Anti-Neoplastic Drugs-1.pptx

Study

1. A nti-neoplastic drugs By: Muhammad Aurangzeb Lecturer-INS/KMU

2. Objectives By the end of this unit, students will be able to: Review the characteristics of normal and malignant cells. Explain characteristics of anti-neoplastic drugs. Classify anti-neoplastic drugs. Discuss the nursing care of patients who are on anti-neoplastic drugs. Calculate the drug dosage for Anti-neoplastic drugs .

3. Introduction Normal cells… Differentiate, grow, mature, divide Regulated, balanced; cell birth=cell death Regulation: intracellular signaling H y pe r plasi a : n e w c e lls p r o d uctio n with g r o wth s timulus via hormones , endogenous signals Ex: hyperplasia of endometrial tissue during menstrual cycle is normal and necessary BUT if intense, prolonged demand May  cell structural, functional abnormalities – Metaplasia : replacement of one cell type by another

4. Introduction Dysplasia : replacement cells are disordered in size, shape Increased mitosis rate Somewhat reversible, often precancerous Neoplasia : abnormal growth/invasion of cells “New growth” Neoplasm = tumor Irreversible Cells replicate, grow with /out control

5. Neoplasms Tumors = groups of neoplastic cells Two major types: benign, malignant Benign – “noncancerous” Local; cells cohesive, well-defined borders Push adjacent tissue away Doesn’t spread beyond original site Often has capsule of fibrous connective tissue M a l i gn a n t– g r o w mo r e r apid l y ; of t en c al l ed “cancer” Not cohesive; seldom have capsule Irregular shape; disrupted architecture Invade surrounding cells Can break away to form second tumor “Metastasis” from 1 o to 2 o site

6. Some basic Facts about Cancer Cancer cells have lost the normal regulatory mechanisms that control cell growth and multiplication Cancer cell have lost their ability to differentiate (that means to specialize) Benign cancer cell stay at the same place Malignant cancer cells invade new tissues to set up secondary tumors, a process known as metastasis Chemicals causing cancer are called mutagens Cancer can be caused by chemicals, life style (smoking), and viruses genes that are related to cause cancer are called oncogenes . Genes that become onogenic upon mutation are called proto- oncogenes .

7. Cancer (Neoplastic) b e en Can c er occu r s transformed no rmal ce l ls h a v e neoplastic cells th r ough al t e r a tion of a f t er into their g e n e t i c m a t e r i a l and t he abnormal expression of certain genes. Neoplastic cells usually exhibit chromosomal abnormalities and the loss of their differentiated properties. These changes lead to uncontrolled cell division and many result in the invasion of previously unaffected organs, a process called metastasis

8. Cell Cycle Phases Synth DNA precursors, proteins, etc.

9. Cycle Checkpoints 1 8 _ 4 _ F e e d b ac k. j pg

10. Cont… Af t er c ompl e tion of mi t os i s , t h e r esult i n g daug h t er ce l l s have two options: they can either enter G1 & repeat the cycle or they can go into G0 and not participate in the cell cycle. (Quiescent phase outside cell cycle )

11. Phases of the Cell Cycle G1 phase (gap 1): Cell grows in size and prepares to copy its DNA in response to various growth factors S phase (synthesis): Replication of DNA, copying of the chromosome G2 phase (gap 2): Preparation for cell division. Check copied DNA and repair damaged copies. M phase (mitosis): Formation of the mitotic spindle, and separation into two individual cells (cell division).

12. Control of Cell Cycle Progression by CDKs Progression through the cell cycle is controlled by cyclin-dependent kinases (CDKs). Binding of cyclin with its associated kinase triggers to move the cell cycle to another phase inhibitory proteins are present that can modify the effect of cyclins . These include p21 , that is controlled by the tumor suppressor protein p53 . over-active cyclins or CDKs have been associated with many tumors. Excessive production of cyclins or CDKs or insufficient production of CDK inhibitors leads to disruption of the normal regulation of the cell cycle.

