MDU- Neoplasia (Complete)

- Uncontrolled cellular proliferation - Loss of apoptosis - Tissue invasion metastasis - Common characteristics of many cancer cells - Necrosis= Always pathological, synchronous in multiple cells, caused by noxious stimuli, early loss of membrane integrity, generalised cell and nucleus swelling, chromatin disintegration, in- Compare Apoptosis and and Necrosis flammation - Apoptosis= physiological, single cells, genetically controlled, late loss of membrane, condensation of nuclear contents, - Apoptosis definition - A controlled process of cell destruction - 2 stages= Decision phase: - Execution phase: - Extrinsic pathway= Activation of death receptors, withdrawal of growth factors - 2 pathways that stimulate Apoptosis to occur - Intrinsic pathway = DNA damage, stimulation of apoptosis pathway, direct cell damage (UV, heat) - Death receptors - Includes the Fas receptor and TNF receptor family - Binding of Fas ligand to Fas recruits Fas- associated death domain (FADD)an adapter molecule - A family of cysteine proteases specifically activated in apoptotic cells - Inactivates many enzymes - Cleaves substrates at Asp - Caspases - Not all apoptotic events are caused by caspases - Unfinished 1 / 11 - Mitochondria cause the release of proapoptotic factors, for example: - Mitrochondria - Cytochrome C - AIF - Main classes of anti- cancer drugs ? - Cytotoxic drugs - Hormones/ antagonists - Monoclonal antibodies - Protein kinase inhibitors - Miscellaneous - Cytotoxic drugs - Alkylating drugs - Antimetabolites - Cytotoxic antibiotics - Plant derivatives - Hormones/ Antagonists - SERM's - SERD's - Monoclonal Antibodies - Avastin - Cetuximab - Proliferating cells are therefore targeted - The general principles of cytotoxic anti - The anti- proliferative effects occur due cancer drugs ? (Cell Cycle) to action during the S phase and resultant damage to DNA initiates apoptosis - Cytotoxicity of anti cancer drugs - Toxic effects= Bone marrowsuppression - Solid tumours - Most drugs are only active against cells in compartment A- they only target about 5% of tumour mass - Alkylating agents - The nitrogen at position 7 of guanine, being strongly nucleophilic, is the main molecular target for alkylation of DNA - Antimetabolites - Structurally similar to naturally occurring metabolites required for DNA and RNA synthesis 2 / 11 - Folate antagonists - The main folate antagonists= Methotrexate - Antimetabolites - Purine analogues - Mercaptapurine - Is converted to a fraudulent nucleotide - Anti metabolites act on the S phase - Pyramidine analogues - 5- Fluorouacil - Unfinished - Cytotoxic antibiotics - For example, the Anthracyclines - Anthracyclines - intercalates with DNA and inhibits both DNA and RNA synthesis - Plant derivatives - Taxanes - Act on mitotic phase - Docetaxel and Paclitaxel= naturally occurring compounds derived from bark of yew tree - Preventable risk factors for cancer - Carcinogens - Lifestyle choices ( smoking, alcohol) - Environment - Reproduction - Treatment options for cancer - Hormone therapy - Surgery - Bone marrow transplant - Principles of cancer treatment - Chemotherapy is used in many different ways - can be given with curative intent or as primary treatment in incurable disease ~ Study pack ~ - Define Neoplasia - An abnormal tissue mass caused when cells divide more than they should or don't die when they should 3 / 11 - Neoplasms= May be benign or malignant - Most common cell types among can- - Epithelial cancers, referred to as carcicers ? nomas - Sarcomas ? - Cancers of the mesoderm cells (bone and muscle) - Adenocarcinomas ? - Cancers in the glandular tissue - Autonomy from growth signals= mutations affect signal pathways so that cancer cell growth doesn't require normal growth factor signalling - Evasion of growth inhibiton= Mutations affect signal pathways so they are reduced or are ineffective - Unlimited replication= Normal circum- Although different cancers have differ- stances cells have pre programmed ent causes, they have similar modular number of cell divisions before they die mechanisms of development called 'hallmarks'. Summarise them below : - Invasion/ metastases= Mutations prevent cellular adhesion and increase enzymes involved in invasions - Angiogenesis= Growth of new blood vessels stimulated by cancer cells/ tumours to maintain nutrient supplies as the tumour grows - Evasion of cell death= Cancers evade apoptotic signals - What are hallmarks of cancer enabled by ? - Inflammation and genomic instability and mutations - Malignant= Invasion and spread of cells from their origin - Benign= Localised and can still result in 4 / 11 - What allows us to distinguish between death, but may not spread from organ to malignant and benign tumours ? organ - A single cell can mutate and become the dominant cell type and can then undergo additional mutations - Cancer is referred to as a clonal dis- - Therefore the dominant cell type can ease, what does this mean ? change over the course of the disease - This is why combinations of chemotherapy drugs are often used - ... Alterations to DNA ranging from simple single point mutations to more catastrophic chromosomal deletions, rearrangements or translocations - Cancer is a consequence of .... - Genomic changes or germ like mutations are passed on as they are present in DNA of eggs or sperm - The number of cancer cells is controlled through what 3 processes ? - Proliferation - Cell death (apoptosis, necrosis, autophagy) - Differentiation - Factors affecting cancer occurrence in humans - Environmental - Reproduction - Diet - Alcohol - Smoking - Carcinogen= An agent that can cause - What is a carcinogen and how can they cancer in humans be classified ? - They can be radiation, chemicals or infections - Their electrophilic form interacts with nucleophilic sites in the DNA base pair - Chemical carcinogen mechanism of ac- rings tion ? - This can occur directly or after they've been metabolised by cytochrome P450 in the liver 5 / 11 - 1st type of chemical carcinogen ? - Polycyclic aromatic hydrocarbons (coal tar, benzopyrene) - 2nd type of chemical carcinogen ? - Aromatic amines from cooked meats - 3rd type of chemical carcinogen ? - Azo dyes - 4th type of chemical carcinogen ? - Nitosamines and nitrosamides from smoked fish - 5th type of chemical carcinogen ? - Hyazo and azoxy compounds - 6th type of chemical carcinogen ? - Carbamates - 7th type of chemical carcinogen ? - Halogenated compounds - 8th type of chemical carcinogen ? - Natural products - 9th type of carcinogenic compound ? - Inorganic carcinogens - Miscellaneous compounds like alkylat- 10th type of carcinogenic compound ? ing agents: for example mustard gas, asbestos - What is fractional cell kill or log kill hypothesis ? - The idea that chemotherapy kills a constant proportion or percentage of cancer cells every time it's given - Assumes that all cancerous cells are equally exposed to the drug (however this isn't actually the case) - The structure of a tumour ? - Necrotic centre = All cells are dead or drying due to lack of blood supply or nutrients - The outer layers of the tumour= The drugs can get to these cells because they have a good blood supply and source of nutrients so they can divide - Alkylating and platinum based agents - Antimetabolites - Different types of chemotherapy drugs - Plant alkaloids/ topoisomerase in? hibitors - Anthracyclines/ antitumour antibiotics 6 / 11 - Alkylating agents and platins - They cross link DNA strands resulting in breaks in the DNA strand which can't be repaired and form DNA adducts - The platins have different activities in different cancers and different toxicity profiles - Carboplatin is the least renally toxic - Cisplatin works like anthracyclines by interacting directly with the nucleotide bases in DNA of cancer cells - Platins consist of strong Pt-N bonded ligands and weaker Pt-LG links where LG represents a leaving group - This enables the N atoms in nucleotide bases to form strong N-Pt links accompanying he loss of a Cl- leaving group in - How do platins work ? Give 3 examples Cisplatin of platins - In carboplatin and oxaliplatin the leaving group will be a dicarboxylate anion so the platinum bonds to neighbouring bases in the DNA preventing replication of DNA - 3 examples= Cisplatin, Carboplatin and Oxaliplatin - Antimetabolites - They interfere with nucleoside inclusion (cytosine,uracil) in RNA or DNA or inhibiting enzymes involved in DNA synthesis - They are purine or pyrimidine analogues except methotrexate which is a folate antagonist - Plant alkaloids - Vinca alkaloids block formation of the mitotic spindle - Therefore preventing assembly of tubulin dimers and cell division 7 / 11 - Vincristine - Name an example of a vinca-alkaloid - Topoisomerase inhibitors - Used to treat multiple myelomas, lymphomas and solid tumours - Irinotecan and topotecan inhibit topoisomerase 1 which is an enzyme - By inhibiting it, it prevents supercoiling of DNA, needed to allow the DNA to fit the available space - Etoposide inhibit topoisomerase II which