- ANTI-CANCER DRUGS and moa of these drugs

Anticancer drugs presentation

1. Caption the picture

2. A 45-year-old woman with a history of stage II breast cancer is undergoing chemotherapy with a regimen that includes cyclophosphamide . She presents to the emergency department with complaints of burning sensation during urination , blood in her urine , and lower abdominal pain . She also reports feeling fatigued and has noticed hair loss over the past few weeks. On examination: Vital signs : BP 120/80 mmHg, HR 88 bpm, Temp 37.5°C, RR 16/min Physical exam : Mild suprapubic tenderness , no costovertebral angle tenderness Laboratory findings : Hemoglobin: 9.5 g/dL (low) WBC: 2,000/µL (low) Platelets: 120,000/µL (low) Urinalysis: RBCs 50-100/ hpf , no casts, no bacteria Serum creatinine: 1.0 mg/dL (normal)

3. Cancer Chemotherapy Prof. Dr Maryam Rashid MBBS, MPhil, PhD (UHS) HOD Pharmacology & Therapeutics AMDC, Lahore

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

5. Major approaches to therapy of cancers

6. Cell Cycle Specific (CCS) & Cell Cycle Non-Specific Agents (CCNS)

7. Log kill hypothesis According to the log-kill hypothesis , chemotherapeutic agents kill a constant fraction of cells (first order kinetics), rather than a specific number of cells , after each dose

8. General problems with anticancer drugs Most of them are antiproliferative, i.e. they damage DNA and so initiate apoptosis. They also affect rapidly dividing normal cells. This leads to toxicity which are usually severe. To greater or lesser extent the following toxicities are exhibits by all anticancer drugs.

9. Adverse effects

10. 1. Alkylating agents

11. 2. Anti-metabolites

12. 3. Plant alkaloids

13. 4. Anti- biotics

14. 5. Hormones

15. 6. Antibodies

16. ALKYLATING AGENTS Cyclophosphamide

17. Cyclophosphamide Prodrug Activated by the P-450 enzymes to its active form phosphoramide mustard Alkylates nucleophilic groups on DNA bases (Particularly at the N-7 position of guanine) Leads to cross linking of bases, abnormal base pairing and DNA strand breakage 23

18. Uses Non-Hodgkin’s lymphoma Breast Ca Ovarian Ca Neuroblastoma 25

19. SIDE EFFECTS Acrolein is the metabolite Responsible for causing hemorrhagic cystitis Suprapubic pain Hematuria Cyctoscopic findings ***This is prevented/treated by MESNA ( mercaptoethanesulfonate ) 26

20. 28

21. ALKYLATING AGENTS CISPLATIN

22. Cisplatin Platinum analog Same MOA as cyclophosphamide USES: Testicular carcinoma Ca of bladder, lung and ovary ADVERSE EFFECTS: Nephrotoxicity (prevented by Amifostine ***) Ototoxicity (acoustic nerve damage) Peripheral neuritis 30

23. Nephrotoxic drugs: Aminoglycosides Vancomycin Cisplatin Amphotericin B

24. ototoxic drugs Aminoglycoside Cisplatin Amphotericin B Loop diuretics

25. ALKYLATING AGENTS PROCARBAZINE

26. Procarbazine MOA : forms hydrogen peroxide, which generates free radicals that cause DNA damage USES: Important component of regimens especially for Hodgkin’s lymphoma ADR *** Disulfiram like reactions 34

27. Disulfiram -like reaction inducing drugs " PM PMT " as in Pre Medical Test in the PM: P rocarbazine M etronidazole Cefo ( P erazone, M andole , T etan ).

28. ANTI-METABOLITES

29. Antimetabolites They are structurally similar to endogenous compounds They act as antagonists of: Folic acid ( methotrexate ) Purines ( Mercaptopurine and thioguanine ) Pyrimidine (fluorouracil, cytarabine ) 39

30. Antimetabolits: sites of drug action 40

31. ANTI-FOLATES METHOTREXATE

32. METHOTREXATE MTX is a folic acid analog Binds to the active catalytic site of dihydrofolate reductase (DHFR) Interferes with the synthesis of tetrahydrofolate (THF) Inhibition of these various metabolic processes thereby interferes with the formation of DNA, RNA, and key cellular proteins.

