1. Anticancer and Chemotherapy By: Mohamed Fahad Al-Ajmi

2. INTRODUCTION  Definition: Under the influence of chemicals in the environment, radiation or viruses, the DNA in normal cells may be transformed, possibly by a single alteration or substitution of one of the constituent purine bases, in such a way that the normal control mechanisms, which restrict cell proliferation are removed.

3. INTRODUCTION Cancer incidence and death by organ sites  Most common new cancer cases: Male:Female: Prostate (29%) Breast (30%) Lung (15%) Lung (13%) Colon/rectum (10%) Colon/rectum (11%)  Leading cancer deaths: Male:Female: Lung (32%) Lung (25%) Prostate (13%) Breast (16%) Colon/rectum (9%) Colon/rectum (11%)

5. INTRODUCTION  Terminology Hypertrophy: is the increase in size of a tissue or organ through increase in the size of the consistuent cells. Hyperplasia: is the increase in organ or tissue size through increase in cell number. Both hypertrophy and hyperplasia are reversible on removal of the growth stimuli

6. INTRODUCTION Nomenclature

9. CARCINOGENESIS  The process by which a normal cell is converted to a cancer or malignant cell.

11. CARCINOGENESIS Before discussing the details of molecular basis of CARCINOGENESIS we need to now how a normal cell divide (cell cycle).

13. The eukaryotic cell cycle M G0 G1 S G2 M: Mitosis S: Synthesis G1, G2: Gaps between M and S G0: Quiescent phase

14. DNA content change in cell cycle

15. Checkpoints: Point in the eukaryotic cell cycle where progress through the cycle can be halted until conditions are suitable for the cell to proceed to the next stage. M G0 G1 S G2 DNA damage Incomplete DNA replication Chromosomes Unattached to the spindle DNA damage Unfavorable growth conditions G1 checkpoint G2 checkpoint Mitotic checkpoint

16. Relationship of antitumor drug action to the cell cycle

17. CARCINOGENESIS Causes of cancer

19. CARCINOGENESIS Causes of cancer:  Radiation Ionizing radiation UV light.  Viruses Papelloma virus AIDS virus Hepatitis virus

22. Major classes of anti-cancer drugs  Alkylating agents  Antimetabolites  Antibiotics  Antimitotics  Hormones and antagonists  Molecularly-targeted therapy

23. Alkylating agents Damage DNA in resting and cycling cells  Most toxic to rapidly proliferating cells Cell-cycle nonspecific. Toxicities include bone marrow suppression, acute and delayed GI effects Example: cyclophosphamide (Cytoxan)  May cause hemorrhagic cystitis, particularly in dogs  Keep well hydrated, encourage drinking

24. Alkylating agents  Mechanism of action: cross-link 2 strands of DNA leading to impairment of DNA replication and RNA transcription.

25. Alkylating agents: examples  cyclophosphamide: creates guanine adducts that block cell proliferation.  cisplatin and its analogues, such as oxaliplatin: form DNA adducts and create inter or intrastrand crosslinks that disrupt DNA synthesis.

26. Antimetabolites  Analogues of normal metabolites, incorporated into DNA or RNA, resulting in abnormal nucleic acids and inhibition of enzymes involved in nucleotide biosynthesis Purine Synthesis Pyrimidine Synthesis Ribonucleotides Deoxyribonucleotides DNA RNA

27. Antimetabolites  Act in G 1, S, G 2 or M phases  Effective for high growth fraction cancers

28. Antimetabolites Act the S phase: inhibit DNA synthesis Example: methotrexate  Mimics folic acid, which is needed for synthesis of DNA, RNA and some amino acids  Toxicities include delayed GI effects and bone marrow suppression

29. Antimetabolites: examples  Methotrexate: a folate analog inhibits dihydrofolate reductase (DHFR), the enzyme essential for nucleic acid synthesis.  5-fluorouracil (5-FU): a pyrimidine analog that inhibits thymidylate synthase and also interferes with RNA synthesis and function.  Gemcitabine: a pyrimidine analog that inhibits DNA polymerase.

30. FH2: dihydrofolate FH4: tetrahydrofolate TMP: thymidine monophosphate dUMP: deoxyuridine monophosphate 5-FU Methotrexate DNA

31. Antibiotics  Bacterial or fungal derivatives,  Mechanism of action: intercalates within the DNA, causes single and double strand breaks, and inhibits topoisomerase II. Damage DNA in cycling and noncycling cells. Examples: 1- Bleomycin:

32. Antibiotics 2- doxorubicin (Adriamycin) Rapid IV administration causes histamine release, severe pruritis and swelling (facial). Pretreat with H 1 and H 2 receptor antagonists Produces free radicals that damage heart muscle, particularly in dogs Vesicant

33. Inhibitors of topoisomerases Topoisomerases: Cleavage, unwinding and re-annealing of DNA, necessary for DNA replication and RNA transcription Etoposide (VP-16): Inhibits topoisomerase II, leading to double- strand DNA breaks Etoposide

34. Antimitotics  Mechanism of action: natural products that interfere with microtubule synthesis and degradation, leading to inhibition of cell division. Cell-cycle specific.  Examples: 1- Paclitaxel (Taxol): stabilizes microtubules, inhibit the cell cycle during mitosis.

