Anti neoplastic agents

Introduction
Classification
Treatment
Chemistry of Anti Cancer Agents

1. Anti-neoplastic Agent Dr. Naga Prashant Koppuravuri, M.Pharm , Ph.D , FAGE., Assistant Professor, Department of Pharmaceutical Chemistry

2. Introduction Malignant disease accounts for a high proportion o f deaths in industrialised countries. The treatment with anticancer drug is to give palliation, induce remission and if possible, cure .

3. Introduction  Cancer occurs after normal cells have been transformed into neoplastic cells through alteration of their genetic material and the abnormal expression of certain genes.  Neoplastic abnormalities cells and usually exhibit of their chromosomal differentiated the loss properties. These changes lead the to uncontrolled cell division and many result in invasion of previously unaffected organs a process called metastasis .

4. Treatment options of cancer:  Surgery: before 1955  Radiotherapy: 1955~1965  Chemotherapy: after 1965  Immunotherapy and Gene therapy

5. According to chemical structure and  resource of the drug ; According to biochemistry mechanisms of  anticancer action ; According to the cycle or phase specificity  of the drug

6.  According to chemical structure and resource Alkylating of the drug : Agents, Antimetabolite, Antibiotics, Plant Extracts ， Hormones ， ImmunotherapyRadiotherapeutic Agents, Cytoprotective Agents, Antineoplastic Platinum Compounds

7.  According to biochemistry mechanisms of anticancer action: Block nucleic acid biosynthesis Direct ly influence the structure and function of DNA Interfere Interfere Influence transcription and block RNA synthesis protein synthesis and function hormone homeostasis

8. According specificity to the cycle or phase of the drug : Cell cycle specific agents (CCSA) Cell cycle nonspecific agents (CCNSA)

9. The cycle of cell replication includes: G1 （ Gap1, period before S ） phase S （ DNA synthesis ） phase G2 （ Gap2,period after S ） phase M （ Mitosis ） phase

10. The Basic Concept of Cell Generation Cycle The G1 phase is the period when newly created cell is remains in the G1 phase born. The period depends upon the cell).Cells can be state. of time the cell type of cell (tumor cell or normal born in proliferated or non-proliferated If the cell is a proliferating cell,it will move quickly to or synthesis phase. In this period, DNA replicates and two copies of DNA are present in the cell. The next phase is G2 phase and cells are prepared for final cell cycle M phase or Mitosis. There are two major control points in cell cycle, G1/S phase, the cell replicates and G2 / M phase, the cell divides. G1 / S phase is important in understanding cancer and cancer treatment. S

11.  Tumor cells can be classified as proliferating cells and  The ratio non-proliferating of proliferating cells. cells in the whole (GF). tumor tissue is called growth fraction Proliferating cell group GF ＝ Total tumor cell group

12.  The faster the tumor cells proliferate, the bigger the GF is and the higher the sensitivity of tumor to a drug is.  Generally, in the early stage, the GF of a tumor is bigger and the effect of a drug on the tumor is better CCNSA ： drugs that are active throughout the cell cycle. CCSA: drugs that act during a specific phase of the cell cycle.

13.  Cell Cycle Nonspecific Agents (CCNSA) drugs cycle that are active throughout the cell Alkylating Agents Platinum Compounds Antibiotics   

14.  Cell Cycle Specific Agents (CCSA) drugs that act d uring a specific phase of the cell cycle S Phase Specific Drug: Antimetabolites, Topoisomerase Inhibitors M Phase Specific Drug: Vinca Alkaloids, Taxanes G2 Phase Specific Drug: Bleomycin

15.  Block nucleic acid (DNA, RNA) biosynthesis  Directly destroy DNA and inhibit DNA reproduction  Interfere  Interfere  Influence transcription and block RNA synthesis protein synthesis and function hormone homeostasis

16.  Alkylating Agent: mechlorethamine, cyclophosphamide and  Platinum: cis-platinium thiotepa  Antibiotic: bleomycin and mitomycin C  Topoismerase inhibitor: camptothecine and podophyllotoxin

17.  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.

18. Alkylating Agents Alkylating agents were one of the earliest classes of drugs used to treat cancer, beginning in the 1940’s. The biggest weakness of most cancer cells is very sensitive to DNA damage. that they are Alkylating agents work by reacting with the proteins that double helix bond together to form the very delicate structure of a DNA molecule, adding an alkyl group to some or all of them. This prevents the proteins from linking up as they should, causing breakage of the DNA strands and eventually, the death of the cancer cell.

