Beruflich Dokumente
Kultur Dokumente
Drugs ?
Dr.lokendra Sharma
Associate Professor
Department of Pharmacology
Cell Cycle
Etoposide
Platinum compounds
Antimetabolites
Alkylating agents
G2 M
Bleomycin
Etoposide
(Ref Harrison
17th/525)
Anthracyclines
Dactinomycin
Vinca alkaloids
Taxanes
Ixabepilone
Estramustine
Mitomycin
Camptothecins
Goals of Therapy ?
Cure or induce prolonged remission
so that all macroscopic and
microscopic features of the cancer
disappear
Acute Lymphoblastic Leukaemia
Wilm`s tumor, Ewing`s sarcoma etc.
In children, Hodgekin`s lymphoma, testicular
teratoma and choriocarcinoma
Goals of Therapy ?
Palliation:
Shrinkage of evident tumour,
Alleviation of symptoms and
prolongation of life
Breast cancer, ovarian cancer,
endometrial carcinoma,
CLL, CML,
Small cell cancer of lung and NonHodgekin lymphoma
Goals of Therapy ?
Insensitive or less sensitive but life
may be prolonged
Cancer esophagus, cancer stomach,
sq. cell carcinoma of lung,
melanoma,
pancreatic cancer,
myeloma,
colorectal cancer
General Principles
Analogous with Bacterial chemotherapy
differences are
General Principles
Drug regimens or combined cycle
therapy after radiation or surgery
Complete remission should be the
goal
Formerly single drug now 2-5
drugs in intermittent pulses
Total tumour cell kill
COMBINATION CHEMOTHERAPY
COMBINATION CHEMOTHERAPY
- SYNERGISTIC ?
Drugs which are effective when used
alone
Different mechanism of action
Differing toxicities
Different mechanism of toxicities
Synergistic biochemical interactions
Optimal schedule by trial and error
method
More importantly on cell cycle specificity
Classification ?
Cell cycle nonspecific agents (CCNSA) & Cell cycle specific agents
(CCSA)
Clinical Considerations ?
Early intensive start . helpful
Complete remission.. goal
Combined chemotherapy useful
..delayed emergence of resistance
Combined chemotherapy ..curative
Treatment must continue past the
time when cancer cells can be
detected using conventional
techniques
Resistance ?
Intrinsic:
malignant melanoma, renal cell cancer, and
brain cancer, exhibit primary resistance
Acquired:
Single drug:
change in the genetic apparatus amplification or
increased expression of one or more specific
genes
Multidrug resistance:
Resistance variety of drugs exposure to a single variety
of drug
increased expression of a normal gene (the MDR1 gene)
for a cell surface glycoprotein (P-glycoprotein) involved in
drug efflux
Toxicities ?
Harmful to normal tissues too
Steep dose response curve
Low therapeutic index
Particularly harmful to rapidly
multiplying normal tissues: GI
mucosa, Bone Marrow, RE system and
gonads and hair cells
Effects are in dose dependent manner
Toxicities ?
Toxicity
Cyclophosphamide
Ifosfamide
Busulfan
Procarbazine
Cisplatin
Mechanism
Indications
Allopurinol
Rasburicase
Mesna
Neutralizing agent
Leucovoring
Amifostine
Dexrazoxane
Iron chelator
Palifermin
Pilocarpine
Cholinergic agonist
Pamidronate and
Zolendronate
Bisphosphonates
Hypercalcemia of malignancy
Mechanism
Indications
Epoetin alpha
and darbopoetin
alpha
Erythropoietin
Anemia
Filgrastim, pegfilgrastim
G-CSF and
Sargramostim
GM - CHF
Oprelvekin
IL-11
Thrombocytopenia
Ondansetron
5-HT3 antagonist
NK 1 antagonist
Granisetron
Palonosetron
Aprepitant
Route of
Admin.
Delayed Toxicity
1. Busulphan
Oral
CML, PV
2. chlorambucil
Oral
CLL, PV
BMD, bleeding
3.
Cyclophosphamide
Oral, i.v
BMD, bleeding,
hemorrhagic, cystitis
4. Melphalan
Oral
Multiple myeloma
BMD, Bleeding
5. Mechlorethamine
i.v.
Hodgkins disease
6. Cisplatin
i.v.
7. Dacarbazine
i.v.
BMD
8. Carmustine
(BCNU)
i.v.
Brain tumours
Leukopaenia,
thrombocytopaenia
9. Lomustine
(CCNU)
Oral
Brain tumours
Leukopaenia,
thrombocytopaenia
10. Thiotepa
i.v.
