1

Enzyme inhibitors

Anthracy clines

1) Daunorubicin

2) Doxorubicin

3) Epirubicin

4) Idraubicin

5) Mitoxantrone

Topoismerase inhibitors

6) Etoposide

7) Irinotecarn

8) Topotecan

2

Anthracyclines

Inhibit topoisomerase

High –affinity binding to DNA through intercalation –

blockade of synthesis of DNA & RNA, & DNA strand

scission

Generation of Seiquinone & O2 free radicals though

Fe dependent process

Binding to cellular membranes to alter fluidity & non

tram sport

3

Doxorubicin - Used in Many Cancer

Carditoxicity - Acute

Chronic

DEXRAZOXANE

“ Radiation recall reaction”

4

Plant Alkaloids

Vinca Alkaloids Podophyllotoxins Camptothecins Taxanes

Vinblastine Etoposide Topotecan Paclitaxel

VinblastineVincristineVinorelbine

Teniposide Irinotecan Docetaxel

5

Vinka 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

6

Vinka alkaloids

• ADR

• Severe neurotoxicity– Paresthesias– Loss of reflexes– Foot drop– Ataxia

7

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

8

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

9

Topoisomerase inhibitors

10

Paclitaxel & Docetaxel

• These drugs act by interfering with mitotic spindle

• They prevent micotubule disassembly into tubulin monomers

• Taxanes animation

ADR• Neutropenia• Peripheral neuropathy

11

Anticancer Antibiotics

• Anthracyclines:– Doxorubicin (Adriamycin)– Daunorubicin

• Bleomysin

• Dactinomycin

• Mitomycin

12

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

13

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

14

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

15

Hormonal agents

• Glucocorticoids

• Sex hormone antagonists

• GnRH analogs

• Aromatase inhibitors

16

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

17

Sex hormone antagonists

18

Tamoxifen • It is a SERM• 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

carcinomaADR:• Hot flushes, vaginal bleeding and venous

thrombosisOther drugs• Flutamide: androgen receptor antagonist used in

prostatic carconima • ADR for flutamide includes: gynecomastia, hot

flushes

19

MOA of drugs

20

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 receptorsADR• Leuprolide may cause gynecomastia, hematuria,

impotence and testicular atrophy

21

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.

22

Contd..

23

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

24

Miscellaneous agents

Asparaginase, imatinib, interferons, monoclonal antibodies

25

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*****

26

Contd..

27

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

28

MOA of imatinib

• Imatinib MOA

29

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.

30

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

31

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.

32

FDA approved MAb

33

Treatment of Specific cancersHodgkin’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

34

Prevention/management of Cancer Chemotherapy induced ADR

• Nausea and vomiting : 5-HT3 antagonist (ondansetron)

• Bone marrow suppression : Filgrastim, Sargromastim (colony stimulating factors)

• MTX toxicity : Leucovorin

• Cyclophosphamide toxicity : MESNA

• Cisplatin toxicity : Amifostine

• Anthracycline toxicity ; Dexaroxazone