33. 43 USES: Anticancer drug. Cell cycle specific (CCS) drug & acts during S phase Immunosuppressant Antiinflammatory Used in RA, psoriasis Weak acid Excreted better at high urine Ph Appropriate hydration and alkalinizing the urine is important to prevent renal toxicity with MTX

34. 44 SIDE EFFECTS: Bone marrow suppression Mucositis Folic acid deficiency The toxic effects of MTX on normal cells is reduced by administering folinic acid ( leucovorin ) This is called leucovorin rescue **** Higher the dose of MTX more the leucovorin you give**

35. Folinic acid/ leucovorin 5-formyl derivative of tetrahydrofolic acid . Converted to other reduced folic acid derivatives (e.g., tetrahydrofolate) Thus, has vitamin activity that is equivalent to that of folic acid. Since it does not require the action of dihydrofolate reductase for its conversion, its function as a vitamin is unaffected by inhibition of this enzyme by methotrexate.

36. Maintenance of a high urinary pH is important during methotrexate treatment in this patient because (A) Bladder irritation is reduced (B) It decreases renal tubular secretion of methotrexate (C) Leucovorin toxicity is increased in a dehydrated patient (D) Methotrexate is a weak acid (E) Reabsorption of purine metabolites occurs at high urinary pH

37. Answer D Methotrexate is a weak acid , and like other weak acids, it is more likely to precipitate in acidic urine , especially at high doses. Precipitation in the renal tubules can cause nephrotoxicity . Alkalinizing the urine (i.e., maintaining a high urinary pH ) helps to keep methotrexate in its ionized, water-soluble form , enhancing its excretion and preventing crystal formation in the renal tubules.

38. ANTI-METABOLITES 6-Mercaptopurine (6-MP) Thioguanine 5-FU

39. 6-Mercaptopurine (6-MP) & Thioguanine Activated by HGPRT to toxic nucleotides that inhibit several enzymes involved in purine metabolism 50

40. 5-FU 5-FU is converted to 5-FdUMP, which competes with deoxyuridine monophosphate ( dUMP ) for the enzyme thymidylate synthetase. . 51

41. 52 Causes, “thymidineless death” of cells USES: Breast and the GI tract, hepatoma Carcinomas of the ovary, cervix, urinary bladder, prostate, pancreas, and oropharyngeal areas Combined with levamisole for Rx of colon cancer SIDE EFFECTS: nausea, mucositis, diarrhea, *** hand and foot syndrome , Alopecia, hyperpigmentation, neurologic deficits, bone marrow depression

42. PLANT ALKALOIDS VINCRISTINE & VINBLASTINE

43. Vincristine Vinorelbine Teniposide Irinotecan Docetaxel

44. Vinblastine , Vincristine 55

45. Mechanism of action These drugs block the formation of mitotic spindle by preventing the assembly of tubulin dimers into microtubules ***They act primarily on the : M phase of cancer cell cycle

46. 57 V in B lastine V in C ristine ( oncovan ) Uses ; (ABVD) Hodgkin’s disease Lymphomas Carcinoma B reast Testicular tumors Toxicity: B one marrow suppression, anorexia, nausea, vomiting & Diarrhea, Alopecia Uses : (MOPP) C hildhood leukemias C hildhood tumors- Wilm’s tumor, Neuroblastoma , Hodgkin’s disease Toxicity: Peripheral neuritis with Paresthesia , Muscle weakness *** Vincristine has marrow sparing effect

47. PLANT ALKALOIDS Etoposide & Teniposide

48. 59 Etoposide & Teniposide Inhibits topoisomerase II Late S and early G2 phase Used in combination Tx of small cell carcinoma of lung, prostrate and testicular carcinomas Other topoisomerase inhibitors: Topotecan , Irinotecan Both act by inhibiting topoisomerase -I

