Neoplasia Course Materials

What is neoplasia? An abnormal mass of tissue that results when cells divide more than they should and do not die when they should What are neoplasms? An abnormal growth of tissue that can be benign or malignant What is a benign tumor? not cancerous, doesn't spread What is a malignant tumor? cancerous tumor What is the definition of cancer? Abnormal, disordered and uncontrollable growth of a type of cells How does cancer form? Cancer starts in a single tissue cell type in an organ/structure and as a disease progresses the cancer grows and spread locally or spread to distant organs/body sites. What are metastases? Distant growths and secondary tumors that separate from the original (primary) tumor What are metastatic tumors? Tumors that originate in one organ and spread to another What are the most common cancer cell Epithelial cancers-known as carcinomas types? Epithelial cancers-known as carcinomas Cancer of mesoderm cells(bones/musWhat are the different cancer cell types? cle)-known as sarcomas Glandular tissue cancers-adenocarcinomas What are hallmarks? Cancers that have difference causes but have similar molecular mechanisms of development 1 / 11 Autonomy from growth signals-mutations affect signal pathways in a way that cancer cell growth doesn't need normal growth factors signalling Evasion of growth inhibition-mutations affect signal pathways making them reduce and become ineffective Unlimited replication-in normal situations cells are pre-programmed to have a number of cell divisions before death. This is mediated by preventing loss of telomeres What's a summarisation of the hallmarks from chromesome ends of cancer? Invasion/metastases-mutations prevent cellular adhesion and increase enzymes in invasion Angiogenesis-the growth of new blood vessels. This is stimulated by cancer cells to maintain nutrient supplies as tumour increases in size Evasion of cell death-apoptosis is natural cell death and cancer cells evade apostolic signals What happens is the Autonomy from growth signals stage of hallmarks? mutations affect signal pathways in a way that cancer cell growth doesn't need normal growth factors signalling What happens is the Evasion of growth mutations affect signal pathways making inhibition of hallmarks? them reduce and become ineffective What happens is the Unlimited replication of hallmarks? in normal situations cells are pre-programmed to have a number of cell divisions before death. This is mediated by preventing loss of telomeres from chromesome ends 2 / 11 What happens is the Invasion/metastases of hallmarks? mutations prevent cellular adhesion and increase enzymes in invasion What happens is the Angiogenesis of hallmarks? the growth of new blood vessels. This is stimulated by cancer cells to maintain nutrient supplies as tumour increases in size What happens is the evasion of cell death of hallmarks? apoptosis is natural cell death and cancer cells evade apostolic signals How are the hallmarks of cancer enabled? By: Inflammation Genomic instability Mutations And they help provide environment for cancer cells to develop and grow Clonal disease-a single cell can mutate What is cancer often referred to and what and become the dominant cell type and it does it mean? undergoes additional mutations and this changes the course of disease Why are a combination of chemotherapy drugs used? In a single tumour there are different clones that can be heterogeneous What does cancer range between? It's a consequence of alteration to DNA from a single point mutation to a more serious chromosomal deletion, rearrangement or translocation. Why does cancer likelihood increase with age? The DNA alterations accumulate over time Can mutations be inherited? Yes, genomic changes or germ-line mutations can be passed on in the DNA of eggs or sperm What are the 3 processes that control number of cancer cells? Proliferation Differentiation Apoptosis/necrosis-cell death They look and behave like normal cells What are well-differentiated cancer cells in tissue and are slow growing and less like? aggressive 3 / 11 They look immature and nothing like tisWhat are undifferentiated/poorly differ- sue of origin. They grow quickly and are entiated cancer cells like? likely to spread and cause a poor prognosis What is a prognosis? a forecast about the probable course of an illness How are oncogenes formed? When gene mutation produces a higher level/activity of protein products(cell receptor or growth factors) Where the receptors always on and inWhat is an important example of recepduces cell signal regardless of growth tor change? factors being present What do tumor suppressor genes do? Regulate cell growth by suppressing risk of tumor formation What does a mutation to genes cause? Loss of function What environmental factors increases risk of cancer? Chronic soot Sun Uv exposure Age of first child Use of hormone therapy What reproduction factors increases risk Barrier contraception-reduces HPV + of cancer? HIV transmission therefore reducing cervical cancer What diet factors increases risk of can- Changes in diet when migrants move this cer? is to match local population What alcohol factors increases risk of cancer? Chronic alcohol intake + Synergistic with smoking What smoking factors