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 : 1. Radiation (sunlight and radio frequency) 2. Chemical carcinogens (polyaromatic hydrocarbons) 3. Mutagens and viruses (Human papilloma virus) 4. 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. Tumor benign Is a tumor that lacks the ability to metastasize Example: Thyroid adenomas Pre-malignant If left untreated may develop into cancer Examples: Atrophic gastritis and Barrett’s esophagus Malignant (cancer) medical term used to describe a severe and progressively worsening disease is capable of invading into adjacent tissues

5. 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.

6. Terminology – Side effects Neutropenia (or neutropaenia is 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.

7. 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 is an abnormally low level of magnesium in blood serum.

8. 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

9. 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

10. 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

11. 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, …).

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

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

14. Doxorubicin R= -OH Daunorubicin R= -H Cytotoxic drugs of microbial origin Anthracyclines For acute leukemia and lymphoma s/e: fatal cardiotoxicity

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

16. Antimetabolites Normal cell division is impaired Inhibit enzymes involved in the synthesis of a normal metabolite essential for normal cellular division Incorporated instead of a normal metabolite essential for normal cellular division

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

18. Methotrexate is an antifolate agent Methotrexate Folic acid Methyl group Amine function 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.

19. Related to methotrexate structure Carboxylic acid (polar drug), rapidly excreted unchanged in urine by carrier in proximal tubule Other carboxylic acids (aspirin, warfarin) can compete for carrier and delay excretion of MET>>>>>high plasma levels of MET Contra-indicated if renal impairment.

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

21. Cytarabine Deoxycytidine triphosphate Mimic Stops DNA synthesis by inhibiting DNA polymerase Leads to lethal synthesis by incorporating cytarabine instead of cytosine into DNA.

22. 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).

23. 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

24. Mustards – mode of action

25. Clinically used mustards Orally available through phenylalanine transport system

26. Clinically used mustards

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

28. 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

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

30. 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.

31. 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

32. Platinum-based drugs Cisplatin Carboplatin Oxaliplatin

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

34. 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 30 o. This prevents DNA transcription and Replication.

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

36. 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.

37. 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

38. Platinums in clinical trial BBR3464 (0.9-1.1 mg/m 2 ) Active in a range of cisplatin resistant cell lines ZD0473 (120-150 mg/m 2 ) Overcome glutathione- mediated resistance JM216 (Satraplatin™) Orally active