Antineoplastic Agents

1. Antineoplastic Agents Antineoplastic medications: drugs used to treat cancer, also called cancer drugs ,cytotoxic agents and anticancer drugs. Cancer Along with heart disease, cancer is the largest cause of death in the developed world Cancer affects 1 in 3 people and is responsible for 25% of all deaths Cancer is an unregulated proliferation of cells due to loss of normal controls, resulting in unregulated growth, lack of differentiation, local tissue invasion, and, often, metastasis. Cancer can develop in any tissue or organ at any age. There is often an immune response to tumor. Many cancers are curable if detected at an early stage, and long-term remission is often possible in later stages. Causes of Cancer: 1. 30 % is due to smoking: lung, mouth, pharynx, larynx, esophagus, urinary bladder, pancreas, and kidney cancers. 2. Lifestyle � diet, alcohol consumption, reproductive behavior, sexual behavior, exposure to sunlight, etc. 3. At least 15% are related to viruses, e.g. cervical cancer caused by human papillomavirus.

2. Types of Tumors: -Benign: non cancerous and not an immediate threat to life, even though treatment eventually may be required for health. -Malignant: tending to worsen and cause death, invasive and metastasis Characteristics of cancer cells: Persistent cell proliferation Invasive growth Metastases (a tumor may shed cells into the circulation. Although most circulating tumor cells die as a result of intravascular trauma, a tiny number adhere to the vascular endothelium and penetrate into surrounding tissues, generating independent tumors (metastases) at distant sites.) Etiology of Cancer Genetics Viruses Occupational and Environmental Carcinogens Radiation

3. Cont.: Etiology of Cancer Genetic mutations are largely responsible for the generation of malignant cells. Two major categories of mutated genes are oncogenes and tumor suppressor genes. 1-Oncogenes are abnormal forms of normal genes (proto-oncogenes) that regulate cell growth. Mutation of these genes may result in direct and continuous stimulation of the molecular biologic pathways that control cellular growth and division. For example, the ras gene encodes the Ras protein, which regulates cell division. Mutations may result in the inappropriate activation of the Ras protein, leading to uncontrolled cell growth and division.

4. 2-Tumor suppressor genes are inherent genes that play a role in cell division and DNA repair and are critical for detecting inappropriate growth signals in cells. If these genes, as a result of inherited or acquired mutations, become unable to function, genetic mutations in other genes can proceed unchecked, leading to neoplastic transformation. Another important regulatory protein, p53, prevents replication of damaged DNA in normal cells and promotes cell death (apoptosis) in cells with abnormal DNA. Inactive or altered p53 allows cells with abnormal DNA to survive and divide. The p53 gene is defective in many human cancers. Telomeres are nucleoprotein complexes that cap the ends of chromosomes and maintain their integrity. Telomere shortening occur with aging .Telomerase is an enzyme that provides for telomere synthesis and maintenance, thus telomerase may potentially allow for cellular immortality. Telomerase activity may promote tumors through multiple, complex mechanisms, especially by subverting the normal DNA synthetic checkpoints.

5. Viruses contribute to the pathogenesis of human malignancies through the integration of viral genetic elements into the host DNA. These new genes are expressed by the host; they may affect cell growth or division, or disrupt normal host genes required for control of cell growth and division. Alternatively, viral infection may result in immune dysfunction, leading to decreased immune surveillance for early tumors. E.G. :Epstein-Barr, nasopharyngeal carcinoma -Hepatitis B virus, hepatocellular carcinoma -HIV Kaposi's sarcoma. Immune system dysfunction as a result of genetic mutation, acquired disease, aging, or immunosuppressants interferes with normal immune surveillance of early tumors and results in higher rates of cancer. Known cancer-associated immune disorders include : immune deficiency secondary to immunosuppressants or HIV infection ( Kaposi's sarcoma)& rheumatologic conditions, such as Rheumatoid Arrhythrities (B-type lymphoma). Carcinogenesis can result from ionizing radiation and may develop from 2 different mechanisms; 1. Direct ionization � damages DNA and other molecules can cause direct somatic mutations 2. Secondary effectors such as oxygen radicals can be formed by interaction with ionizing radiation. Oxygen free radicals can damage and kill cells and also induce mutations.

