CBIO 8 Cancer therapy

Cancer therapy - depends on tumour type, location, grade + stage of the disease and general health of the patient What is cancer therapy? - purposes: 1) prolong survival time 2) improve quality of life - goals: 1) cure 2) control 3) palliative care (can’t be cured => alleviate symptoms + improve life qual.) => eliminate cancer cells & reduce chance of recurrence - 5 pillars of cancer treatment => most common 1st treatments : surgery (45%) > chemotherapy (28%) > radiotherapy (27%) - example of treatment: Key terminology - adjuvant therapy = treatment given in addition to the primary treatment - neoadjuvant therapy = treatment given to shrink the tumour before primary treatment - cancer grade = appearance of tumour compared to original normal cells - cancer stage = size of tumour & how far it has spread from the original site - complete remission = treatment has eliminated cancer as measured by medical tests BUT not cure Surgery - functions: prevention - diagnosis - staging - primary treatment - debulking - relieve symptoms - often 1st line of treatment for localised solid tumours/ at an early stage dvlp => NOT if systemic cancer (leukaemia, lymphatic cancer), metastasised cancer or near a risky area - aim: remove the tumour mass/ whole organ (with or without surrounding lymphatic systems) => margin of healthy tissue also removed => reduce chance of recurrence - often used in combination => before chemo/ radiotherapy (adjuvant treatment) => radiation given before surgery to reduce the tumour size (neoadjuvant treatment) 1) debulking => remove as much of the tumour as possible but not all of it => better chances of successful chemo- or radiotherapy => ex: advanced cancer of the ovary 2) laparoscopic surgery => less invasive: a laparoscope inserted into small incisions => relays images of the inside of the abdomen/ pelvis 3) radical surgery => remove all nerby tissue including lymph nodes, muscles, nerves => lower change of recurrence => ex: radical mastectomy removes breast & associated lymph nodes 4) preventive (prophylactic) surgery => remove non-cancerous areas of tissue in patients at high risk => ex: family history of breast cancer or adenomatous polyposis (large intestine) - risks: => bleeding => blood clots => damage to nearby tissues, nerves, other organs => adverse reactions to drugs => pain => infections => slow recovery of other body functions Radiotherapy - 40 % of patients at some pt in their treatment - ionising radiation (IR) delivered by a linear accelerator to match the 3D shape of the tumour => cause DNA damage + kill malignant cells w/ less exposure to healthy tissue => curative when tumour is localised & can be used instead of surgery (or (neo)adjuvant) => not suitable for metastatic cancers + some radio-resistant cancers (renal cell carcinoma...) - given as doses over days => time for normal cells exposed to IR to repair & recover - 3DCRT (3-dimensional conformal radiotherapy) => most commonly used - computer programmes match exact tumour shape - IMRT (intensity-modulated radiation therapy) => deliver different intensities of radiation to ≠ segments of the 3D shape of the tumour - IGRT (image guided radiotherapy) => treat tumours in areas that move (lungs...)/ close to critical organs => frequent imaging before & during radiotherapy - SBRT (stereotactic body radiation therapy) => consolidative SBRT (after cancer has disappeared) => imaging & computer programmes to deliver at high dose => single/ small number of treatments => alternative to surgery for small to moderately-sized cancers - brachytherapy => place a radioisotope source (in a capsule) in or near the tumour => ex: for prostate cancer - ionising radiation = particles, X-rays or gamma rays w/ sufficient E to cause ionisation => remove tightly bound electrons from the orbit of the atom => damage DNA directly => or indirectly (via H2O which become free radicals) => sensor p recruit transducer p which recruit mediator p => effector proteins give the cellular outcome: apoptosis here - cells can repair DNA damage BUT cancer cells are often overwhelmed => double-stranded DNA breaks trigger cell death via: => apoptosis => mitotic catastrophe (cell death during mitosis because of premature/ inappropriate entry) => necrosis => IR-induced senescence (cells cease to divide + grow) followed by apoptosis => IR-induced autophagy (cells self-degrade their cellular components) followed by apoptosis main - adjacent cells/ cells in the path of radiation are exposed to IR => BUT proliferate more slowly => time to repair + repair more effectively => BUT damage can happen => side-effects => sore, red skin => feeling tired (low RBCs (bone marrow affected) + body uses E to repair healthy tissue) => hair loss in area treated (proliferate at fast rate) => feeling sick, sore mouth, loss appetite => diarrhoea => lymphoedema (swelling of limbs due to lymphatic system damage) Chemotherapy - history of chemotherapy: - genetic mutations causing cancer => chr translocation => gene amplification => pt mutation within promoter/ enhancer region of gene => deletion/ insertion => epigenetic alterations to gene expression => germline mutations - chemotherapy: cytotoxic drugs to kill cancer cells => systemic treatment (travel through blood stream & affect cells all over the body) => administered intravenously or by mouth & given in cycles, w/ a recovery period of months - targets rapidly dividing cells => affect cells in mouth, digestive tract, reproductive system - cells in bone marrow - hair follicles => nasty side effects - given alone (often several in combination) or as an adjuvant/ neoadjuvant or w/ steroids... => MIC (non-small cell lung cancer & oesophageal cancer): mitomycin/ ifosfamide/ cisplatin => CHOP (non-Hodgkin lymphoma...): cyclophosphamide/ doxorubicin/ vincristine/ prednisolone Alkylating agents: => nitrogen mustards: they add alkyl groups to guanine residues in DNA => strands cross-linking => replication arrest => apoptosis => pseudo-alkylating agents add platinum to guanine residues => replication arrest => apoptosis => most are also carcinogenic: encourage mispairing during repair => toxic to cells that divide frequently (GI tract, bone marrow, testicles + ovaries) => side effects => hair loss => nephrotoxicity (kidneys) => ototoxicity (platinum toxic to ear) => nausea, vomiting, diarrhoea => immunosuppression => tiredness Antimetabolites: => interfere with enzymes necessary for DNA synthesis => purine (A, G) + pyrimidine (T, U, C) analogues/ folate antagonists => cell death during S phase => side effects => fatigue => hair loss => bone marrow suppression => anaemia, low WBCs & platelet count => risk of neutropenic sepsis (inflammatory response to infection)/ bleeding => nausea, vomiting => mucositis + diarrhoea => palmar-plantar erythrodysesthesia (PPE): reddening, peeling... of hand palms + soles of feet Anti-microtubule agents: => inhibit cell proliferation by binding microtubules & suppressing their dynamics => cell death => also antiangiogenic => from natural sources => vinca alkaloids inhibit assembly of mitotic microtubules => taxanes: inhibit disassembly of mitotic microtubules => side effects => peripheral neuropathy (nerve damage), autonomic neuropathy (autonomic sys. nerve damage) => hair loss => nausea, vomiting, bone marrow suppression (myelosuppression) => arthralgia (pain in joints) => allergy Topoisomerase inhibitors: => topoisomerases regulate DNA unwinding => temporary single-strand break (topoisomerase 1) // double-strand break (topoisomerase 2) => then re-ligate DNA segments => bind enzyme + prevent re-ligation => repair mechanisms BUT overwhelmed => apoptosis => side effects => acute cholinergic type syndrome (diarrhoea...) => give atropine to counteract side effects => hair loss => nausea, vomiting => fatigue => bone marrow suppression