13. Cancer cells are often called immortal since there seems to be no limit for how often they can divide Life-time of normal cells is limited to 50-60 cell divisions. This is regulated by telomeres. The telomeres are at the 3’ end of the chromosomes. After each replication about 50-100 base pairs are lost At some point telomeres are too short to be effective and the DNA becomes unstable thereby limiting replication. Cancer cells possess an enzyme called telomerase which maintains the length of the telomeres and thereby allows more DNA replications. Telomeres A few short telomeres Critically short telomeres Apoptosis Cancer (1 in 10,000,000)

14. Intrinsic Tumor Suppression : p53 In response to DNA damage, oncogene activation or other harmful events the tumor suppressor gene p53 is induced Various kinases phosporylate p53 which help stabilizing it. Activated p53 results in DNA binding and transcriptional activation p53 triggers cell-cycle arrest in untransformed cells via cell-cycle regulators such as CDKs It also triggers apoptosis in transformed cells In most tumor cells p53 is mutated and inactivated

15. Uncontrolled Proliferation Result of activation proto-oncogenes ( Ras ) or inactivation of tumor suppressor genes (p53) Change in growth factors, receptors Increased growth factors produced Change in cell cycle transducers Cyclins, CDK’s , CDK inhibitors (p21) Change in apoptotic mechanism Change in telomerase expression

16. Principles of cancer chemotherapy Cancer chemotherapy strives to cause a lethal cytotoxic event or apoptosis in the cancer cells that can arrest a tumor’s progression. The attack is generally directed toward DNA or against metabolic sites essential to cell replication, for example , the availability of purines and pyrimidines, which are the building blocks for DNA or RNA synthesis. Ideally , these anticancer drugs should interfere only with cellular processes that are unique to malignant cells. Unfortunately , most currently available anticancer drugs do not specifically recognize neoplastic cells but , rather, affect all kinds of proliferating cells, both normal and abnormal.

17. Mechanisms of Action of Antineoplastic Drugs Prevent DNA synthesis Disrupt DNA, prevent DNA repair, and/or prevent RNA synthesis Interrupt mitosis Interfere with protein or hormone synthesis

18. Goal of Chemotherapy The GOAL is to eradicate the cancer cells without affecting normal tissues. The REALITY is that all cytotoxic drugs affect normal tissues as well as malignancies due to a narrow therapeutic index

19. The Goal of Cancer Treatments Curative Total irradication of cancer cells Curable cancers include testicular tumors, Wills tumor Palliative Alleviation of symptoms Avoidance of life-threatening complications Increased survival and improved quality of life Adjuvant therapy Attempt to eradicate microscopic cancer after surgery e.g. breast cancer & colorectal cancer

20. Classification of cancer drugs Cancer drugs can be divided into two general classes: CELL CYCLE SPECIFIC DRUGS ( CCS ; esp. plant alkaloids and antimetabolites), and CELL CYCLE NON-SPECIFIC DRUGS ( CCNS ; esp. alkylating agents and some natural products). Antineoplastic agents can also be organized according to their chemical class, mechanism of action, therapeutic use or their toxicities.

21. Toxicity Toxicity: Therapy aimed at killing rapidly dividing cancer cells also affects normal cells undergoing rapid proliferation (for example, cells of the buccal mucosa, bone marrow, gastrointestinal [ GI] mucosa , and hair follicles), contributing to the toxic manifestations of chemotherapy.

22. Common adverse effects: Most chemotherapeutic agents have a narrow therapeutic index. Severe vomiting, stomatitis, bone marrow suppression, and alopecia occur to a lesser or greater extent during therapy with all antineoplastic agents. Vomiting is often controlled by administration of antiemetics . Some toxicities, such as myelosuppression that predisposes to infection, are common to many chemotherapeutic agents, whereas other adverse reactions are confined to specific agents, such as bladder toxicity with cyclophosphamide, cardiotoxicity with doxorubicin, and pulmonary fibrosis with bleomycin . The duration of the side effects varies widely . For example, alopecia is transient, but the cardiac, pulmonary, and bladder toxicities can be irreversible.