6. Pathogenesis of Neoplasia : Cancer development can begin with a brief exposure (hours or days) to a chemical into an activated form and the chemical need not be present ever again. However, DNA is altered via mutagens including chemical carcinogens, viruses, and radiation. This mutations is inherted by at least one cell division (intiation). This mutation mainly lead to activation of proto-oncogene into oncogenes (leading to uncontrolled cell proliferation) and/or inactivation of tumor suppressor genes (leading to resistance to apoptosis.) Upon exposure to other epigenetic factors (hormones, co- carcinogens, immunosuppressant�which themselves are non carcinogenic) tumor growth is promoted (promotion)

7. � Initiation - point at which an irreversible alteration, usually genetic, is introduced into a target cell. Initiation: (1) is essentially irreversible (2) caused only by carcinogenic compounds (3) occurs rapidly after carcinogen exposure (4) alone does not result in tumor formation

8. � Promotion is the process whereby an initiated tissue or organ develop focal proliferations and it requires the presence of continuous stimulation. Promotion (1) reversible (2) acts only after exposure to an initiating agent (3) requires repeated administration of a promoter (4) is not carcinogenic in itself

9. Etiology and Pathogenesis of NeoplasiaInitiation and Promotion

11. How long does it take to produce a clinically detectable neoplasm ? 1. It can be readily calculated tat it takes at least 30 population doublings to produce 10 9 cells (about 1 gram in weight) from a single, initial transformed cell. It then takes only about 10 population doublings to produce a neoplasm of 10 12 cells (weight about 1 Kg, which is the maximal size compatible with life). 2. By the time a solid neoplasm is clinically detected, it has already completed a major portion of its life cycle (The latent period before which a neoplasm becomes clinically detectable is quite unpredictably long, usually years). 3. The rate of growth of a neoplasm is determined by the proportion of cells in the growth fraction and the degree of imbalance between cell proliferation and cell loss. In the submicroscopic phases of neoplastic growth most cells are in the proliferative pool (growth fraction). By the time a neoplasm is clinically detectable most cells in a neoplasm are not in the growth fraction. 4. The growth fraction of neoplastic cells has a profound effect on their susceptibility to cancer chemotherapy.

12. There are three basic treatment possibilities for cancer: surgery, radiotherapy, and chemotherapy. Some cancers where chemotherapy works very well: Childhood leukemia Retinoblastoma Osteosarcoma Testicular cancer Hodgkin�s Disease Some lymphomas Some early breast cancers Cancers that are very difficult to treat with chemotherapeutics (need surgery or radiotherapy first): Colon Lung Late stage breast cancer Pancreatic cancer (WHY???).

13. Problems associated with chemotherapy1-Resistance to chemotherapy Resistance to chemotherapy may develop by several mechanisms: Decrease in the amount of drug uptake by cancer cells E.G. Methotrexate Increase in the amount of drug removed by cancer cells. (Transporters=P-glycoprotein). E.G. Vinblastine ,doxorubicin, bleomycin ,etapsoid�. Decrease or alteration in target molecule sensitivity � this is caused by mutation in the molecule targeted by the drug E.G. Methotrexate,Mercaptopurine,doxorubicin Increase in DNA repair ability of the cell via an increased expression of DNA repairing enzymes. E.G. Alkylating agent

14. 2-Toxicity and side Effects of Antineoplastic Agents: Normal cells in the body that tend to be injured the most due to chemotherapy are those which have a high growth fraction. Those are bone marrow, GI Tract ,hair follicles, reproductive organs .Leading to the followings: Alopecia- hair loss Myelosuppression-bone marrow loss Emetic potential: disruptive to cells in stomach which causes: Nausea/vomiting Low WBC count- low immunity

15. Treatment of Chemotherapy Toxicity

16. 3-Treatment-induced tumor Many anticancer drugs are mutagens and can cause the rise of neoplasm ten or more years after the original cancer was cured.