19. Alkylating Agents This phenomenon is essentially a mutation the cancer cell’s ability to multiply. that takes away While there are many different classes of alkylating agents, they all work by this same chemical mechanism. Alkylating agents are highly electrophilic compounds which react with nucleophiles to form a strong covalent bond. It acts by transfer of alkyl group to biologically important constituents such as amino, sulfhydryl or phosphate group whose function is then impaired.

20. Alkylating Agents Alkylating agents are known to react RNA and protein with DNA, They act by alkylating N - 7 position of guanine in DNA, which results in the formation of apurinic site. The alkylating agent most effective in G 1 or S phase. appears to be H + Y + nu – H + alkyl - Y alkyl – nu + + A l k y l a t i n g age n t N u c l e o ph i l e o f b i o p o l y m er

21. Alkylating Agents The five major categories of alkylating agents are

22. Nitrogen Mustards & aziridine mediated alkylators

23. Nitrosoureas

24. DNA Methylators

25. Organo Platinum Complexes

26. Miscellaneous DNA Alkylators

27. Resistance to causes: alkylating agents has several  Membrane transport may be decreased.  The drug may be bound by glutathione (GSH) via GSH-S-transferase or metallothioneins in the cytoplasm and inactivated.  The drug species. may be metabolized to inactive

28.  Myelosuppression is the dose-limiting adverse effect for alkylating agents.  Nausea and vomiting are as common as teratogenesis and gonadal atrophy, although in the latter cases these are variable, according to the drug, its schedule, and route of administration.  Treatment also carries a major risk of leukemogenesis and carcinogenesis.

29. O O H 2 O P (ClCH 2 CH 2 ) 2 N HN 2-[Bis (2-chloroethyl) amino] tetrahydro - 2H -1,3,2- oxazo - phosphorin -2- oxide monohydrate Use: It is used against multiple myeloma, chronic lymphocytic leukemia and acute leukemia of children

30. Cisplatin: Mechanism of Action:  Cisplatin binds to guanine in DNA and RNA, and the interaction is stabilized by mechanism hydrogen bonding. The molecular of action is unwinding and shortening of the DNA helix.

31. Cisplatin: Indications:  Cisplatin has efficacy against a wide range of neoplasms. It is given intravenously as a first- line drug for testicular, ovarian, and bladder cancer, and it is also useful in the treatment of melanoma and a number of other soild tumors.  Cisplatin produces relatively little myelosuppressio but can cause severe nausea, vomiting and nephrotoxicity. Adverse Effect:

32. Carboplatin: Indication:  Carboplatin has a similar spectrum of activity, but it is approved only as a second-line drug for ovarian cancer.

33. Antimetabolites: • Folic Acid reductase • Pyrimidine Antagonist: inhibit dihydrofolate (methotrexate) Antagonist: inhibit thymidylate synthetase (fluorouracil) ; inhibit DNA polymerase (cytarabine) • Purine Antagonist: inhibit interconversion of purine nucleotide (mercaptopurine) • Ribonucleoside Diphosphate Reductase Antagonist: (hydroxyurea)

34. In the 1950's a biochemical difference in metabolism related to the amino acid asparagine was found. Normal cells cells they apparently can synthesize asparagine while leukemia cannot. If leukemia cells are deprived of asparagine, will eventually die If the enzyme L-asparaginase is given to humans, various types of leukemias can be controlled. Tumor cells, more specifically lymphatic tumor cells, with an require huge amounts malignant destroys of asparagines to keep up is their rapid, growth. asparagine L-asparaginase enzyme that are external to the cell. Normal cells able to make all the asparagine they need internally whereas tumor cells become depleted rapidly and die.  Bind with DNA to block RNA production. doxorubicin

35. General Characteristics ：  Antimetabolites are S phase-specific drugs that are structural analogues of essential metabolites and that interfere with DNA synthesis.  Myelosuppression is the dose-limiting toxicity for all drugs in this class.

36.  Folic acid Antagonists : MTX  Purine Antagonists : 6MP 6TG  Pyrimidine Antagonists ： 5FU araC HU

37. Methotrexate （ MTX ） Mechanism of Action ：  The structures of MTX and folic acid are similar. MTX is actively transported into mammalian cells and inhibits dihydrofolate reductase, the enzyme that normally converts dietary folate to the tetrahydrofolate form required for thymidine and purine synthesis.

