1 By: Abdulaziz bin saeedan P h.D. Department of Pharmacology E mail: P harmacology – IV PHL-425 Chapter 4: CANCER CHEMOTHERAPY

2 Plant Alkaloids Vinca Alkaloids Vinblastine Podophyllotoxins Etoposide Camptothecins Topotecan Taxanes Paclitaxel Vinblastine Vincristine Vinorelbine Teniposide Irinotecan Docetaxel

3 Vinca alkaloids (Vinblastine, vincristine)  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  Resistance is due to  d efflux of drugs from tumor cells

4 VinBlastine VinCristine (oncovan) Uses ; (ABVD) Hodgkin’s disease Lymphomas Carcinoma Breast Testicular tumors Toxicity: Bone marrow suppression, anorexia, nausea, vomiting & Diarrhea, Alopecia Uses: (MOPP) Childhood leukemias Childhood tumors-Wilm’s tumor, Neuroblastoma, Hodgkin’s disease Toxicity: Peripheral neuritis with Paresthesia, Muscle weakness Vincristine has marrow sparing effect

5 Etoposide & Teniposide  Acts by inhibiting topoisomerase II  These drugs are most active in 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

6 Topoisomerase inhibitors

7 Paclitaxel & Docetaxel  These drugs act by interfering with mitotic spindle  They prevent microtubule disassembly into tubulin monomers ADR  Neutropenia  Peripheral neuropathy

8 Anticancer Antibiotics  Anthracyclines:  Doxorubicin (Adriamycin)  Daunorubicin  Bleomysin  Dactinomycin  Mitomycin

9 Doxorubicin & Daunorubicin  These drugs intercalate between base pairs, inhibit topoisomerase II and also 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

10 ADR  Cardiac toxicity (due to generation of free radicals)  Acute form: arrthythmias, 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

11 Bleomycin  Acts through binding to DNA, which results in single and double strand breaks following free radical formation and inhibition of DNA synthesis  The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations  CCS drug that causes accumulation of cells in G 2 Uses  ABVD regimen for Hodgkin’s  Intracavitary therapy in ovarian and breast cancers ADR  Pulmonary fibrosis

12 Hormonal agents  Glucocorticoids  Sex hormone antagonists  GnRH analogs  Aromatase inhibitors

13 Glucocorticoids (Prednisone)  Because of their marked lympholytic action, they are used in acute leukemias and lymphomas.  Have anti-inflammatory effect  Increase appetite  Produce euphoria (feeling of well being)  Increase body weight  Suppress hypersensitivity reaction due to certain anticancer drugs  Control hypercalcemia  Control bleeding  Have non-specific antipyretic effect  Increase the antiemetic effect of ondansetron/granisetron/ metoclopramide

14 Sex hormone antagonists

15Tamoxifen Blocks the binding of estrogen to receptors of estrogen sensitive cancer cells  It is used in receptor positive breast carcinoma  Also useful in progestin resistant endometrial carcinoma ADR:  Hot flushes, vaginal bleeding and venous thrombosis Other drugs  Flutamide: androgen receptor antagonist used in prostatic carconima  ADR for flutamide includes: gynecomastia, hot flushes

16 MOA of drugs

17 GnRH (Gonadotropin-releasing hormone) Analogs  Leuprolide, Gosarelin and Naferelin  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

18 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.

19 Contd..

20 Contd..  Anastrozole and Letrozole  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

21 Miscellaneous agents AsparaginaseImatinibInterferons Monoclonal antibodies

22 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

23 Contd..

24 Imatinib  Example of a drug, whose development was guided by knowledge of a specific oncogene  Used for the treatment of chronic myeloid leukemia  Acts by inhibiting tyrosine kinase activity of the protein product of the Bcr-Abl oncogene  This gene is expressed in CML

25 MOA of Imatinib

26 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.  Recombinant technology has led to the creation of “humanized” antibodies that overcome the immunologic problems previously observed following administration of mouse (murine) antibodies.  Currently, several monoclonal antibodies are available in the United States for the treatment of cancer.  Trastuzumab, Rituximab, Bevacizumab, and Cetuximab

27 Trastuzumab  In patients with metastatic breast cancer, overexpression of transmembrane human epidermal growth factor–receptor protein 2 (HER2) is seen in 25 to 30 % of patients.  Trastuzumab is a recombinant DNA–produced, humanized monoclonal antibody, specifically targets the extracellular domain of the HER2 growth receptor that has intrinsic tyrosine kinase activity.  Trastuzumab binds to HER2 sites in breast cancer tissue and inhibits the proliferation of cells that overexpress the HER2 protein, thereby decreasing the number of cells in the S phase.

28 FDA approved MAb

29 Interferons  Human interferons have been classified into three types—α, β, and  —on the basis of the type of cell that produces the interferon and the functional characteristics of the protein.  The α interferons are primarily leukocytic, whereas the β and  interferons are produced by connective tissue fibroblasts and T lymphocytes, respectively.  Recombinant DNA techniques in bacteria have made it possible to produce two species designated interferon-α-2a and -2b used in Tx of neoplastic diseases.  Interferon-α-2a is presently approved for the management of hairy-cell leukemia, chronic myeloid leukemia, and acquired immunodeficiency syndrome (AIDS)–related Kaposi sarcoma.  Interferon-α-2b is approved for the treatment of hairy-cell leukemia, melanoma, AIDS-related Kaposi's sarcoma, and follicular lymphoma.

30 Treatment of Specific cancers Hodgkin’s disease:  ABVD regimen (doxorubicin,bleomycin,vinblastine,dacarbazine)  MOPP regimen (mechorethamine,vincristine,procarbazine,prednisone)  Non-Hodgkin's lymphoma: CHOP regimen (cyclophosphamide,doxorubicin,vincristine,prednisone)  Multiple myeloma : MP protocol (melphalan and prednisone) Breast ca:  CMF protocol (cyclophosphamide-MTX-fluorouracil)  Tamoxifen  Anastrozole, letrozole

31 Prevention/management of Cancer Chemotherapy induced ADR  Nausea and vomiting : 5-Ht3 antagonist (ondansetron)  Bone marrow suppression : Filgrastim, Sargramastim.  MTX toxicity : Leucovorin  Cyclophosphamide toxicity : MESNA  Cisplatin toxicity : Amifostine  Anthracycline toxicity ; Dexaroxazone

32 THANK YOU