17. Cell cycle Scientists have determined that cell cycle can be divided into:. Gap 0 (G0): There are times when a cell will leave the cycle and quit dividing. This may be a temporary resting period or more permanent. An example of the latter is a cell that has reached an end stage of development and will no longer divide (e.g. neuron). Gap 1 (G1): Cells increase in size in Gap 1, produce enzymes needed for DNA synthesis S Phase: To produce two similar daughter cells, the complete DNA instructions in the cell must be duplicated. DNA replication occurs during this S (synthesis) phase. Gap 2 (G2): It is the gap between DNA synthesis and mitosis, the cell will continue to grow and produce new proteins & RNA. Mitosis or M Phase: Cell growth and protein production stop at this stage in the cell cycle. All of the cell's energy is focused on the complex and orderly division into two similar daughter cells.

18. Cancer chemotherapeutic agents They are classified into: Cell-cycle non specific agents(CCNS): are cytotoxic in any phase of the cycle even on G0 phase and so are more effective against large slowly growing tumors. E.G.Bleomycin. Cell-cycle specific (CCS): are cytotoxic on all phases but not on cells out of the cycle(at G0 ) and so are more effective against rapidly growing tumors. Work better in combination than alone E.G. Mitomycin, doxorubicin,�.etc. Phase specific : act on specific phase of the cycle E.G.Vinca alkaloids act more in M-phase ,antimetabolites (mainly act on S-phase.)

19. Anticancer Drugs There are three Major Groups of Anticancer Drugs: 1) Cytotoxic Drugs (largest group) -Alkylating agents -Antimetabolites -Antitumor antibiotics -Plant alkaloids -Miscellaneous cytotoxic drugs 2) Hormones and hormone antagonists These are among the best-tolerated chemotherapeutics because they target specific receptors, and thus only specific cell types e.g. Tamoxifen 3) Immunomodulators -Immunostimulants, including interferons and interleukins -Immunosuppressant

20. 1-Cytotoxic Drugs

22. I-Alkylating Agents (CCNS) Mechanism of Alkylating Agents These drugs work by alkylation with nucleophilic substitution . They alkylate a variety of cellular constituents, such as cell membranes, proteins, and most importantly DNA. More specifically, the nitrogenous bases of DNA are what get alkylated. The drugs start off as pro-drugs that become activated when a chlorine atom is extracted. A carbonium ion is thus formed. This �carbonium ion� is very electrophilic and will then attack any free pair of electrons (i.e. on the N7 of guanine). This electrophilic attack results in a bond being formed between the drug and the guanine of DNA. As a result of this �alkylation�, there are a few consequences: 1) Miscoding (In transcription) 2) Cross linking- this only occurs if the drug is bifunctional The net result is cancer cell undergo apoptosis.

23. Alkylating Agents(CCNS)

25. Subgroups of Alkylating Agents 1) Nitrogen mustards 2) Nitrosoureas 3) Alkyl sulfonates 4) 4-Platinum Coordination Compounds  1-Nitrogen Mustards E.G.: Mechlorethamine, cyclophosphamid, melphalan & chlorambucil a-Mechlorethamine - first alkylating agent employed clinically - bifunctional, thus can crosslink DNA - extremely unstable and is inactivated within a few minutes following administration. Thus it is given IV. Clinical Uses -Hodgkin�s Disease -Non-Hodgkin�s Lymphoma Toxicity/ Side Effects - Dose limiting toxicity is bone marrow depression - Nausea/ Vomiting - Alopecia - Diarrhea - Sterility

26. b-Cyclophsphamid -It acts as cytotoxic and immunosuppressor agent. - Prodrug which must be activated by the cytochrome p450 system, which turns it into a nitrogen mustard. - bifunctional agent -most widely used alkylating agent Clinical Uses - Hodgkin�s Disease - Non-Hodgkin�s lymphoma - Solid tumors of head, neck, ovaries, and breast - frequently used in combination with methotrexate (anti-metabolite) or doxorubicin (anti-tumor antibiotic), or fluorouracil as adjuvant therapy post breast cancer surgery - Organ transplant recipients (due to immunosuppressive actions) Toxicity/ Side Effects - bone marrow depression - severe nausea and vomiting - acute hemorrhagic cystitis and renal damage???? (can be minimized via high fluid intake/infusion and the use of���?) - sterility - hypersensitivity reactions

