1 introduction of cancer-medicinal chemistry

carcinogenesis, oncogene

1. Antineoplastic Agents (Drugs used in treatment of Neoplasm ) 1

2. Cancer According to the ACS, cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells . If the spread is not controlled, it can result in death. Can originate in almost any body organ Most common site for women is the breast Most common site for men is the prostate gland CANCER OVERVIEW 2

3. Benign prostatic hyperplasia (BPH). 3

4. CANCER TERMS Cancer: Un wanted growth. Greek word crab , because the cancer cells adheres to any part the crab.  Tumor: literally means "swelling" or "mass.“ of cells In the body, which does not have any physiological function of the body. Neoplasm is medical term for cancer Metastasis: Process by which malignant cells spread to other parts of the body- secondary tumour. Malignant: t ending to become worse and cause death 4

5. Following are some major cancer risk factors identified by researchers with the support of scientific statistics: Smoking (lung, oral, larynx, esophagus) Diet (A high-fat diet has been associated with an increased risk for cancer of the prostate, endometrium , and colon and rectum) Genetics (Alteration in gene- Mutation) Occupation and Environment (UV, asbestose ) Infectious Agents (Bacteria, virus) 5

6. Properties of cancer/ Hallmarks of cancer Self-sufficiency in growth signal Insensitivity to anti-growth signals Evading programmed cell death (Apoptosis) Limitless replicative potential Developing blood vessels (Angiogenesis) Tissue invasion and metastasis They escape from the immune system Tumour promoting inflammation Gene instability and mutation No contact inhibition Deregulating cellular energitics 6

7. 1.Self-sufficiency in Growth Signals/Abnormal Signaling Pathway Cancer cells do not need stimulation from external signals (in the form of growth factors) to multiply. They can produce their own GF Such as PDGF, TGF-alpha, Tyrosine Kinase Receptor, EGF (Epidermal Growth factor) They can produce their own receptor by auto phosporylation. (e.g. Erb-B 2 receptors in breast cancer increased, now these receptor is activated even at low concentration of GFs). 7

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9. 2. Insensitivity to anti-growth signals Increased growth of cell Growth Inhibitory Factors (P 53 , P 21 , Caspases, Bax) Cell growth & division Insensitivity to these signals raises the risk of a cell becoming cancerous This can arise from damage to the genes coding for the receptors for these inhibitory hormones—the tumour suppression genes. 9

10. 3.Evading programmed cell death (Apoptosis) Apoptosis  is a form of programmed cell death (cell suicide) due to aging, abnormal/faulty cells. Apoptosis is also important in destroying cells that escape from their normal tissue environment. Cancer cells are characteristically able to bypass this mechanism. Cancer cells even though cells may become grossly abnormal , they do not apoptose . The cancer cells do this by altering the mechanisms of apoptosis by improper functioning of TNF, caspases,P53, P27,P21 gene, Bad and bax proteins 10

11. 11 Intrinsic pathway Extrinsic pathway

12. 4 . Limitless R eplicative Potential/cell Division (immortality ) At the end of our chromosome we have excess DNA called “Telomeres ” Telomere shorten after multiple replication (60–70 doublings, at which point they reach a stage of senescence (unable to divide) Cancers involve the up regulation of  telomerase , the enzyme that maintains telomeres. So cell can now divide indefinitely without entering senescence 12

13. 5. Developing blood vessels (Angiogenesis) Angiogenesis  is the process by which new blood vessels are formed. Cancer cells appear to be able to kick start this process, ensuring that such cells receive a continual supply of oxygen and other nutrients. VEGF, basic Fibroblast Growth Factor( bFGF ) 13

14. These factors interact with receptors on endothelial cells near by B.V and stimulate these cells to divide, leading to branching, extension of capillaries called Angiogenesis. (Thalidomide, Endostatin , Angiostatin , Combretastatin , are some antiangiogenic drugs) The newly formed BV are disorganised in structure, dialated , and leaky. They also produce Integrins (absent in normal cells) Which block apoptosis . 14 Rapid growth in cancer cell Increased demand O2, Food Material Hypoxia Inducible Factors (HIF) Eg : VEGF,, bFGF

