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. Pathogenesis of cancer DNA mutations – Inborn mutations of cancer susceptibility genes – Acquired mutations Other epigenetic factors – Chemical carcinogens – Virus-induced cancer – X-rays – Other risk factors (tobacco, alcohol, Asbestos, diet)

3. Cancer 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.

4. Cancer Types categorized based on the functions/locations of the cells from which they originate: – Carcinoma: a tumor derived from epithelial cells, those cells that line the surface of our skin and organs (80-90% of all cancer cases reported) – Sarcoma: a tumor derived from muscle, bone, cartilage, fat or connective tissues. – Leukemia: a cancer derived from white blood cells or their precursors. – Lymphoma: a cancer of bone marrow derived cells that affects the lymphatic system. – Myelomas: a cancer involving the white blood cells responsible for the production of antibodies (B lymphocytes).

5. 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.

6. The Classification of Anticancer Drugs According to chemical structure and : According to chemical structure and resource of the drug: – Alkylating Agents – Anti-metabolite – Antibiotics – Plant Extracts – Hormones

7. 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

8. 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, …).

9. alkylating agents Nitrogen mustard Nitrosourea Busulfan Cisplatin and Cisplatin Analogues Dacarbazine and Procarbazine Mitomycin C

10. Chemical Warfare – circa 1914 Two most common agents: Chlorine gas Mustard gas

11. Alkylating Agents Mechanism of Action Nitrogen mustards inhibit cell reproduction by binding irreversibly with the nucleic acids (DNA). The specific type of chemical bonding involved is alkylation. After alkylation, DNA is unable to replicate and therefore can no longer synthesize proteins and other essential cell metabolites. Consequently, cell reproduction is inhibited and the cell eventually dies from the inability to maintain its metabolic functions.

12. Alkylating Agents Alkylating agents are reactive compounds that act on DNA, RNA or enzymes. Cells are killed by the alkylation of DNA – Formation of a covalent bond between drug and DNA (usually N7 on G) to form crosslinks – Methylation at N7 Procarbazine, streptozocin, dacarbazine, temozolomide Drug resistance is common Alkylating agents are reactive compounds that act on DNA, RNA or enzymes. Cells are killed by the alkylation of DNA – Formation of a covalent bond between drug and DNA (usually N7 on G) to form crosslinks – Methylation at N7 Procarbazine, streptozocin, dacarbazine, temozolomide Drug resistance is common

13. nitrogen mustard amino acid, nucleic base or hormone uptake by carrier protien L-phenylalanine (amino acid) Melphalan Estradiol (sex hormone) Uracil Mustard Uracil (nucleic base) Estramustine nitrogen mustard

14. Nitrogen Mustard Mechlorethamine (or Chlormethine) chloroethylamino structure (N- CH 2 CH 2 -Cl) nucleophile electrophile Electrophilic carbon

15. MOA: Nitrogen Mustards Generation of highly reactive “aziridinium ions” that act as alkylating agents to cross-link DNA producing defective DNA and abnormal cellular function and eventually cell death

16. Nitrogen Mustards N,N-bis(2-chloroethyl)methylamine Extravasation a problem – 0.16 M sodium thiosulfate and ice packs, {antidote for extravasation} highly reactive aziridinium ion Injection only, monitor renal, hepatic and bone marrow MOST reactive of the mustards

17. Theoretical rationales used to improve nitrogen mustards -Substituting an aromatic ring for methyl group can be predicted to increase chemical stability and thereby decrease the rate of alkylation because of electron-withdrawing effect. This also, will lead to good oral bioavailability, tissue distribution, before alkylation is widespread. E.g. Chlorambucil, and melphalan. Nitrogen Mustards 4-(p-bis(2-Chloroethylamino)phenyl)butyric acid. Chlorambucil

18. Synthesis Ethylene oxide (oxirane) Phosphoryl chloride

19. Oral or IV, severe bone marrow suppression resulting in infection and bleeding Dosage reduction may be necessary in renal failure as measured by BUN Known to cause chromosome abnormalities Nitrogen Mustards

21. To increase selectivity, nitrogen mustards was bonded with natural carrier e.g. estramustine which is active against prostate cancer, another examples is the bonding with antimetabolites e.g. uracil mustard. Nitrogen Mustards

22. Estramustine phosphate Estracyt® Pro-drug

23. 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, …).