23. General problems with anticancer drugs Side effects greatest in other rapidly-dividing cells Bone marrow toxicity Impaired wound healing Hair follicle damage G I epithelium damage Growth in children Gametes Fetus May themselves be carcinogenic

24. Anticancer Drugs Antimetabolite Antibiotics Alkylating Agent Microtubule inhibitors Topoisomerase inhibitors Tyrosine kinase inhibitors Hormones Monoclonal antibodies Pl a tinu m complex compounds etc.

25. ANTIMETABOLITES Antimetabolites are structurally related to normal compounds that exist within the cell. They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors, either by inhibiting their synthesis or by competing with them in DNA or RNA synthesis. Their maximal cytotoxic effects are in S-phase and are, therefore, cell cycle specific. Methotrexate ( MTX ), pemetrexed and pralatrexate are antifolate agents

26. Classification of Antimetabolites Folic acid Antagonists: ( Methotrexate) MTX Purine Antagonists: 6-Mercaptopurine Pyrimidine Antagonists ： 5 Fluorouracil (5-FU)

27. Mechanism of Action MTX is structurally related to folic acid and acts as an antagonist of the vitamin by inhibiting dihydrofolate reductase (DHFR), the enzyme that converts folic acid to its active, coenzyme form, tetrahydrofolic acid (FH4 ) required for thymidine and purine synthesis. MTX is specific for the S-phase of the cell cycle. Pemetrexed is an antimetabolite similar in mechanism to methotrexate . However, in addition to inhibiting DHFR , it also inhibits thymidylate synthase and other enzymes involved in folate metabolism and DNA synthesis. Pralatrexate is a newer antimetabolite that also inhibits DHFR

28. Therapeutic uses: MTX , usually in combination with other drugs, is effective against acute lymphocytic leukemia, Burkitt lymphoma in children, breast cancer, bladder cancer, and head and neck carcinomas. Pemetrexed is primarily used in non–small cell lung cancer . Pralatrexate is used in relapsed or refractory T-cell lymphoma

29. Adverse Effects ： MTX is myelosuppressive, producing severe leukopenia, bone marrow aplasia (failure), and thrombocytopenia. This agent may produce severe gastrointestinal disturbances. Renal toxicity may occur because of precipitation (crystalluria) of the 7-OH metabolite of MTX.

30. Purine Antagonists 6-Mercaptopurine （ 6-MP ） The drugs are believed to act similarly to inhibit purine base synthesis , although their exact mechanisms of action are still uncertain . Indications: Mercaptopurine is used primarily for the maintenance of remission in patients with acute lymphocytic leukemia and is given in combination with MTX for this purpose . Adverse Effects: Well tolerate. Myelosuppression is generally mild with this drug . Long-term mercaptopurine use may cause hepatotoxicity.

31. Pyrimidine Antagonists : 5-Fluorouracil (5-FU) Mechanism of Action ： Fluo r ou r acil is an anal o gue o f t h ymi n e in w hic h the m et h yl g r ou p is r epl a c e d b y a fluorin e at om . 5-FU is converted to 5-fluorodeoxyuridine monophosphate (5-FdUMP ), which competes with deoxyuridine monophosphate ( dUMP ) for the enzyme thymidylate synthetase and prevents the synthesis of thymidine, a major building block of DNA.

32. Pyrimidine Antagonists 5-Fluorouracil (5-FU) Indications ： Fluorouracil is exclusively used to treat solid tumors, especially breast, colorectal, and gastric tumors and squamous cell tumors of the head and neck. Adverse Effects ： Fluorouracil may c au s e nau se a and v om i tin g , m y elosup p r ess i o n , o r al and g a s t r o i n t e s t inal ulceration . Nausea and vomiting are usually mild .