27. Treatment of cyclophsphamid toxicity

28. 2-Nitrosoureas - bifunctional - active against broad spectrum of neoplastic disease - inhibits synthesis of both DNA and RNA, as well as proteins - These drugs are highly lipophilic, so they can easily cross blood-brain-barrier, and are great for CNS tumors. - Big problem in this class is that they are highly mutagenic and highly carcinogenic. - Major toxicity is DELAYED bone marrow depression & Pulmonary fibrosis. Clinical uses - primary and metastasis tumors of the brain - Hodgkin�s Disease - Non-Hodgkin�s lymphoma - Adenocarcinoma of stomach, colon, and rectal cancer - Hepatocarcinoma E.G.: a-Carmustine b-Lomustine

29. 3-Alkyl Sulfonates Busulfan Clinical uses Great effect on for Chronic granulocytic Leukemia Toxicity/ Side Effects - Dose limiting toxicity is bone marrow depression. - Pulmonary infiltrates and pulmonary fibrosis - Tonic-clonic seizures in epileptics - Nausea and vomiting - Alopecia - Sterility - Skin hyper pigmentation - Cataracts - Hepatitis

30. 4-Platinum Coordination Compounds E.G.: Cisplatin forms crosslinks within DNA strands. Cis-platin is not really an �alkylating� agent, but since it operates via the same mechanism as the alkylating agents, it is placed within that group. Clinical Uses - Very powerful against TESTICULAR CANCER - Also good for carcinomas of ovary, bladder, head, and neck Toxicity/ Side Effects - Renal tubular damage (minimized via massive hydration coupled with anti-emetics) - Ototoxicity and peripheral neuropathy - VERY SEVER vomiting( Ondanosetron�?) Carboplatin: is a derivative of cisplatin with less nephero- ,neuro- & ototoxicity.

31. II-Antimetabolites (CCS) An antimetabolite is a chemical with a similar structure to a metabolite required for normal biochemical reactions, yet different enough to interfere with the normal functions of cells, including cell division. All antimetabolites are used in cancer treatment, as they interfere with DNA production and therefore cell division and the growth of tumors (mainly in S-phase specific). They are classified into: 1- Folic acid analogues 2- Purine analogues 3- Pyrimidine analogues Purin and pyrimidine antagonists are phosphorelated inside the body into nucleotid form in order to be cytotoxic Uses leukemia. non-Hodgkin's lymphoma inflammatory bowel disease such as Crohn's Disease and ulcerative colitis It is widely used as immunosuppressant in transplantations to control rejection reactions.

32. Methotrexate: -A folic acid analogue, prevents the formation of tetrahydrofolate, essential for purine and pyrimidine synthesis, by inhibiting dihydrofolate reductase. This leads to inhibition of production of DNA, RNA and proteins (as tetrahydrofolate is also involved in the synthesis of amino acids as serine and methionine). It is actively taken up into the cells by the same transport system for folate (resistance�..?) The most common toxicity is nepherotoxicity (pptn of the drug in renal tubule.) 1-Folic acid analogues

33. Cont: Folic acid analogues1-Methotrexate compete with folic acid for DHFR and inhibits it . Therefore, it inhibits the synthesis of DNA, RNA and proteins.2-Also,DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolat which is needed for the de novo synthesis of the deoxynucleoside thymidine phosphate DTMP ( required for DNA synthesis)

34. 2-Purine analogues Mercaptopurine (6-mercaptopurine, or 6-MP) : -It is immunosuppressive cytotoxic substance. It is widely used in transplantations to control rejection reactions. -It is acts as a purine analogue and once enter the cell, it is converted to 6-MP-ribosephophate and can be incorporated into RNA&DNA resulting in non functioning RNA & DNA &finally inducing cell cycle arrest and apoptosis. -It also inhibits purring ring biosynthesis Adverse reactions Diarrhea, nausea, vomiting, loss of appetite, Allergic reaction include rash, itching, swelling, dizziness, trouble breathing. Mercaptopurine cause myelosuppression. Those taking mercaptopurine should get permission from a doctor in order to receive immunizations and vaccinations. Azathioprine: It is one of the main immunosuppressive cytotoxic substance. It is widely used in transplantations to control rejection reactions. It is nonenzymatically cleaved to 6 - M P that acts as a purine analogue and inhibits DNA synthesis