increases risk of cancer? Smoking causes lung cancer Reduce exposure to carcinogens/wear sunblock What lifestyle changes can help reduce Use barrier contraceptions and get HOV cancer risk? vaccine Adopting a Mediterranean diet-also reduces risk of CVD 4 / 11 Reduce alcohol intake Smoking cessation An agent that causes cancer What's a carcinogen and how can it be classified? What is radiation carcinogenicity? Radiation, chemical, infections A level of energy released and it causes DNA damage. These are UV and ionising. DNA by direct ionisation of the DNA atoms or indirectly by generating reactive What does ionising radiation damage? oxygen species. Can also be used for radiotherapy to treat different cancers but have the risk to produce others What is the moa for chemical carcinogens? The electrophilic forms interact with nucleophilic sites in the DNA base pair rings(purines/pyrimdines). This can be direct effect or after they have been metabolised by cytochrome p450w What are the 10 types of chemical carcinogens? Azo dyes Carbamates Inorganic carcinogens Polycyclic aromatic hydrocarbons Aromatic amines Hyazo and azoxy compounds Halogenated compounds. Natural products Miscellaneous compounds Nitosamines and nitrosamides What does UV radiation do? It produces a unique mutation and is only seen in skin cancer How can infections be related to cancer? The infections can be viral and bacterial HPV, HIV, Epstein Barr virus, Hepatitis What examples of infections are related B/C to cancer? Bacterial infections-helicobacter pylori and S typhi 5 / 11 What's the difference between modifiable and non modifiable risk factors What are the most common inherited cancers? Breast and colorectal Genes that usually result in clinically imWhat are high penetrated genes and exportant diseases e.g BRCA1 BRCA2 that amples? cause breast and ovarian cancer What are low penetrants genes These are genes that are less likely to cause important diseases e.g. CHEK2 PALB2 It raises awareness and avoids the canWhy is early cancer detection important? cer getting worse. This is improved by highlighting specific early symptoms What is cancer screening and what doesn't it do? A process of identifying apparently healthy people who may be at a high risk of a disease or condition. But it doesn't diagnose the cancer What does cancer screening not reduce? An individual's risk of getting cancer but it allows earlier detection and improve morbidity or mortality. HPV vaccination programme. All girls What's the most recent change that will 12-13 must get the vaccine and it occurs prevent cervical cancer? at a younger age since the exposure to the virus is less likely What is chemotherapy? the use of chemicals to treat a disease using different agents What happens in the cell cycle? G0-resting phase. Cell preform a pre-programmed role or specialised function. Cells are stubborn to chemotherapy here G1-interphase. Cell proteins and RNA, enzymes for the synthesis of DNA are synthesised S-synthesis. Cell produces another copy of DNA G2-DNA synthesis ends but RNA and 6 / 11 protein synthesis continue and the micro tubular precursors go mitotic spindles are made M-mitosis. Cell divides after segregation of DNA producing a copy of the original cell Effect on only specific point in cell cycle(Phase specific drugs) Effect anywhere in the cell except G0(phase non-specific drugs) Affecting any point in the cell cycle including G1(cycle non-specific drugs) What are chemotherapy agents classified as? They may work on more than one phase but they have their predominant action What's important to know about phase in one specific phase. Cycle and phase specific drugs? specificity used to help determine how often drugs are given and for how long. Why do the number of cells active in the Due to the type of tissue/organ the cell is cell cycle vary? part of. What are growth fractions? The relative different proportions of the cells in cycle and at rest in all tissues/organs and tumours/cancer cells What do tissues with a high growth fraction have? They have more cells in the cell cycle High growth fraction tissues and this exWhich tissues are more responsive and plain why some cancers are more resusceptible to chemo? sponsive to chemo than others How does chemo kill and what does it assume? It's hypothesised to kill a constant proportion of cancer cells every time it's given and it assumes that all cancer cells are equally exposed to the drug but this is different for solid tumours What do tissues with a low growth fraction have? They have fewer cells in the cell cycle 7 / 11 Necrotic centre-all cells are dead or dying due to lack of blood supply/nutrients Outer laters-invasive potential. Drugs can get these cells due to good blood supply and nutrients(oxygen) What are the sections of solid tumours? Hypoxic centre-blood/nutrient supply is not enough to allow growth but is enough to prevent cell death. Cells aren't exposed to chemo initially but when exposed they may be resistant to chemo used previously and change in treatment required Cells aren't exposed to chemo initially What is chemotherapy acquired drug re- but when exposed they may be resistant sistance? to chemo used previously and change in treatment required How are most solid tumours cured? By surgery How are most disseminated tumours cured? By prolonged chemotherapy According to their MOA or the type of drug it's derived from. Alkylating and platinum based(platins) What's another way chemo is classified agents + examples? Antimetabolites Plant alkaloids/topoisomerase inhibitors Anthracyclines/antitumour antibiotics Cross-linking DNA strands causing a What's the moa for Alkylating and Platbreak in strand which can't be repaired inum Based(platins) Agents and forms DNA adducts. Have Different activities in different canWhat's the toxicity profile like for platins cers and toxicity profiles. The least reand what is the least toxic example? nally toxic is carboplatin but they're all renally toxic and are cleared renally. 