33. Pyrimidine Antagonists : Cytarabine Cytarabine acts as a pyrimidine antagonist. Indications ： Cytarabine has a narrow clinical spectrum and is primarily used in combination with daunorubicin for the treatment of acute nonlymphocytic leukemia. Adverse Effects : High doses of cytarabine can damage the liver, heart, and other organs.

34. Anti-tumor Antibiotics The antitumor antibiotics owe their cytotoxic action primarily to their interactions with DNA, leading to disruption of DNA function . In addition to intercalation, their abilities to inhibit topoisomerases (I and II) and produce free radicals also play a major role in their cytotoxic effect. They are cell cycle nonspecific with bleomycin as an exception

35. Antibiotics Anthracyclines: Doxorubicin (Adriamycin) Daunorubicin Bleomysin Actinomycin D Mitomycin

36. Doxorubicin & Daunorubicin Mechanism of action These drugs intercalate between base pairs, inhibit topoisomerase II and also generate free radicals They block RNA and DNA synthesis and cause strand scission Doxorubicin interacts with molecular oxygen, producing superoxide ions and hydrogen peroxide, which cause single-strand breaks in DNA

37. Adverse D rug R eaction Cardiac toxicity (due to generation of free radicals) Acute form: arrhythmias, ECG changes, pericarditis, myocarditis Chronic form: *** Dilated cardiomyopathy , heart failure ****Rx with dexrazoxane – This is an inhibitor of iron mediated free radical generation Bone marrow depression, Total alopecia

38. Mitomycin C: Mechanism: Mitomycin C is an antineoplastic antibiotic that alkylates DNA and thereby causes strand breakage and inhibition of DNA synthesis. Indications: It is primarily used in combination with vinvristine as salvage therapy for breast cancer. Adverse Effects: Mitomycin produces delayed and prolonged m y elo su pp ressi on tha t p r e f ere n tia l ly a f f e c ts platelets and leukocytes

39. Actinomycin D: Actinomycin D intercalates DNA and thereby prevents DNA transcription and messenger RNA synthesis. The drug is given intravenously, and its clinical use is limited to the treatment of trophoblastic (gestational) tumors and the treatment of pediatric tumors, such as Wilms ’ tumor and Ewing’s sarcoma.

40. Bleomycin : Mechanism: The drug has its greatest effect on neoplastic cell in the G2 phase of the cell replication cycle. Although bleomycin intercalates DNA, the major cytotoxicity is believed to result from ironcatalyzed free radical formation and DNA strand breakage. Indications: It is useful in Hodgkin’s and non-Hodgkin’s lymphomas, testicular cancer, and several other solid tumors. Adverse Effects: Bleomycin produces very little myelosuppression. The most serious toxicities of Bleomycin are pulmonary and mucocutaneous reactions.

41. ALKYLATING AGENTS Alkylating agents exert their cytotoxic effects by covalently binding to DNA. Alkylation of DNA is probably the crucial cytotoxic reaction that is lethal to the tumor cells . Alkylating agents do not discriminate between cycling and resting cells , even though they are most toxic for rapidly dividing cells. They are used in combination with other agents to treat a wide variety of lymphatic and solid cancers. In addition to being cytotoxic, all are mutagenic and carcinogenic and can lead to secondary malignancies such as acute leukemia .

42. Alkylating Agents One of the frightening developments of World War I was the introduction of chemical warfare. These compounds were known as the nitrogen mustard gases. The nitrogen mustards were observed to inhibit cell growth, especially of bone marrow. Shortly after the war, these compounds were investigated and shown to inhibit the growth of cancer cells.

43. 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.