38. Methotrexate （ MTX ） Indications ：  MTX is used in the treatment of choriocarinoma , a trophoblastic tumor, was the first demonstration of curative chemotherapy.  It is especially effective for treating lymphocytic leukemia and for treating meningeal metastases of a wide range acute the of tumors.

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

40. 6-Mercapapurine （ 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 MTX for this purpose. Adverse Effects: with  Well tolerate.  Myelosuppression is generally mild with thioguanine.Long-term mercaptopurine use may cause hepatotoxicity.

41. 5-Fluorouracil (5-FU) Mechanism of Action ：  Fluorouracil is an analogue of thymine methyl group is replaced by a fluorine tw o active metabolites: 5-FdUMP and in which the atom. It has 5-FdUTP. 5- FdUMP inhibits thymidylate synthetases and the synthesis of thymidine, a major building DNA. 5-FdUTP is incorporated into RNA by prevents block of RNA polymerase and interferes with RNA function.

42. 5-Fluorouracil (5-FU) Indications ：  Fluorouracil is exclusively used to treat solid tumors, especially breast, colorectal, and gastric tumors and and squamous cell neck. tumors of the head

43. 5-Fluorouracil (5-FU) Adverse Effects ：  Fluorouracil may cause nausea and vomiting, myelosuppression, and oral and gastrointestinal ulceration. Nausea and vomitting are usually mild.  With fluorouracil, myelosuppression is more problematic after bolus injections, whereas mucosal damage is dose-limiting with continuous infusions.

44. Cytarabine Indications ：  Cytarabine has a narrow clinical spectrum and is primarily used in combination with daunorubicin or thioguanine for the treatment of acute nonlymphocytic leukemia.  High doses of cytarabine can damage the liver, heart, and other organs. Adverse Effects :

45. Pyrimidine antagonists:

46. Purine antagonists:

47. Folate antagonists:

48. DNA polymerase and chain elongation inhibitors:

49. Miscellaneous antimetabolites:

50. A. Fluorouracil (5FU – CBC, Flocil) O F HN O N H 5-Fluoro - 2, 4- (1H, 3H) pyrimidindione. O O CF 3 OF Fluoroxy tri fluoro methane HN F HN O Fluorination N H Uracil O N H Fluorouracil Use: It is effective in palliative management of carcinoma of the breast, colon, pancreas, rectum and stomach in patient who cannot be cured by surgery. It is also used in the treatment of skin and basal cell carcinomas.

51. S H N N N H 2 N N H 2-Amino-7H-purin-6-thiol It is a guanine analogue, belongs to the family of drugs called antimatabolites. Its act by integrated into DNA and RNA, which result in the inhibition of synthesis and metabolism of purine nucleotides.

52. Topoisomerase Poisons Three chemically distinct classes of anticancer agents can be classified as topoisomerase poisons: Camptothecins , Epipodophyllotoxins Anthracyclines (discussed under antineoplastic antibiotics).

53. Topoisomerases are enzymes that control the degree of DNA supercoiling and, in so doing, maintain proper DNA structure during replication and transcription to RNA. Topoisomerase IIα ( TopII α) cleaves doublestranded DNA during the replication phase via a transesterifi cation reaction involving a topoisomerase tyrosine residue and a terminal 5′ phosphate but, through a reverse transesterifi cation, repairs its own damage after replication is complete. Topoisomerase I ( TopI ) functions in essentially the same way, but cuts and relegates a single DNA strand. Antineoplastic agents that MECHANISM OF ACTION

54. Epipodophyllotoxins

55. Classification of Antibiotics:  Adriamycin (Anthracyaline Antibiotics)  Mitomycin  Bleomycin C  Actinomycin D

56. Adriamycin and Daunorubicin ： Properties:  Adriamycin and Daunorubicin are tetracycline rings with the sugar daunosamine. They are DNA intercalating agents that block the synthesis of DNA and RNA.  These of cell  These agents are primarily toxic during the S phase cycle. agents imparts a red tinge to the urine.  Adramycin is used to treat acute leukemias, lymphoma, and a number of solid tumors.

57. 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 delays and prolonged affects myelosuppression that preferentially platelets and leukocytes.

58. 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.

59. 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.