15. 6. Tissue invasion and metastasis Cancer cells can break away from their site or  organ  of origin to invade surrounding tissue and spread ( metastasize ) to distant body parts Breakdown of cell-cell adhesion (E- cadherin ) Degredation of the extracellular matrix (ECM) Increase motility ( chemotaxis ) Eg Breast cancer – Bone, brain 2 o tumour 80-90% of cancer deaths is caused by metastasis. 15

16. Steps in metastasis & Invasion Detachment of tumour cells from each other Attachment to matrix components Degradation of the ECM Migration of tumour cells This process is repeated in reverse when tumor cell emboli extravasate at a distant site

17. a) Detachment of Tumour Cells Normal cells are adhered to one another via transmembrane glycoproteins (E- cadherins ) Downregulation of E- cadherin expression in adenocarcinoma of the colon Decreased ability for adherence and facilitation of detachment from the primary tumour b) Attachment of Matrix Components Expression of integrins by tumour cells serve as receptors for ECM components Receptor-mediated attachment of tumour cells to laminin & fibronectin Increased density of receptors = increased invasiveness

18. c)Degradation of ECM Secretion of proteolytic enzymes by tumour cells Induction of host cell protease synthesis ( eg . type IV collagenase ) Cleavage of type IV collagen of the epithelial & vascular basement membranes d) Migration of Tumour Cells Cleavage products of matrix components have growth-promoting, angiogeneic and chemotactic activities Promotion of migration of tumour cells through loosened ECM, and through the degraded basement membrane to some other place in the body.

19. 7. Avoiding Immune destruction Majority of small tumours are destroyed by the immune system eg T-lymphocytes, Nk cell Large tumours avoid detection by immune system by masking antigenic property . So inhibition of stimulatory signals of immunity Decreased the function of antigen presenting cells Decrease the function of interferon Decrease the activity of TNF(decrease angiogenisis ) Reduce the number of NK, Th cells Greater incidence cancer is observed in immunosuppressed individuals with HIV, Autoimmunediseases , patients consuming immunosppresent drugs. 21

20. 8.Tumour promoting inflammation Chronic inflammation (autoimmune, bacterial, viral, parasitic) can cause normal cell to develop pro- neoplastic mutations and resistance to apoptosis. COX-2 is over expressed in many tumour cells . Inflammation recruit leukocytes such as neutrophils and mcrophages , which release cytokines and growth factors which aid in nourshing the toumour . 22

21. 23 9. Genome instability and Mutations. Tumour cells continuously evolve by mutation of Genes like P 53 P RB Growth factors gene etc 10. No contact inhibition When clumps of cell grown, then signal arises to stop the cell division, ie over crowded and stop division

22. Properties of cancer cells Normal cells show contact inhibition Cancer cells lack contact inhibition

23. Properties of cancer cells They keep growing And growing And growing And growing

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26. Cancers by Type in U.S. from American Cancer Society 28

27. Invasive Cancer versus Age data from National Cancer Institute http://www.cdc.gov/cancer/npcr/uscs/report/ 29

28. Classification of Neoplasms (Metastasis) BENIGN MALIGNANT NON-INVASIVE INVASIVE / METASTATIC well-defined borders irregular borders well differentiated poorly differentiated regular nuclei irregular, larger nuclei rare mitoses more frequent and/ or abnormal mitoses 30 A common feature for both benign & malignant tumour is Abnormal growth (tumour/swelling) & contact inhibition

29. Benign Tumor Usually encapsulated Cells similar in structure to cells from which they originate Well-defined borders Slow growing and limited to one area Possible growth displacement (but not invasion) to adjacent tissue In most cases the outlook with benign tumours is very good. However, benign tumours can cause problems if they press on vital structures such as  blood  vessels or nerves. For this reason sometimes they require treatment, but other times they do not. Eg  A common type of adenoma is a polyp in the  colon . Adenomas might also grow in the  liver  or the adrenal, pituitary or  thyroid  gland. 31

30. Benign Tumor images 32

31. Malignant tumour Not encapsulated; not cohesive, and irregular pattern of growth No resemblance to cell of origin No well-defined borders Metastasis Rapid growth through rapid cell division and multiplication 33