44. ALKYLATING AGENTS Cyc l op h os p h a mi d e Busulfan Carmustine (BCNU) Lomustine (CCNU) Melphalan Thiotepa

45. Alkylating Agents— Cyclophosphamide It is a prodrug and is activated by the P-450 enzymes to its active form phosphoramide mustard Th e acti v e dr u g alkyl a t es n u c leophi l ic g r ou p s on DNA bases – Particularly at the N-7 position of guanine This leads to cross linking of bases, abnormal base pairing and DNA strand breakage Indications ： It is used in the treatment of chronic lymphocyctic leukemia, non-Hodgkin’s lymphomas, breast and ovarian cancer, and a variety of other cancers. It is also a potent immunosuppressant, it is used in the management of rheumatoid disorders and autoimmune nephritis. Adverse Effects: Alopecia, nausea, vomiting, myelosuppression, and hemorrhagic cystitis.

46. Alkylating Agents——Nitrosoureas Carmustine, Lomustine, Carmustine and lomustine are closely related nitrosoureas. Nitrosoureas are highly lipophilic and reach cerebrospinal fluid concentrations that are about 30% of plasma concentrations. Mechanism of action: The nitrosoureas exert cytotoxic effects by an alkylation that inhibits replication and, eventually, RNA and protein synthesis. Indications: Because of their excellent CNS penetration, carmustine and lomustine have been used to treat brain tumors.

47. Alkylating Agents — Phenylalanine Nitrogen Mustard Melphalan an alkylating agent which is a phenylalanine derivative of nitrogen mustard. Although melphalan can be given orally, the plasma concentration differs from patient to patient due to variation in intestinal absorption and metabolism. Melphalan is primarily used to treat multiple myeloma (plasma cell myeloma), breast cancer, and ovarian cancer.

48. Alkylating Agents: Alkysulfonates Busulfan Indications : Busulfan is ad m ini s t e r e d o r a l ly t o t r e a t c h r on ic granulocytic leukemia. In aged patients, busulfan can cause pulmonary fibrosis (“ busulfan lung ”). Like other alkylating agents, all of these agents are leukemogenic. Adverse Effects : Busulfan produces adverse effects related to m y el o su pp r essio n . It only occasionally produces nausea and vomiting. In high doses, it produces a rare but sometimes fatal pulmonary fibrosis, ”busulfan lung”.

49. Alkylating Agents——Thiotepa Thiotepa is converted rapidly by liver to its active metabolite triethylenephosphoramide (TEPA); it is active in bladder cancer

50. Microtubule Inhibitors The mitotic spindle is part of a larger, intracellular skeleton (cytoskeleton) that is essential for the movements of structures occurring in the cytoplasm of all eukaryotic cells. The mitotic spindle consists of chromatin plus a system of microtubules composed of the protein tubulin. The mitotic spindle is essential for the equal partitioning of DNA into the two daughter cells that are formed when a eukaryotic cell divides. Several plant-derived substances used as anticancer drugs disrupt this process by affecting the equilibrium between the polymerized and depolymerized forms of the microtubules, thereby causing cytotoxicity.

51. Microtubule Inhibitors Tubulin-Binding Agents Vinca Alkaloids: The cellular mechanism of action of vinca alkaloids is the prevention of microtubule assembly, causing cells to arrest in the late G2 phase by preventing formation of mitotic filaments for nuclear and cell division Vinblastine, vincristin, vindesine and vinorelbine are all alkaloids derived from the periwinkle plant (Vinca rosea).

52. Mechanism of action of the microtubule inhibitors .

53. Vinca Alkaloids Indications: Vinblastine is used in combination with Bleomycin and Cisplatin for metastatic testicular tumors. Vincristine is used in combination with prednisone to induce remission in childhood leukemia. Vinorelbine is used to treat non-small-cell lung cancer and breast cancer. ADR Severe neurotoxicity Paresthesias Loss of reflexes Foot drop Ataxia

54. Microtubule Inhibitors Paclitaxel & Docetaxel (Taxans) These drugs act by interfering with mitotic spindle by preventing microtubule disassembly into tubulin monomers Mechanism of action: Both drugs are active in the M-phase of the cell cycle, but unlike the Vinca alkaloids, they promote polymerization and stabilization of the polymer rather than disassembly, leading to the accumulation of microtubules . The overly stable microtubules formed are nonfunctional, and chromosome desegregation does not occur. This results in death of the cell Therapeutic Uses. Docetaxel and paclitaxel have become central components of regimens for treating metastatic ovarian, breast, lung, and head and neck cancers ADR: Neutropenia & Peripheral neuropathy