35. 3-Pyrimidine analogues 5-flurouracil (5-FU) It act as a uracil analogue, it is transformed inside the cell into 5-FU deoxynucleotide which compete with deoxyuridine monophosphate DUMP for thymidylate synthase leading to inhibition of deoxythymidine monophosphate DTMP synthesis inhibition of DNA synthesis (Not RNA or protien) Also it is incorporated into DNA non functioning DNA . finally inducing cell cycle arrest and apoptosis by inhibiting the cell's ability to synthesize DNA. It is an S-phase specific drug 5-FU may be used in combination with other chemotherapy agents to treat cancers of the breast, stomach,colon, rectum, and pancreas. Side effect 1- Most unwanted effect is GIT epithelial damage, diarrhea and mouth ulcers. 2-the most dangerous side effect is bone marrow suppression Cytarabine It is analogue to 2-deoxycytidine and in the body it is converted into cytosine triphosphate and inhibit DNA polymerase thus inhibiting DNA synthesis.

36. 5-flurouracil (5-FU)

37. Cytarabine

38. III-Antitumor antibiotics (CCNS) : 1-Dactinomycin is isolated from soil bacteria of the genus Streptomyces. It was the first antibiotic shown to have anti-cancer activity and used in treatment of a variety of cancers. It inhibits transcription by binding to DNA at the transcription initiation complex and preventing elongation by RNA polymerase. As it can bind DNA duplexes, it can also interfere with DNA replication 2-Doxorubicin (adriamycin) Mechanism of action Doxorubicin is anthracyclin antibiotic interferes with the cells' production of DNA and RNA by inserting itself between adjacent base pair causing local uncoiling thus blocking DNA and RNA synthesis. Also its antitumor effect is related to its inhibition of topoisomerase II enzyme (responsipole for DNA repair). CYTP 450 catalyzes the conversion of Dox. into semiquinone free radicals which produce superoxide ion & H2O2 that mediate single strand scission in DNA

39. Uses Multiple cancers including breast, bone, ovarian & leukemia. Acute lymphocytic leukemia (ALL). Non-Hodgkin's lymphoma Side effects A major problem with the use of doxorubicin is that it cause irreversible heart problems specially heart failure ��.(why?) Hypersensitivity, myelosuppression Nausea, vomiting & diarrhea Urine and tears may take on a red color. 3-Mitomycin-C Mitomycin-C is an antitumor antibiotic. Mechanistically however, it belongs to DNA alkylating agents. Upon bioactivation inside the cell ,it preferentially alkylates O6 of guanine base in DNA leading to cross linking of DNA. It also degrade DNA through formation of free radicals. Side effects -mitomycin-C may cause bone marrow suppression. -Lung fibrosis may occur. If these lung problems do occur, corticosteroids may provide effective therapy. Stopping mitomycin-C therapy may also be recommended.

40. 4-Bleomycin It is cytotoxic in any phase of the cycle even on G0 phase Bleomycin degrade performed DNA causing chain fragmentation and release of free bases through the formation of free radicals (superoxide and hydroxyl radicals). Uses -Bleomycin is used in the treatment of a number of different cancers, including cancer of the head and neck, skin, esophagus, lung, testis, and genitourinary tract. -In addition, it is used in the treatment of Hodgkin's disease and non-Hodgkin's lymphomas. Side effects Pulmonary fibrosis Raynaud's phenomenon (which affects the fingers and toes, may involve pain, pale color, and abnormal sensation as burning) In addition, headache, and nausea and vomiting may occur.

41. 5-Procarbazine Procarbazine is an anticancer agent inhibits DNA and RNA synthesis in cells interfering with mitosis. Uses Procarbazine is used in the treatment of various cancers, although the best established usage is with Hodgkin's disease. Other cancers in which procarbazine is sometimes used include lymphomas, brain tumors, skin cancer, lung cancer, and multiple myeloma. Side effects it decreases the white blood cells and the platelet cells. The most severe side effect is nausea and vomiting. There may be neurological side effects such as confusion, sleepiness, depression, nightmares, agitation, and nervousness (it is weak MAOI���hypertension???)