32. Preferential metastatic sites Primary tumour Common distant site (s) Breast’ adenocarcinoma Bone, brain, adrenal Prostate adenocarcinoma Bone Lung small cell carcinoma Bone, brain, liver Skin cutaneous melanoma Brain, liver, Bowel Thyroid adenocarcinoma Bone Kidney clear cell carcinoma Bone, liver, thyroid Testis carcinoma Liver Bladder carcinoma Brain Neuroblastoma Liver, adrenal 34

33. Types of cancer (Structure) Carcinoma (> 80%) cancer in epithelial cells(skin, liver, colon, prostrate, lung, Breast cancer) Sarcoma (<2%) cancer in connective tissue or non-epithelial tissues like bones, muscles, fatty tissue ( Osteosarcoma , Gum cancer) Leukemia is called "liquid cancers/blood cancers”  overproduction of immature white blood cells, No immune action,  patient is often prone to infection. Leukemia also affects red blood cells and can cause poor blood clotting and fatigue due to anemia.  lymphomas develop in the glands or nodes of the lymphatic system, (specifically the spleen, tonsils, and thymus) Both leukemia & lymphomas (15%) 35

34. Transformation of healthy cell to cancer cell (Molecular Mechanism of cancer, Oncogene) Mutation in Normal or healthy cell cause cancer It may due to Irradiation Virus Food Healthy cell/ Normal cell Cancer cell ? 36

35. What Are Mutations? Changes in the nucleotide sequence of DNA May occur in somatic cells (aren’t passed to offspring) May occur in gametes (eggs & sperm) and be passed to offspring Mutations happen regularly Almost all mutations are neutral Chemicals & UV radiation cause mutations Many mutations are repaired by enzymes 37

36. Types of Mutation 1.Point Mutation 2.Chromosomal mutation 38 Deletion Translocation Insertion

37. Point Mutation Exposure to solar UV radiation (280 – 315 nm) results in the formation of dimers of adjacent thymine or cytosine bases in the DNA molecule. four-membered cyclobutane ring formed between the two thymine bases. The  dimer causes  local distortions in the helix, weakening the interaction with the paired adenine bases and kinking the backbone slightly. The cellular processes ( photolyase ) that repairs (when we come to shade/evening /night) this lesion often make errors that create mutation and cause skin cancer called Xeroderma Pigmentosum 39

38. Cyclobutane structure 40

39. Chromosome Mutations May Involve: Changing the structure of a chromosome The loss or gain of part of a chromosome

40. Deletion Due to breakage A piece of a chromosome is lost from chromosome no:13

41. Translocation Involves in two chromosomes Part of one chromosome is transferred to another chromosomes Eg formation of Burkitt’s lymphoma

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43. Mutations by insertion

44. Proto-oncogene: A normal gene which, when altered by mutation, becomes an oncogene  that can contribute to cancer.  Proto - oncogenes  may have many different  functions  in the cell. Some  proto - oncogenes  provide signals that lead to cell division and growth in controlled manner . Involved in signal transduction proto - oncogenes  regulate programmed cell death (apoptosis). 46

45. Oncogenes ( Onco means Cancer) The defective versions of proto-oncogenes, known as oncogenes, can cause a cell to divide and grow in an unregulated manner. This growth can occur in the absence of normal growth signals such as those provided by growth factors. A key feature of oncogene activity is unregulated growth. The resultant protein encoded by an oncogene is termed Oncoprotein 47 Proto-oncogene  “Mutation”  Oncogene

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47. The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic methods of activation: A mutation within a proto-oncogene, or within a regulatory region (for example the promoter region), can cause a change in the protein structure. An increase in the amount of a certain protein A chromosomal Translocation(another type of Chromosome abnormality) 49

48. CHROMOSOME MUTATION The abl gene on chromosome 9 has been translocated (moved) onto chromosome 22, right next to the bcr gene. This makes a fusion of two genes that would not normally be together. It is called the bcr-abl fusion gene and it sits on chromosome 22. Patients with leukaemia have this gene rearrangement Rearrangement - translocation

49. 51 Results of oncogenes Activation Over production of growth factors Flooding of the cell with replication signals Uncontrolled stimulation in the intermediate pathways Cell growth by elevated levels of transcription factors

50. Mechanisms of oncogene activation

51. Types of proteins encodes by oncogenes

52. It is easy to kill cancer, but the challenge is keeping the patients alive at the same time