55. Paclitaxel stabilizes microtubules, rendering them nonfunctional.

56. Hormones Several types of hormone-dependent cancer (especially breast, prostate, and endometrial cancer) respond to treatment with their corresponding hormone antagonists. Estrogen antagonists are primarily used in the treatment of breast cancer, whereas androgen antagonists are used in the treatment of prostate cancer. Corticosteroids are particularly useful in treating lymphocytic leukemias and lymphomas.

57. Glucocorticoids: They are integral components of curative therapy for acute lymphocytic leukemia, non-Hodgkin’s lymphoma, and Hodgkin’s disease. Prednisone is a potent, synthetic, anti-inflammatory corticosteroid (at high doses, lymphocytolytic and leads to hyperuricemia due to the breakdown of lymphocytes) Prednisone is primarily employed to induce remission in patients with acute lymphocytic leukemia and in the treatment of both Hodgkin and non-Hodgkin lymphomas.

58. Tamoxifen Tamoxifen is an estrogen antagonist with some estrogenic activity, and it is classified as a selective estrogen receptor modulator (SERM). It is used for first-line therapy in the treatment of estrogen receptor–positive breast cancer. Mechanism of action: Tamoxifen binds to estrogen receptors in the breast tissue, but the complex is unable to translocate into the nucleus for its action of initiating transcriptions. That is, the complex fails to induce estrogen-respons e , and RNA synthesis does not occur. The result is a depletion of estrogen receptors, and the growth-promoting effects of the natural hormone and other growth factors are suppressed. ADR: Hot flushes, vaginal bleeding and venous thrombosis

59. Aromatase inhibitors The aromatase reaction is responsible for the extra- adrenal synthesis of estrogen from androstenedione This takes place in liver, fat, muscle, skin, and breast tissue, including breast malignancies. Peripheral aromatization is an important source of estrogen in postmenopausal women. Aromatase inhibitors decrease the production of estrogen in these women. Anastrozole and Letrozole are aromatase inhibitors These drugs inhibit the aromatase enzyme **** Used in Tx of postmenopausal women with metastatic breast ca (1 st line drug) ADR includes : bone pain and peripheral edema

60. Estrogens Estrogens had been used in the treatment of prostatic cancer. Estrogens inhibit the growth of prostatic tissue by blocking the production of LH , thereby decreasing the synthesis of androgens in the testis . Thus, tumors that are dependent on androgens are affected. Adverse effects: Estrogen treatment can cause serious complications, such as thrombo-emboli, myocardial infarction , strokes, and hypercalcemia. Men who are taking estrogens may experience gynecomastia and impotence.

61. GnRH analogs GnRH analogs: Leuprolide , gosarelin and triptorelin Effective in management of Prostatic carcinomas When given in constant doses they inhibit release of pituitary LH and FSH These drugs suppress gonadal function due to down regulation and desensitization of Gn -RH receptors ADR Leuprolide may cause gynecomastia, hematuria, impotence and testicular atrophy

62. Monoclonal Antibodies They are created from B lymphocytes (from immunized mice or hamsters) fused with “immortal” B-lymphocyte tumor cells. The resulting hybrid cells can be individually cloned, and each clone will produce antibodies directed against a single antigen type. Currently, several monoclonal antibodies are available for the treatment of cancer. Trastuzumab, rituximab, bevacizumab, and cetuximab Monoclonal antibodies have become an active area of drug development for anticancer therapy and other non-neoplastic diseases, because they are directed at specific targets and often have fewer adverse effects.