35. Antimitotics 2- Vinca (plant) alkaloids Act in M phase to inhibit mitosis Vincristine and vinblastine Both can cause bone marrow suppression and neurotoxicity Vesicants: cause blisters on contact with skin, extravasation causes tissue necrosis Protective gear absolutely essential

36. Mechanism of antimitotics Paclitaxel Vinblastine

37. Hormones and antagonists  Mechanism of action: inhibits synthesis or effects of the steroid hormones that are necessary for growth of certain tumors, such as breast and prostate tumors.  Examples: Tamoxifen: binds to estrogen receptors (ER) as an antagonist inhibitor of estrogen. Anastrozole: inhibits aromatase, the enzyme that catalyzes the final step in estrogen production.

38. Mechanisms of Tamoxifen

39. STI-571 (Gleevec, Imatinib)  A small molecule that inhibits Bcr-Abl tyrosine kinase  Targets this enzyme which is over-expressed in CML (chronic myeloid leukemia)  Taken by mouth daily for treatment of refractory CML

40. Gefitinib (Iressa)  It inhibits the intracellular tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR).  Recent research indicates that it inhibits growth of cancer cells with mutations of the TK domain of EGFR.  It is approved for treatment of non-small cell lung cancer refractory to standard chemotherapy. (~10% patients have EGFR mutations)

41. Antibodies  Herceptin (Trastuzumab) A recombinant monoclonal antibody against epidermal growth factor receptor 2 (Her2); used for treating refractory breast cancer over- expressing HER2 protein  Avastin (Bevacizumab) A recombinant monoclonal antibody against VEGF, which plays an important role in blood vessel formation (angiogenesis); used for treatment of colon cancer

42. Enzymes L-asparaginase  Breaks down blood asparagine – needed by some cancer cells for protein synthesis  Used against lymphomas and some leukemias  Antigenic (large protein): hypersensitivity reactions common

43. Side effects of chemotherapy

44. Common toxicities of chemotherapy  Organs with active cell division are affected: Bone marrow GI tract mucosa Hair follicles  These side-effects are often reversible.

45. Common toxicities  Bone marrow suppression: Leukopenia, thrombocytopenia and anemia Caused by most anti-cancer drugs except: Bleomycin, vincristine, hormones, and most of the molecularly-targeted agents.

46. Common toxicities  Gastrointestinal toxicity: Nausea and vomiting: cisplatin and anthracyclines Diarrhea: 5-FU, topotecan Mucositis: 5-FU  Alopecia (Hair loss): Paclitaxel, carboplatin, anthracyclines.  Renal toxicity: Cisplatin  Pulmonary toxicity: Bleomycin (pulmonary fibrosis)  Peripheral neuropathy: Cisplatin, oxaliplatin and paclitaxel

47. Long-term complications  Cardiomyopathy: Anthracyclines (Incidence exceeds 5% for high-dose of doxorubicin)  Leukemia: high-dose etoposide  Infertility: Alkylating agents

48. Management of side-effects  Use antiemetics to prevent nausea/emesis e.g. Zofran; a serotonin antagonist  Anemia Blood transfusion and/or erythropoietin (Epogen)  Neutropenia: Granulocyte-colony-stimulating factor (G-CSF, Neuprogen) To shorten duration of neutropenia  Thrombocytopenia: Platelet transfusion and/or thrombopoietin

49. Guidelines for handling/administering chemotherapeutic agents  Wear latex gloves, surgical mask, goggles, protective clothing (eg, lab coat) when handling  Dilute or mix drugs under laminar flow hood (if available) or in low-traffic area without air currents. This helps prevent aerosolization of particles  Try to use drugs available as preservative- free solutions to avoid having to dilute them

50. Guidelines for handling/administering chemotherapeutic agents  If drug must be diluted, use needle guard (available from manufacturers)  Never “ prime ” needle by squirting drug into air  Never use mouth to remove needle cap  Administer drugs through IV catheter to avoid extravasation Place carefully and check throughout infusion Guidelines for handling/administering chemotherapeutic agents

51.  Pregnant women should not handle/administer antineoplastic agents  Thoroughly wash hands before and after handling/administering antineoplastic agents  Prevent contact of agent with skin or mucous membranes. If this occurs, wash area immediately with large volumes of water, document the contact and seek medical assistance

52. Guidelines for handling/administering antineoplastic agents  Place absorbent pad under patient ’ s leg If drug spills, allows disposal of pad without contaminating table  Wear latex gloves when disposing of vomit, urine or feces from animals receiving antineoplastic agents  Maintain record of all exposure during preparation, administration, clean-up and spills