49. 60 Topoisomerase inhibitors

50. PLANT ALKALOIDS Paclitaxel & Docetaxel

51. Paclitaxel & Docetaxel 62

52. Paclitaxel & Docetaxel These drugs act by interfering with mitotic spindle They prevent micotubule disassembly into tubulin monomers

53. 64 Questions What is the diff between MOA of taxanes and Vinca alkaloids Which is the marrow sparing anticancer drug Topoisomerase-1 inhibitors Topoisomerase-2 inhibitors

54. An adult patient is being treated for acute leukemia with a combination of anticancer drugs that includes cyclophosphamide, mercaptopurine, methotrexate, vincristine, and prednisone . He is also using dronabinol for emesis, a chlorhexidine mouthwash to reduce mucositis, and laxatives . The patient complains of “ pins and needles” sensations in the extremities and muscle weakness . He is not able to execute a deep knee bend or get up out of a chair without using his arm muscles. He is also very constipated . If these problems are related to the chemotherapy, the most likely causative agent is: (A) Cyclophosphamide (B) Dronabinol (C) Mercaptopurine (D) Prednisone (E) Vincristine

55. The patient's symptoms— peripheral neuropathy , muscle weakness , and constipation —are classic signs of vincristine toxicity : Vincristine is a vinca alkaloid that inhibits microtubule formation, affecting neuronal axonal transport. It commonly causes neurotoxicity , including: Peripheral neuropathy ("pins and needles") Motor weakness (especially of proximal muscles) Autonomic dysfunction (leading to constipation , urinary retention, orthostatic hypotension)

56. Other options are less likely: (A) Cyclophosphamide → causes hemorrhagic cystitis, not neuropathy. (B) Dronabinol → can cause CNS effects but not neuropathy or motor weakness. (C) Mercaptopurine → hepatotoxicity, myelosuppression, but not neuropathy. (D) Prednisone → long-term use may cause proximal muscle weakness but not acute neuropathy.

57. Alkylating agents: G0 Anti-metabolites: S Plant alkaloids : (vinca & taxens): M (Podophyllotoxins): late S and early G2

58. LYMPHOMAS REGIMEN NON-HODGKINS HODGKINS LYMPHOMA CHOPP C yclopHosohamide O ncovin (vincristine) P rednisolone ABVD A driamycin (doxorubicin) B leomycin V inblastine D acarbazine MOPP M ethotrexate O ncovin (vincristine) P rednisolone p rocarbazine

59. ANTI-BIOTICS

60. 71 Anticancer Antibiotics Anthracyclines: Doxorubicin (Adriamycin) Daunorubicin Bleomycin Dactinomycin Mitomycin

61. Doxorubicin ( Adriamycin ) Daunorubicin ANTI-BIOTICS

62. 73 Doxorubicin & Daunorubicin

63. Doxorubicin & Daunorubicin These drugs intercalate between base pair Inhibit topoisomerase II Generate free radicals They block RNA and DNA synthesis and cause strand scission *These are CCNS drugs Used as a component in ABVD regimen in Hodgkin’s lymphoma

64. 75 SIDE EFFECTS Cardiac toxicity (due to generation of free radicals) Acute form : arrthythmias , ECG changes, pericarditis , myocarditis Chronic form: *** Dilated cardiomyopathy , heart failure ****Rx with dexrazoxane Bone marrow depression, Total alopecia Radiation recall reaction

65. BLEOMYCIN ANTI-BIOTICS

66. 77 Bleomycin

67. Bleomycin Binds to DNA Results in single and double strand breaks Following free radical formation Inhibition of DNA synthesis The DNA fragmentation is due to : oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations CCS .Acts on G 2

68. USES: ABVD regimen for Hodgkin’s Intracavitary therapy in ovarian and breast cancers ( Sclerosing agent )

69. SIDE-EFFECTS ***Pulmonary fibrosis

70. 81 Questions ADR of anthracyclines? (clinical symptoms) Why ADR with anthracyclines? How to treat it? ADR of bleomycin?