42. IV-Plant alkaloids (Phase specific) 1-The vinca alkaloids Vincristine & vinblastine (M-phase) Mechanism of action Tubulin is a structural protein which polymerises to form microtubules. The cell cytoskeleton and mitotic spindle, amongst other things, are made of microtubules. Vincristine binds to tubulin inhibiting polymerization of microtubule structures. Disruption of the microtubules arrests mitosis in metaphase. The vinca alkaloids therefore affect all rapidly dividing cell types including cancer cells, but also intestinal epithelium and bone marrow. Side effects The main side-effects of vincristine are peripheral neuropathy. Accidental injection of vinca alkaloids into the spinal canal (intrathecal administration) is highly dangerous, with a mortality rate approaching 100%. (vinblastin is less neurotoxic) Uses Non Hodgkin's& Hodgkin's disease, malignant lymphomas and leukemia.

43. 2-Taxanes Paclitaxel & docetaxel it is used for treatment of lung, ovarian and breast cancer. Mechanism of action paclitaxel hyper-stabilizes microtubule structure (freez them). Paclitaxel binds to the � subunit of tubulin ,the resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules is necessary for their function. Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function. Side effects Bone marrow suppression and neurotoxicity

44. 3-Etoposide Chemically it is deriven from podophyllotoxin, a toxin found in the mandrake root. An inhibitor of the enzyme topoisomerase II. cause breaks in the DNA inside the cancer cells and prevent them from further dividing and multiplying. Then the cells die. Side effect Vomiting & alopecia Bone marrow suppression uses It has been useful for treatment of testicular cancer and small cell lung cancer.

45. V-Miscellaneous cytotoxic drugs 1-Crisantaspase It is a preparation of asparaginase which kills cancer cells by breaking down certain protein (L-asparagine) that is necessary for survival and growth of certain tumors incapable of forming such protein e.g. acute lymphoblastic leukemia ALL. Fortunately, normal cells are not dependent on L-asparagine for survival. Asparaginase is mainly given in combination with vincristine and steroids (either prednisone or dexamethasone). 2-Mitotan effective in the treatment of adrenocortical carcinoma. As a chemical, mitotane resembles the insecticides DDD and DDT, although mitotane does not harm people as these do. Scientists do not understand why, but the drug causes damage to the adrenocortex in such a way as to be helpful for some patients with adrenocortical tumors. In addition, mitotane restricts the ability of the gland to produce steroids.

46. 2- Hormones and hormone antagonists

47. 1-Corticosteroids Corticosteroids have broad use in cancer treatment. Some are used to treat adult leukemias, adult lymphomas, and acute childhood leukemia. Immunosuppressive mechanism Glucocorticoids suppress the cell-mediated immunity. They act by inhibiting genes that code for the cytokines interlukin and TNF-?, the most important of which is the IL-2. The inhibition of cytokine production reduces the T cell proliferation. Glucocorticoids also suppress the expansion and antibody synthesis. Side effects Hyperglycemia due to increased gluconeogenesis, insulin resistance caution in those with diabetes mellitus reduced bone density (osteoporosis, higher fracture risk, slower fracture repair) weight gain due to increased visceral and truncal fat deposition (central obesity) and appetite stimulation adrenal insufficiency (if used for long time and stopped suddenly without a taper) muscle breakdown (proteolysis), weakness; reduced muscle mass and repair growth failure, pubertal delay Increased urea formation; negative nitrogen balance The most common corticosteroids used in cancer treatment are: � dexamethasone (Decadron) � hydrocortisone � methylprednisolone (Medrol)

48. 2-Estrogens & Progestons Mainly used in androgen dependent prostatic tumors 3-Gonadotropin-releasing hormone analogues Goserelin Acetate� Goserelin acetate is a synthetic hormone that acts similarly to the naturally occurring gonadotropin-releasing hormone (GnRH). In men, this results in decreased blood levels of the male hormone testosterone. In women, it decreases blood levels of the female hormone estrogen. It is used for treatment of breast and prostatic cancer Side effects � sweating ,hot flashes, impotence (erectile dysfunction),sterility & gyncomestia � depression or other mood changes � Other common side effects in women include: light, irregular, vaginal bleeding & no menstrual period