60. Antibiotics

61. Anthracycline-based antineoplastic agents act by poisoning TopII α through the stabilization of the ternary drug–enzyme–DNA cleavable complex. Like the topoisomerase poisons discussed earlier, they allow DNA to be cut and covalently linked to the conserved topoisomerase Tyr residue but inhibit the resealing reaction. MECHANISM OF ACTION

62. Antitubulin: Mitotic spindles serve as molecular railroads with "North and South Poles" in the cell when a cell starts to divide itself into two new cells. These spindles are very important because they help to split the newly copied DNA such that a copy goes to each of the two new cells during cell division. These drugs disrupt the formation of these spindles and therefore interrupt cell division vinca alkaloids and taxanes ;  ribosome: harringtonines ； Interfere the function of  Influence amino acid supply: L-asparaginase Bind tubulin, destroy spindle to produce mitotic arrest. 

63.  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.

64.  Tubulin-Binding Agents  Vinca alkaloids: Vinblastine,vincristin, vindesine and vinorelbine are all alkaloids derived from the periwinkle plant (Vinca rosea). 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.

65.  Tubulin-Binding Agents  Paclitaxel: Taxane enhance all aspects of tubulin polymerization an action that is the opposite to tha of vinca alkaloids, but they are also cytotoxic, emphasizing the dynamic importance of tubulin polymerizatio as a target for cytotoxic drugs. Paclitaxel, Taxotere

66.  Interfere the Function of Ribosome:  Cephalotaxus Alkaloids Harringtonine Homoharringtonine :

67. These drugs bind to hormone receptors to block the actions of the sex hormones which results inhibition of tumor growth. Estrogens and estrogen antagonistic drug Androgens and androgen antagonistic drug Progestogen drug Glucocorticoid drug gonadotropin-releasing hormone inhibitor: leuprolide, goserelin aromatase inhibitor: aminoglutethimide, anastrazole in      

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

69. Estrogens:  Estrogens inhibit the effects of endogenous androgen and androgen-dependent metastatic prostati carcinoma. Diethylstilbestrol is usually the agent of choice.  Cardiac and cerebrovascular complications and carcinoma of the male breast are potential adverse effects.

70. Progenstins:  Progestins are useful in the management of endometrial carcinoma and back-up therapy for metastatic hormone-dependent breast cancer.

71. Antiestrogen: Tamoxifen  Tamoxifen is the drug of choice in postmenopausal women with or recovering from metastatic breast cancer. It is most effective in patients who have estrogen receptor-positive tumors.  Tamoxifen is also used as adjunvctive therapy to oophorectomy to leuprolide or goserelin in premenopausal women with estrogen receptor- positive tumors.

72. Androgens:  Androgen activity in breast cancer is similar to that of estrogens, perhaps for the same mechanistic reasons.  Virilizing effects and hepatic toxicity make them unacceptable to most patients.  Fluoxymesterone is the most widely used agent.  Danazol has use in hematol o gy in aplastic anemia and congenital anemias.

73. Glucocorticoids:  They are integral components of curative therapy for acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, and Hodgkin’s disease.  Glucocorticoids have essential roles in the prevention of allergic reaction, emesis control, relief of intracranial hypertension or spinal cord compression in neurologic complications, and pain relief.

74.  Drug  Drug Resistance Toxicity

75.  De novo Resistance  Acquired Resistance  Multidrug Resistance (MDR)

76. De novo resistance:  De novo resistance can be de novo genetic (i.e. the cells are initially inherently resistant), or can arise because drugs are unable to reach the target cells because of permeability barriers such as the blood-brain barrier.

77. Acquired Resistance:  Acquired drug resistance may result from genomic mutations, such as the induction or deletion of enzymes involved in drug inactivation or drug activation, respectively.

78. Multidrug Resistance (MDR):  P-glycoprotein transports many naturally occurring drugs out of neoplastic cells, and its induction may lead to multidrug resistance.  As scientific understanding of the mechanisms of dru resistance increases, new treatments may be developed to counteract resistance.

79.  The most common toxicities of antineoplastic drugs result from inhibition of cell replication in the bone marrow, gastrointestinal epithelium, and hair follicles. Many antineoplastic drugs also stimulate the chemoreceptor trigger zone in the medulla and thereby elicit nausea and vomiting.

80. Immunosuppressive Agents:  Act to suppress immune mechanisms and are used to treat autoimmune diseases or to prevent graft rejection following tissue transplantation.  Ciclosporin, Tacrolimus, adrenocortical hormones, antimetabolites, alkylating agent, antilymphocyte globulin, Mycophenolate Mofetil

81. Synthesis of chlorambucil Chlorambucil

82. Mercaptopurine Synthesis of Mercaptopurine

83. Synthesis of Busulphan

84. Synthesis of Methotrexate

85. Synthesis of 5- fluro uracil

86. Synthesis of Cyclophosphamide

87. Thanks!