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Cancer

Cancer. Cancer accounted for 7.1 million deaths world-wide (12.5%). Ranks as 3 of the top 10 leading causes of death world wide . 11 million are diagnosed with cancer each year and by 2020 the World health organisation expects this rise to 16 million .

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Cancer

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  1. Cancer • Cancer accounted for 7.1 million deaths world-wide (12.5%). • Ranks as 3 of the top 10 leading causes of death world wide. • 11 million are diagnosed with cancer each year and by 2020 the World health organisation expects this rise to 16 million. • Second cause of death in the West (after cardiovascular diseases). Sources: WHO and Cancer Research UK

  2. Causes of cancer Multifactorial origin. Several factors associated with development of malignancy : • Radiation (sunlight and radio frequency) • Chemical carcinogens (polyaromatic hydrocarbons) • Mutagens and viruses (Human papilloma virus) • Others: tobacco, alcohol, diet, asbestos,… Genetic mutations within a single affected cell leads to monoclonal development. Genes affected can be those controlling cell cycle, DNA repair and/or differentiation, This leads to uncontrolled proliferation and tumour formation.

  3. Causes of cancer • 30% of cancer is due to smoking. • 30% of cancer cases is diet related. • 15% of cases are viral related infections: • Papilloma virus… sexually transmitted… cause cervical cancer. • Hepatitis-B is the cause of 80% of liver cancer. • Some are bacteria related: • H.pylori…. Leads to stomach cancer.

  4. Terminology – Cancer types • Leukaemias are cancers of the blood or bone marrow. • Sarcomas are cancers of the connective or supportive tissue (bone, cartilage, fat, muscle, blood vessels) and soft tissue. • Carcinomas are cancers that arises from epithelial cells. These include breast, liver, lung, stomach etc. • Cancer metastasis is the spread of cancer from the primary location to a secondary location.

  5. Terminology – Side effects • Neutropenia (or neutropaeniais a hematological disorder characterized by an abnormally low number of neutrophil granulocytes (a type of white blood cell). • Myelosuppression is a decrease in the production of blood cells. (Red blood cells and platelets). • Ototoxicity is damage of the ear, specifically the cochlea or auditory nerve. • Nephrotoxicity is kidney damage. Results in decreased kidney functions.

  6. Terminology – Side effects • Hepatotoxicity is liver damage. Results in decreased liver function. • Neuropathy is usually short for peripheral neuropathy, and means a damage to peripheral nerve(s). • Hypomagnesaemia isanabnormally low level of magnesium in blood serum.

  7. Treatment • Course of treatment will depend on the type of cancer, progress of the disease, available treatment options and patients choice: • Surgery • Radiation • Chemotherapy (including combination therapy) • Gene therapy • Natural products/herbal

  8. Problems with chemotherapy • Treatments are non-specific, attack healthy cells as well as normal cells since cancer cells are derived from normal cells. • Cancers can develop resistance: for example with platinum-drugs, cancer cells became resistant by many ways: • Decreased drug uptake/increased efflux • Enhanced tolerance of DNA adducts • Enhanced repair of DNA adducts • Increased drug deactivation by intracellular glutathione

  9. Cancer treatment • By surgery. • By radiation. • By anticancer drugs (cytotoxic agents): • Cytotoxic drugs of plant origin • Cytotoxic drugs of microbial origin • Antimetabolites • Alkylating agents • Platinum-based compounds

  10. Ideal cytotoxic drugs should: • Selectively target cancer cells without causing damage to normal cells. • Reduce size of tumors + minimize risks of metastases. • unfortunately, most of the available agents are not selective, they also affect rapidly-proliferating normal tissues (bone marrow, gastro intestinal epithelium, hair cells, …), causing serious side-effects (bone marrow suppression, nausea, vomiting, …).

  11. Cytotoxic drugs of plant origin Vincristine • Vinca alkaloids • Vincristine • Vinblastine • Vindesine • Vinorelbine • Podophyllumlignans • Podophyllotoxin • Etoposide • Yew tree taxanes • Paclitaxel • Docetaxel Etoposide Podophyllotoxin Vinca alkaloids mainly used for Leukemia and lymphoma Paclitaxel

  12. H 10 H 10-deacetylbaccatin III (biosynthetic precursor) Paclitaxel*, Docetaxel (currently semi-synthesised) Paclitaxel levels in plant is only 0.004% Paclitaxel mainly used for breast cancer and ovarian cancer