63. Platinum Coordination Complexes Cisplatin, carboplatin, and oxaliplatin Cisplatin was the first member of the platinum coordination complex class of anticancer drugs Mechanism of action: The mechanism of action for this class of drugs is similar to that of the alkylating agents. It binds to guanine in DNA, forming inter and intrastrand crosslinks. The resulting cytotoxic lesion inhibits both polymerases for DNA replication and RNA synthesis. Cytotoxicity can occur at any stage of the cell cycle, but cells are most vulnerable to the actions of these drugs in the G1 and S-phases.

64. Cisplatin, carboplatin, and oxaliplatin Adverse effects: Severe, persistent vomiting occurs for at least 1 hour after administration of cisplatin and may continue for as long as 5 days. Premedication with antiemetic agents is required . The major limiting toxicity is dose-related nephrotoxicity, involving the distal convoluted tubule and collecting ducts. This can be prevented by aggressive hydration.

65. Topoisomerase Inhibitors These agents exert their mechanism of action via inhibition of topoisomerase enzymes, a class of enzymes that reduce supercoiling of DNA A. Camptothecins are plant alkaloids originally isolated from the Chinese tree Camptotheca. MOA: These drugs are S-phase specific and inhibit topoisomerase I Adverse effects: Bone marrow suppression, (neutropenia) B . Etoposide is a semisynthetic derivative of the plant alkaloid,. It blocks cells in the late S- to G2 phase of the cell cycle. Its major target is topoisomerase II. Dose-limiting myelosuppression (primarily leukopenia) is the major toxicity

66. Tyrosine Kinase Inhibitor The tyrosine kinases are a family of enzymes that are involved in several important processes within a cell, including signal transduction and cell division . Many tyrosine kinase inhibitors are available, and these agents have a wide variety of applications in the treatment of cancer.

67. Tyrosine Kinase Inhibitor Imatinib, dasatinib, and nilotinib Imatinib is used for the treatment of chronic myelogenous leukemia (CML). It acts as a signal transduction inhibitor, used specifically to inhibit tumor tyrosine kinase activity. The ability of imatinib to occupy the “kinase pocket” prevents the phosphorylation of tyrosine on the substrate molecule and, hence, inhibits subsequent steps that lead to cell proliferation. These agents are all available in oral formulations, and they are associated with notable toxicities, such as fluid retention and QT prolongation

68. Miscellaneous agents Asparaginase , , interferons, Asparaginase: L-Asparaginase catalyzes the deamination of asparagine to aspartic acid and ammonia. L- Asparaginase is used in combination therapy to treat childhood acute lymphocytic leukemia Its mechanism of action is based on the fact that some neoplastic cells require an external source of asparagine because of their limited capacity to synthesize sufficient amounts of that amino acid to support growth and function. L- Asparaginase hydrolyzes blood asparagine and, thus, deprives the tumor cells of this amino acid, which is needed for protein synthesis ADR: Acute pancreatitis

69. I n t er f e r ons Human interferons are biological response modifiers. MOA: Interferons interact with surface receptors on other cells , at which site they exert their effects. Bound interferons are neither internalized nor degraded. As a consequence of the binding of interferon, a series of complex intracellular reactions take place . These include synthesis of enzymes, suppression of cell proliferation, activation of macrophages, and increased cytotoxicity of lymphocytes . However , the exact mechanism by which the interferons are cytotoxic is unknown. Interferon is presently approved for the management of hairy-cell leukemia, chronic myeloid leukemia, and acquired immunodeficiency syndrome (AIDS)–related Kaposi sarcoma.

70. Prevention/management of Cancer Chemotherapy induced ADR Nausea and vomiting : 5-Ht3 antagonist (ondansetron) Bone marrow suppression : Filgrastim ( colony stimulating factors) MTX toxicity : Leucovorin (folic acid) Cyclophosphamide toxicity : MESNA Cisplatin toxicity : Amifostine Anthracycline toxicity ; Dexaroxazone

71. References Lippincott Illustrated Reviews: Pharmacology Sixth Edition