71. During the second course of drug treatment ( ABVD regimen ), this patient developed dyspnea , a nonproductive cough , and intermittent fever . Chest x-ray revealed pulmonary infiltration . If these problems are due to the anticancer drugs that he has been exposed to, the most likely causative agent is: (A) Bleomycin (B) Dacarbazine (C) Doxorubicin (D) Prednisone (E) Vinblastine

72. Dacarbazine → myelosuppression, nausea, vomiting. Doxorubicin → cardiotoxicity. Prednisone → actually has anti-inflammatory effects; not a cause. Vinblastine → neurotoxicity, but not pulmonary toxicity.

73. Alkylating agents: G0 Anti-metabolites: S Plant alkaloids : (vinca & taxens): M (Podophyllotoxins): late S and early G2 Antibiotics: Bleomycin: G2

74. HORMONAL ANTI-CANCER AGENTS

75. 86 Hormonal agents Glucocorticoids Sex hormone antagonists GnRH analogs Aromatase inhibitors

76. PREDNISOLONE GLUCOCORTICOIDS

77. 88 Glucocorticoids (Prednisone) Lympholytic action (acute leukemias & lymphomas. Anti-inflammatory effect Increase appetite Produce euphoria (feeling of well being) Increase body weight Suppress hypersensitivity reaction due to certain anticancer drugs

78. TAMOXIFEN (S.E.R.M) (Selective Estrogen Receptor Modulator) SEX HORMONE ANTAGONIST

79. 90 Sex hormone antagonists

80. 91 Tamoxifen It is a SERM Blocks the binding of estrogen to receptors of estrogen sensitive cancer cells in bresat tissue USES Used in receptor positive breast carcinoma Useful in progestin resistant endometrial carcinoma

81. Tamoxifen SIDE EFFECTS: Hot flushes, vaginal bleeding and venous thrombosis

82. FLUTAMIDE : androgen receptor antagonist USES Prostatic carconima SIDE EEFECTS gynecomastia , hot flushes SEX HORMONE ANTAGONIST

83. Leuprolide , gosarelin naferelin GnRH analogs

84. 95 GnRH analogs USES: 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 SIDE EFFECTS: Gynecomastia, hematuria, impotence & testicular atrophy

85. Anastrozole AROMATASE INHIBITORS

86. 97 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.

87. 98 Contd..

88. Asparaginase , imatinib , interferons , monoclonal antibodies Miscellaneous agents 99

89. 100 FDA approved MAb

90. A 45-year-old man is being treated with ABVD chemotherapy for Hodgkin lymphoma. He presents for cycle 4 of a planned 6 cycles with a new-onset cough. He states it started a week ago and he also feels like he has a little trouble catching his breath. Which drug in the ABVD regimen is the most likely cause of his pulmonary toxicity? A. Doxorubicin (Adriamycin) B. Bleomycin C. Vinblastine D. Dacarbazine

91. A patient is about to begin therapy with doxorubicin. Which test should be ordered for baseline assessment before treatment? A. Baseline PFTs B. Baseline stress test C. Baseline echocardiogram D. Baseline urinalysis

92. A 64-year-old man is scheduled to undergo chemotherapy for rhabdomyosarcoma, and the regimen includes ifosfamide . Which is most appropriate to include in chemotherapy orders for this patient? A. IV hydration, mesna , and frequent urinalyses B. Leucovorin and frequent urinalyses C. Allopurinol and frequent urinalyses D. IV hydration, prophylactic antibiotics, and frequent urinalyses

93. Which chemotherapy drug can cause nephrotoxicity, neurotoxicity, ototoxicity, electrolyte abnormalities, and severe nausea and vomiting? A. Cyclophosphamide B. Oxaliplatin C. Etoposide D. Cisplatin