  13. Doxorubicin R= -OHDaunorubicin R= -H

  14. Anthracyclines mode of action DNAintercalation Guanosine Doxorubicin Hydrogen bonding Methylene bridge Guanosine DNA intercalation will prevent action of topoisomerase II (essential enzyme needed to untwist DNA)

  15. Antimetabolites

  16. Folic acid (diet) Dihydrofolate reductase Tetrahydrofolate Dihydrofolate Methylenetetrahydrofolate Thymidylate synthetase dUMP (uridine) dTMP (Thymidine) Folate inhibitors GUT Dihydrofolate reductase DNA synthesis

  17. Amine function Methyl group Methotrexate is an antifolate agent Folic acid Methotrexate Binds more strongly than folic acid to DHFR and to carrier protein which transports folates into cells. Cells are starved of thymine. DNA production is impaired.

  18. Related to methotrexate structure

  19. dUMP Fluorouracil Fluorouracil 5-FdUMP 5‑fluorodeoxyuridine monophosphate binds irreversibly to the active site of thymidylate synthetase (C-F bond) instead of deoxyuridine monophosphate. Stops the production of thymidine Used in solid tumors

  20. Deoxycytidine triphosphate Cytarabine Mimic

  21. Alkylating agents • Very reactive agents that alkylate cell constituents (DNA, enzymes, …). • Possess a highly electrophilic centre (δ+) to react with nucleophilic groups (Nu -) such as OH, SH, NH. • The binding will be irreversible. • No selectivity ( kill normal + cancer cells).

  22. Mustards as alkylating agents • Discovered after the development of sulphur mustard, a chemical agent used during World War 1. • Drugs cause depletion of white blood cells as s/e

  23. Mustards – mode of action

  24. Clinically used mustards Orally available through phenylalanine transport system

  25. Clinically used mustards

  26. OXIDATION IN LIVER TUMOUR b a phosphoramide acrolein 4-hydroxy- cyclophosphamide. aldophosphamide tautomer. normustine. Cyclophosphamide is a prodrug Cyclophosphamide Phosphoramide group Ifosfamide

  27. Other alkylating agents • Do not necessarily contain nitrogen mustard, but it should have the electrophilic species which will react nucleic acids: • Di-epoxide forming compounds: Treosulfan (prodrug) p.o or IV For ovarian cancer Diepoxybutane The active electrophile

  28. Other alkylating agents Ethyleneimine group Tretamine Thiotepa Bladder cancer bis-sulphonic acid esters safe enough to be given by mouth. Busulfan

  29. site-specific delivery of cytotoxic Mustine alkylating agents • Prostate tumour cells have abundant oestrogen receptor sites, and complexation of an Estradiol carrier with normustine enables accumulation of the complex within the tumour. The phosphate group provides water solubility, and the Carbamate linkage between the Mustine and the Estradiol deactivates the nitrogen lone pair through resonance stabilization, rendering the alkylating agent inactive when in the complex. Enzymatic hydrolysis in the tumour cell releases the active drug at the site of action.

  30. Phosphate group improves water solubility the change of the amino group into the carbamate Has reduced the nucleophilicity of it….difficult To form the aziridinium ring (less active)….prodrug

  31. Platinum-based drugs Cisplatin Carboplatin Oxaliplatin

  32. They are prodrugs in general Because this will increase the extracellular Cl- concentration compared to the intracellular

  33. Mechanism of action of cisplatin • Induces cellular apoptosis by forming coordinate bonds to N7 atom of guanosine and adenosine bases. Results in unwinding of the DNA helix and a bend towards the major groove of up to 30o. • This prevents DNA transcription and Replication.

  34. Guanine Guanine Adenine Guanine guanine-platinum-adenine guanine-platinum-guanine Interaction of the aquatic species with DNA: Formation of intrastrand bi-adducts blocking replication and/or prevent DNA transcription

  35. Carboplatin • Delivers the same active aquatic species as cisplatin, but with the chloride ligands replaced with carboxylate. • preferred first line drug for ovarian cancer and small cell lung cancer) and is used particularly with patients who have poor tolerance of cisplatin.

  36. Oxaliplatin • First approved in 1999 for the use cisplatin and carboplatin resistant cancers • One of three enantiomers, only the R,R-diaminocyclohexane ligand is active. • Used primarily to treat colon/colorectal cancer. Good leaving group Responsible for the lack in cross-resistance

  37. ZD0473 (120-150 mg/m2) Overcome glutathione-mediated resistance JM216 (Satraplatin™) Orally active BBR3464 (0.9-1.1 mg/m2) Active in a range of cisplatin resistant cell lines Platinums in clinical trial

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