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

2. 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)

3. 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

4. Topoisomerase inhibitors

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

6. 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

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

8. 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)

9. 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

10. 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

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

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

15. 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

16. MOA of drugs

17. 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.

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 (1st line drug)
ADR includes: bone pain and peripheral edema

21. Asparaginase, imatinib, interferons, monoclonal antibodies
Miscellaneous agents
Asparaginase, imatinib, interferons, 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
Imatinib MOA

26. 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.

27. 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

28. 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.

29. FDA approved MAb

30. 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)

31. 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