Download Cancer Chemotherapy-2

Pharmacology – IV
PHL-425
Chapter 4:
CANCER CHEMOTHERAPY
By:
Abdulaziz bin saeedan
Ph.D.
Department of Pharmacology
E mail: [email protected]
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Plant Alkaloids
Vinca Alkaloids
Podophyllotoxins
Camptothecins
Taxanes
Vinblastine
Etoposide
Topotecan
Paclitaxel
Vinblastine
Vincristine
Vinorelbine
Teniposide
Irinotecan
Docetaxel
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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
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VinBlastine
Uses ; (ABVD)
Hodgkin’s disease
Lymphomas
Carcinoma Breast
Testicular tumors
Toxicity:
Bone marrow
suppression, anorexia,
nausea, vomiting &
Diarrhea, Alopecia
VinCristine (oncovan)
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
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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
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Topoisomerase inhibitors
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Paclitaxel & Docetaxel
 These drugs act by interfering with
mitotic spindle
 They prevent microtubule
disassembly into tubulin monomers
ADR
 Neutropenia
 Peripheral neuropathy
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Anticancer Antibiotics
 Anthracyclines:
 Doxorubicin (Adriamycin)
 Daunorubicin
 Bleomysin
 Dactinomycin
 Mitomycin
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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
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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
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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
ADR
 Pulmonary fibrosis
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Hormonal agents
 Glucocorticoids
 Sex hormone antagonists
 GnRH analogs
 Aromatase inhibitors
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Glucocorticoids (Prednisone)
 Because of their marked lympholytic action, they
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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
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Sex hormone antagonists
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Tamoxifen
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
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MOA of drugs
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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
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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.
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Contd..
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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
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Miscellaneous agents
Asparaginase
Imatinib
Interferons
Monoclonal antibodies
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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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Contd..
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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
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MOA of Imatinib
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Monoclonal Antibodies
 They are created from B lymphocytes (from immunized
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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
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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.
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FDA approved MAb
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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.
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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
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Prevention/management of Cancer
Chemotherapy induced ADR
 Nausea and vomiting : 5-Ht3 antagonist
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(ondansetron)
Bone marrow suppression : Filgrastim,
Sargramastim.
MTX toxicity : Leucovorin
Cyclophosphamide toxicity : MESNA
Cisplatin toxicity : Amifostine
Anthracycline toxicity ; Dexaroxazone
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THANK YOU
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