembly and disassembly of mitotic microtubules which leads to mitotic arrest and cell death. They’re also anti-angiogenic
What are the side effects of anti-microtubule agents?
Peripheral and autonomic neuropathy, alopecia, nausea, vomiting, decreased blood cell production in bone marrow (myelosuppression), joint pain (arthralgia), allergy
What are topoisomerase inhibitors and how do they work?
They bind to and inhibit the religation of DNA by topoisomerase, which results in DSBs that build up and lead to apoptosis.
What are the side effects of topoisomerase inhibitors?
Irinotecan: acute cholinergic type syndrome (diarrhoea, ab cramps, sweating. Given with atropine to block aberrant nerve impulses
Hairloss, nausea, vom, fatigue, myelosuppression
What are cytotoxic antibiotics and how do they work?
They’re naturally occuring drugs that are good at killing cancer cells. They generally interrupt cell division. The main groups are anthracyclins, bleomycins. The main mechanisms are intercalating DNA preventing replication and transcription, inhibiting Top II, producing free radicals to damage DNA, damaging cell membranes.
What are the side effects of cytotoxic antibiotics?
Cardiac toxicity (arrythmia, heart failure), alopecia, neutropaenia, nausea, vomiting, fatigue, skin changes, red urine
By which mechanisms can cancer cells acquire resistance to therapy?
Increased detox/drug clearance, inhibition/loss of apoptosis, increased DNA repair
What is targeted therapy?
Targeted therapy is a cancer cell therapy that targets cancer signalling pathways, which is more specific than traditional therapies. It avoids side effects from traditional chemo and the resistances that cancer cells can acquire to chemo
What are the main 4 types of targeted therapy?
Cancer growth blockers, monoclonal antibodies, PARP inhibitors, anti-angiogenics
What are tyrosine kinase inhibitors and how do they work?
They block the phosphorylation of proteins involved in the transduction of signals - this stops cells from dividing and growing. Gleevec is an example
What are proteasome inhibitors and how do they work?
They inhibit the breakdown of unwanted cellular proteins
What are mTOR inhibitors and how do they work?
mTOR signalling is activated by GFs such as insulin, and increases cell size and proliferation by protein synthesis and cytoskeletal reorganisation. mTOR inhibitors block protein kinase mTOR.
What are PI3K inhibitors and how do they work?
PI3K signalling is involved in growth, proliferation, differentiation, survival, motility, intracellular trafficking. PI3K signalling is often altered in cancer
What are histone deacetylase inhibitors and how do they work?
Histone deacetylaases control the coiling of DNA around histone and hence accessibility of the DNA for transcription.
What are hedgehog pathway blockers and how do they work?
The hedgehog pathway is an embryonic pathway involved in differentiation which is activated in the development of some cancers
How does Gleevec work?
It targets the fusion protein Bcr-Abl which is due to a chromosomal translocation that leads to overproduction of wbc. It’s an example of Oncogene Addiction: a uniquely hyperactive oncogene driving a tumour. Bcr-Abl is an always on membrane protein. Gleevec binds close to Bcr-Abl’s ATP binding site so it can’t phosphorylate other proteins.
What are naked monoclonal antibodies?
They are monoclonal antibodies targeting the TAA/TSA, they can trigger antibody-dependent cell mediated cytotoxicity, or block cancer associated GF receptors. They have no therapeutic module attached to them
What are conjugated monoclonal antibodies?
The antibodies are conjugated to a chemotherapeutic drug or a radioactive particle. The antibody takes the substance directly to the cancer cell
What are bispecific monoclonal antibodies?
A hybrid of two different antibodies, so that it can attach to two different antigens at the same time, bringing two cells together. It can bring together cancer cells and immune cells, enhancing the immune reponse.
How do anti-angiogenics work?
Tumour cells release pro-angiogenic molecules such as VEGF that act on blood vessel lining endothelia. They act in two ways, either blocking the GF binding to the receptor, or blocking the signal (tyrosine kinase inhibitors).
What is synthetic lethality?
When loss of cell viability occurs when both genes are disrupted simultaneously but not one at a time. This occurs when gene A has a loss of function in cancer cells, and Gene B is inhibited by a drug so the cell dies. The only successful case is PARP inhibitors in BRCA1/2 deleted/mutated cancers.
What are PARP enzymes?
They constitute a family of 18 proteins. PARP1/2 are enzymes activated by DNA damage, and facilitate DNA repair of single-strand breaks and base excision repair
What happens when PARP enzymes are suppressed?
Replication fork is stalled due to accumulation of unrepaired SSBs. The stalled replication forks degrade into highly cytotoxic DSBs, normally repaired by HR. BRCA-mutated cells are incapable of HR so PARP inhibition results in genomic instability and cell death
What are the limitations of PARP inhibitors?
Cells can develop resistance to PARP inhibitors - don’t know how but HR is restored in tumour cells. Also, the responses in clinical trials are varied
What is the future of PARP inhibitors?
Combination therapies - with targeted agents like ATR inhibitor (arrests cell cycle to allow for time for DNA repair)
Immunotherapies such as antibodies
Stratified trials, data shows PARPi may be more effective in patients with tumours that are mutated in DNA repair pathways but could be drowned out in trials, need specific trials