8 / 11 What's the moa for antimetabolites? Interfere with nucleoside(C or U) in RNA or DNA or they inhibit enzymes in DNA synthesis What are antimetabolites? Chemotherapy agents that are purine or pyramiding analogues except methotrexate(folate antagonist) Block formation of mitotic spindle, preventing the assembly of tumbling dimes and cell division. What is the moa for plant alkaloids and IV admin examples and admin Vincristine-Vinca-alkaloids Treats leukaemia, myelomas, lymphoma and solid tumours What's the moa Of topoisomerase I inhibitors and examples? Prevent supercooling of DNA Irinotecan and topotecan What's the moa Of topoisomerase II in- Inhibits topoisomerase II and causes irhibitors? reversible double-strand breaks in DNA Whats the 2 moa of anthracycline? Intercalation-drug inserts itself between base pairs of DNA preventing replication or production of mRNA Bind to DNA causing single or double strand breaks making free radicals Structure based on anthraquinone What are the anthracyclines and exam- Daunorubicin-flat, plate-like molecules ple? that slide between strands of DNA, binding strongly to each strand causing a retard in replication process What's the moa for Asparaginase? Depletes asparagine-an amino acid needed for some cancer cells What's the moa for interferons? Cytokine that's acts as an immunomodulator and are antiproliferative and anti-tumour 9 / 11 Glucocorticoids-lympholytic and used for leukaemia and lymphomas GnRH(goserelin)-inhibits release of FSH and LH which reduces testosterone levels in men and oestrogen levels in women Tamoxifen-blocks oestrogen from binding to receptors in oestrogen sensitive breast cancer Aromatase inhibitors-blocks oestrogen production from non-adrenal glands Which hormones can be used as chemotherapy agents? Selectively bind to receptors overexWhat's the moa of monoclonal antibod- pressed on tumour cells inhibiting proies for chemo effect? liferation. Can also conjugate with Irene drugs to allow localised delivery What are the 2 main adjunctive agents? Folinic acid and methotrexate-prevents/lessens side effects Folinic acid and fluorouracil-enhance anti cancer effects Why is florouracil adjuncted to Folinic acid? Alone it's in the body a short time. When binded the acid enhanceds the binding to an enzyme in cancer cell and can stay in cc longer to give anti cancer effect. What's a disadvantage of the combina- It increases the severity of side effects of tion of Folinic acid and fluorouracil? drug What's the moa of methotrexate as a chemo drug? It is able to counteract and compete with folic acid in cancer cells causing a deficiency and eventually cell death. This action can affect normal cells and cause significant side-effects in the body such as low white and red blood cells reduced platelet cells, hair loss, mouth sores, liver, lung, nerve and kidney damage The use of Folinic acid which is used as an active form of Folic acid for body cells this is normally started 24 hours 10 / 11 What can help reverse the complications after methotrexate is given this gives and side effects of methotrexate in can- methotrexate a chance to exert anti-cancer treatment? cer effects. What's The pro drug of fluorouracil? Capecitabine-1) ester bone broken MESNA-prevents urinary tract toxicity caused by metabolites this is a thiol comWhat does the second adjunctive therapound py involve? 2 Alkylating agents-ifosfamide and cyclophosphamide What are two similarities of ifosfamide and cyclophosphamide? They may produce haemorrhagic cystitis as it's dose limiting factor and they are prodrugs that undergo metabolic activation by liver P450 Why are combination drugs used and what are the benefits? They are more effective even if used sequentially by: -preventing form of resistant cell cloned -affecting both cycling/non-cycling cells -allowing access to sanctuary sites -limit toxicity of individual drugs What rules apply to combining drugs? Individually active against the cancer There's no overlapping of toxicities Used at optimal dose Exploits synergy Works at multiple points of cell cycle Some drugs may not be active individually but if combined gives a synergistic How can synergistic properties help the effect or enables direct delivery to speuse of medicine for cancer? cific site which warrants the inclusion in a regimen What's the main reason of chemo failure? Drug resistance-cells have a number of resistance mechanisms to anti cancer drugs What are the 2 types of drug resistance? Cellular mechanisms Non-cellular mechanismsg 11 / 11