49. Tamoxifen Tamoxifen selectively inhibits the effects of estrogen on breast tissue, while selectively mimicking the effects of estrogen on bone (by increasing bone mineral density) and uterine tissues. These qualities make tamoxifen an excellent therapeutic agent against breast cancer. it is known to compete with estrogen by binding to estrogen receptors on the membrane of target cells, thus limiting the effects of estrogen on breast tissue. Tamoxifen may also has other anti-tumor activities :affecting oncogene expression& promotion of apoptosis (cancer cell death) Adverse Effects CNS: Depression, light headedness, dizziness, headache, decreased visual acuity &retinopathy GI: Nausea, vomiting Hematological: Hypercalcemia GU: Vaginal bleeding, vaginal discharge & menstrual irregularities Dermatologic: Hot flashes, skin rash Hormone antagonists

50. 3-Immunomodulators

51. Immune system and cancer The immune system serves as one of the primary defenses against cancer. When normal tissue becomes a tumor or cancerous tissue, new antigens develop on their surface. These antigens send a signal to immune cells such as the T lymphocytes and macrophages, which in turn directly kill the tumor cells or release substances like cytokines that may bring about tumor cell death.

52. Immunomodulators Immunosuppressant Immunostimulants

53. a-Immunosuppressant 1 Glucocorticoids 2 Cytotoxic a- Alkylating agents b- Antimetabolites 1 Methotrexate 2.Azathioprine and Mercaptopurine 3. Drugs acting on immunophilins 1 Cyclosporin 2. Sirolimus

54. Drugs acting on immunophilins Cyclosporin is a calcineurin inhibitor. is one of the most widely used immunosuppressive drugs. It is a fungal peptide, composed of 11 amino acids. Cyclosporin is thought to bind to the cytosolic protein cyclophilin (an immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of cyclosporin and cyclophilin inhibits calcineurin, which under normal circumstances induces the transcription of interleukin-2. The drug also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T-cells. Cyclosporin is used in the treatment of acute rejection reactions, but has been increasingly substituted with newer immunosuppressants, as it is nephrotoxic. Sirolimus Sirolimus is a macrolide lactone, produced by the Streptomyce hygroscopicus It is used to prevent rejection reactions. Although it is a structural analogue of tacrolimus, it acts somewhat differently and has different side effects. Contrary to cyclosporine that affect the first phase of the T lymphocyte activation, sirolimus affects the second one, namely the signal transduction and their clonal proliferation. Therefore, sirolimus acts synergistically with cyclosporine and, in combination with other immunosuppressants, has few side effects. Indirectly it inhibits several T lympohocyte kinases and phosphatases, preventing the transmission of signal into their activity and the transition of the cell cycle from G1 to S phase. Similarly, it prevents the B cell differentiation to the plasma cells, which lowers the quantity of IgM, IgG and IgA antibodies produced. It acts immunoregulatory.

55. b-Immunostimulants Biologic therapy, also called immunostimulants, is a treatment that uses drugs to improve the way your body�s immune system fights disease. Your immune system is your body�s natural defense against disease. A healthy and strong immune system can detect the difference between healthy cells and cancer cells. Biologic therapy attempts to stimulate, or enhance the immune system so that it can fight the cancer

56. 1-Monoclonal Antibodies Monoclonal antibodies are proteins produced in the laboratory from a single clone of a B-cell, the type of cells of the immune system that make antibodies. When used as a treatment for cancer, there are three general strategies with monoclonal antibodies: One uses the ability of the antibodies to bind to the cancer cells having the tumor antigens on their surface. The immune system will see the cancer cells marked with bound antibodies as foreign and destroy them. A second strategy is to use the antibodies to block the binding of cytokines or other proteins that are needed by the cancerous cells to maintain their uncontrolled growth. Monoclonal antibodies designed to work like this bind to the cytokine receptors that are on the tumor cell surface. A final strategy involves special antibodies that are linked (conjugated) to a substance that is deadly to the cancer cells. E.G. radioactive isotopes, have been successfully conjugated to antibodies. The antibodies are then used to specifically destroy he tumor cells with the radioactivity or toxic substance. Trastuzumab Trastuzumab is a humanized monoclonal antibody produced by recombinant DNA technology that binds specifically to the human epidermal growth factor receptor 2 protein (also known as HER2) that is found on the cell surface of some cancer tumors, most notably breast cancer(25-30% of breast malignancies) and also targets it for destruction by the natural killer cells of immune system.

