Vinka alkaloids (animation and ADR) Microtubule Synthesis animation Inhibition of spindle function ADR Severe neurotoxicity Paresthesias Loss of reflexes Foot drop Ataxia

VinCristine (oncovan) 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 Peripheral neuritis with Paresthesia, Muscle weakness ***Vincristine has marrow sparing effect ABVD regimen: • Adriamycin (generic name Doxorubicin) • Bleomycin (common brand name: blenoxane) • Vinblastine (common brand names: velban, velsar, velbe) • Dacarbazine (common brand name: DTIC, DTIC-Dome) MOPP regimen • Mustargen (generic name mechlorethamine, MSD, mustine or nitrogen mustard) • Vincristine (also called Oncovin or VCR) • Procarbazine (also called Matulane or possibly Natulan) • Prednisone (sometimes called Deltasone or Orasone)

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

Topoisomerase inhibitors

Paclitaxel & Docetaxel These drugs act by interfering with mitotic spindle They prevent micotubule disassembly into tubulin monomers Taxanes animation ADR Neutropenia Peripheral neuropathy

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

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

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 ABVD regimen • Adriamycin (generic name Doxorubicin) • Bleomycin (common brand name: blenoxane) • Vinblastine (common brand names: velban, velsar, velbe) • Dacarbazine (common brand name: DTIC, DTIC-Dome)

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 Radiation recall reaction

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 G2 Uses ABVD regimen for Hodgkin’s Intracavitary therapy in ovarian and breast cancers (Sclerosing agent) ADR ***Pulmonary fibrosis

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

Hormonal agents Glucocorticoids Sex hormone antagonists GnRH analogs Aromatase inhibitors

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

Sex hormone antagonists

Tamoxifen Blocks the binding of estrogen to receptors of estrogen sensitive cancer cells in bresat tissue 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

MOA of drugs

GnRH 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 Gonadotropin-releasing hormone is normally secreted by the hypothalamus and stimulates the anterior pituitary to secrete the gonadotropic hormones, luteinizing hormone (LH; the primary stimulus for the secretion of testosterone by the testes), and follicle-stimulating hormone (FSH; which stimulates the secretion of estrogen). The synthetic nonapeptides, leuprolide [loo-PROE-lide] and goserelin [GOE-se-rel-in], are analogs of GnRH. As GnRH agonists, they occupy the GnRH receptor in the pituitary, which leads to its desensitization and, consequently, inhibition of release of FSH and LH. Thus, both androgen and estrogen syntheses are reduced. Response to leuprolide in prostatic cancer is equivalent to that of orchiectomy (surgical removal of one or both testes), with regression of tumor and relief of bone pain.

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.

Contd..

Contd.. Anastrozole and Letrozole These drugs inhibit the aromatase enzyme ****Used in Tx of postmenopausal women with metastatic breast ca (1st line drug) ADR includes: bone pain and peripheral edema

Asparaginase, imatinib, interferons, monoclonal antibodies Miscellaneous agents Asparaginase, imatinib, interferons, monoclonal antibodies

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*****

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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

MOA of imatinib Imatinib MOA

Interferons Human interferons have been classified into three types—α, β, and —on the basis of their antigenicity. 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.

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

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.

FDA approved MAb

Questions??? What are Flutamide and Leuprolide and mention their uses? MOA of tamoxifen? MOA of anastrozole and letrozole? Important clinical indication for these drugs? Important ADR of L-asparaginase? Clinical symptoms of ADR (including lab) MOA and use of imatinib? MABs used in cancer chemotherapy (know four of them circled above)

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