causes irreversible double stranded breaks in DNA - Work in 2 ways: - Intercalation= The drug inserts itself between the base pairs of the DNA, pre- Anthracyclines/ anti-tumour antibiotics venting replication or the production of mRNA - Binding to DNA causing single or double strand breaks by forming free radicals - Daunorubicin - Anthracyclin - Flat, plate-like molecules that slide between DNA strands - Asparaginase= depletes the amino acid asparagine which is an amino acid required by some cells - Other cancer chemotherapy treatments - Interferons= They are cytokine which ? act as immunomodulators and are anti proliferative and have anti tumour activity -Hormones= - Palliative chemotherapy - Neo- adjuvant chemotherapy= Pior to - Aims and intent of using Chemotherapy surgery to improve operative and surgi? cal outcome - Adjuvant therapy= Given after surgery 8 / 11 or radiotherapy to reduce the risk of local recurrence - Chemoradiotherapy= Combination of both chemotherapy and radiotherapy - Existing chemotherapy is used at existing dose but with less time between cycles - What is dose dense chemotherapy ? - Works by damaging DNA of affected cells direly or by formation of free radicals that also damage DNA - What is radiotherapy ? - Can be given internally, externally or systematically - External radiotherapy - Uses a linear accelerator to deliver radiation in a targeted way - Internal radiotherapy - Brachytherapy which involves surgical placement of a radioactive source in or near to the tumour - Systemic radiotherapy - Used in 2 main ways: - Orally= radioactive iodine is given orally for some thyroid cancers - IV= Given in combo with a monoclonal antibody - Salivary glands/ hair loss - Skin irritation - Fatigue - What are the effects of radiotherapy ? - Late effects include: - Fibrosis - Diarrhoea, bleeding - Infertility - Give an example of a targeted therapy - Tamoxifen - How does Tamoxifen work ? - Targeted oestrogen receptors in breast cancer 9 / 11 - They exploit cellular or molecular changes specific to cancer and involved in growth and spread of cancer cells - How do targeted therapies work ? - The cell cycle is controlled by cycling and cyclin dependent kinases - Activation or inhibition of these controls cell division - At checkpoints, tumour suppressor genes prevent cell division - In cancer, it's common for tumour suppressor genes to be mutated meaning that the stop signal is ineffective and cells divide in an uncontrolled manner allowing tumours to form - ... Overactive gene products, increased transcription, gene amplification, gene fusion products with oncogenic potential - Oncogenes have the opposite effect and affect cell differentiation and apop- - Targeted therapies focus on a range tosis to produce ... of different proteins involved in cell signalling - Most common protein group involved is the epidermal growth factor family - Blockade of enzymes/ Growth factor receptors target therapy - PARP Inhibitors Target Therapy - Small molecule cell signalling inhibitors - The drugs that end with "nib" or "mus" - Ordinarily, cells with damaged DNA enter apoptosis and prevent cancer from occurring - The enzyme PARP is responsible for repairing the single strands breaks in DNA enabling cancer cells to survive and proliferate - Olaparib inhibits PARP-1 - Olaparib is used as maintenance therapy in negative ovarian cancer 10 / 11 - Agents involved in regulation of - Modifiers of protein function target thergene expression by targeting proteins= apy Tretinoin and Bexarotene - Bortezomib - Used for Myeloma - Is a proteasome inhibitor - Inducers of Apoptosis Target Therapy - Proteasomes are involved in degradation of the proteins required for regulation of cell proliferation - Angiogenesis= process of blood vessels growing to support tumours as they grow in size - Angiogenesis Inhibitors Target Therapy - Blocking angiogenesis prevents tumours from getting the necessary nutrients for continued growth - Nausea and vomitting= Very highly emetogenic patients can be given Dexamethasone or Metaclopramide - Neutropenia and Neutropenic Sepsis= Prevented though the use of neutrophil growth factors (filgrastim, lenograstim) - Give examples of supportive therapies - Constipation and Diarrhoea= Constipation is managed through laxatives and increasing fibre and water intake. Diarrhoea is managed through anti-diarrhoeals like loperamide and opiates such as codeine. When irinotecan is taken, it can cause early onset diarrhoea which is managed through the use of atropine 11 / 11