57. 2-Biological response modifiers Researchers have been working on stimulating the immune cells during cancer with substances broadly classified as biological response modifiers. Cytokines are one such substance. These are proteins that are predominantly released by immune cells upon activation or stimulation.

58. Aldesleukin Aldesleukin is interleukin, that is used to treat metastasis renal cell carcinoma (a form of kidney cancer) and metastasis melanoma. Aldesleukin is also known as interleukin-2, IL-2 When renal cell carcinoma and metastasis melanoma (cancer of the skin that arises in the pigmented cells of the skin or eyes) do not respond to other therapies, they are candidates for treatment with aldesleukin. Aldesleukin is a biological response modifier (BRM). It promotes the development of T cells, or the cells in the lymphatic system that can fight cancer cells. Side effect Flu-like symptoms (chills, fever, fatigue) Loss of appetite Skin problems such as a rash, itchiness, scaling Cardiac arrhythmias Gastrointestinal disturbance, such as nausea and vomiting Neurological effects, such as depression and poor concentration

59. Interferons Interferons are small, natural cytokines that are produced by leucocytes ,T-lymphocytes, and fibroblasts in response to infection and other biological stimuli. The goal of interferon use is to activate tumor-specific cytotoxic T-lymphocytes. Thus, tumor cells would be destroyed based on immunotherapy. Interferons attach to special receptors on the surface of cell membranes. Then produce variety of functions including enhancing or inhibiting enzymes, decreasing cell proliferation, or enhancing the activity of macrophages and T-lymphocytes. There are several different classes of interferons, cancer therapy primarily focuses on alpha interferons. Alpha interferons are used to treat cancers such as hairy cell leukemia, malignant melanoma, and Kaposi's sarcoma (an AIDS-related cancer) as well as many other cancers Side effects muscle aches, unusual metallic taste in the mouth, fever and chills, and general flu-like symptoms such as headache, loss of appetite (anorexia), nausea and vomiting, and fatigue. To reduce the flu-like symptoms physicians may suggest that the patient take acetaminophen before each dosage. confusion, trouble thinking and focusing, mental depression, nervousness, or numbness or tingling of fingers,

60. Levamisole Levamisole act to restore depressed immune function. It increases the response of T cells, or cells belonging to the lymphatic system that can fight cancer cells. It also seems to increase the activity of cells that attack and destroy invading cancer cells, including both monocytes and macrophages. Side Effects Allergic reaction. Decreased bone marrow function, resulting in fatigue or signs of infection Problems related to the nervous system, such as confusion, loss of consciousness, or speech disturbances

61. 3-Angiogenesis inhibitors Angiogenesis is the normal process by which the human body forms new blood vessels. Angiogenesis is important in the development of cancer because tumors require blood vessels to grow and spread to nearby tissue. Once a tumor reaches a certain size it needs to develop a blood supply in order to grow. Cancer cells will secrete certain chemicals to promote angiogenesis. Angiogenesis inhibitors are drugs that can stop this process. These anti-angiogenesis agents are being investigated as potential cancer therapies.

62. Thalidomide Thalidomide interferes with the growth of rapidly dividing cells.It interferes with the formation of blood vessels. It is called an antiangiogenic drug It is used to treat several types of cancers, including kidney, ovarian, and breast cancer. Side effects : Orthostatic hypotension Thalidomide may cause peripheral neuropathy (numbness, tingling, pain, or burning sensations in the feet or hands). Thalidomide may cause severe birth defects or fetal death if taken by pregnant women (phocomelia). Rash Lack of bowel movements