BMD
Inhibit TK activated
Indication
Axitinib
VEGFR 1,2,3
Bosutinib
CML
Crizotinib
c-MET, ALK
Cabozantinib
c-MET, VEGFR-2
Dasatinib
abl -bcr
CML
Erlotinib
EGFR
Geftinib
Imatinib
her-2/neu, erb-B2
CML GIST
Lapatinib
abl-bcr
Breast carcinoma
Nilotinib
VEGFR-1,2,3 PDGFR
c-KIT
CML
Pazopanib
abl-bcr
Inhibit TK activated
Indication
Regorafenib
VDGFR2, TIE2
Ruxolitinib
JAK 1,2
Myelofibrosis
Sorafenib
Sunitinib
Tofacitinib
JAK
Rheumatoid arthritis
Vandetanib
VEGFR, EGFR
Medullary carcinoma
thyroid
Vemurafenib
BRAF
Maliganant melaonma
Monoclonal Antibodies
S.
No.
Monoclonal antibody
Targeted
against
Indication
Comments
Rituximab
CD - 20
Alemtuzumab
CD - 52
Trastuzumab
HER 2/neu
Breast Carcinoma
Can cause
cardiotoxicity
Cetuximab and
panitumumab
EGFR
Cause rash,
Hypomagnesemia and
tnterstitial lung
disease
Bevacizumab
VEGF
Metastatic colorectal
carcinoma
Combined with 5 - FU
Gemtuzumab
CD-33
Linked to
calicheamicin
I131 Tositumomab
Y90 Ibritumomab
tiuxetan
CD-20
Relapsed lymphomas
Conjugated with
radioisotopes
Denileukin diftitox
Recurrentcutaneous T-cell
lymphoma
Recombinant IL 2
plus diphtheria toxin
Diagnosis
Treatment of choice
All
AML
Cytarabine+Daunorubicin/Idarubicin
CML
Imatinib
CLL
FCR or Fludarabine
Cladribine
Hodgkin disease
ABVD
Non hodgkin
lymphoma
CHOP-R
Multiple Myeloma
Bortezomib+Dexamethasone+Lenalidomide
Waldenstrom
macroglobulinemia
FCR
10
Polycthemia vera
Hydroxyurea
Diagnosis
Treatment of choice
11
12
Cisplatin + Etoposide
13
Mesothelioma
Cisplatin + Pemetrexed
14
Route
of
admin.
Delayed toxicity
1. Cytarabine
i.v.
AML
2. 5- Fluorouracil
i.v.
3. 6Mercaptopuine
Oral
All
BMD, Hyperuricaemia,
immunosuppression,
hepatotoxicity
4. Methotrexate
Oral
All, choriocarcinoma,
osteogenic sarcoma
5. Thioguanine
Oral
AML
BMD, Hyperuricaemia
Delayed toxicity
Antibiotics
1. Bleomycin
2. Dactinomycin
Wilms tumour
3. Daunorubicin
AML
4. Doxorubicin
5. Mitomycin
Carcinoma stomach
Thrombocytopaenia, leukopaenia
6. Streptozotocin
(sreptozocin)
Insulinoma
Delayed toxicity
Plant Alkaloids
1. Docetaxel
Advance case of
carcinoma breast
2. Etoposide
Carcinoma testis,
choriocarcinoma
Alopecia, BMD
3. Paclitaxel
4. Vinblastine
HD
5. Vincristine
ALL, NHL
6. Vinorelbine
Carcinoma lung
Route of admin.
Delayed toxicity
1. Asparaginase
i.v.
All in child
Hepatotoxicity, mental
depression,
pancreatitis
2. Cisplatin
i.v.
CA testis, ovary,
cervix, lung, head &
neck, thyroid,
melanoma
Renal damage,
otoxicity neuropathy,
BMD
3. Hydroxyurea
Oral
BMD
4. Mitotane
Oral
Adrenocortical
carcinoma
Adrenal insufficiency,
diarrhoea, lethargy,
skin rash (transient)
5. Mitoxantrone
Oral
Aml
BMD, cardiotoxicity,
alopecia
6. Imatinib
Oral
Fluid retention
(periorbital and ankle
oedema), diarrhoea,
myalgia
7. Trastuzumab
i.v.
Carcinoma breast
(metaastatic)
BMD,
cardiomyopathy, pulm.
Toxicity, cardiac
failure
Route of admin
Cancer(s) where
preferred
Delayed toxicity
Corticosteroids
Hydrocortisone
Prednisone
Oral
Oral
Fluid retention,
Hypertension, diabetes
mellitus, susceptibility
to infection, moon
face
Androgens
Testosterone
i.m.
Premenopausal breast
cancer (oestrogen
receptor positive)
Fluid retention
masculinization
Oestrogens
Diethylstilboesterol
Oral
Oral
Carcinoma prostate,
Postmenopausal breast
cancer (oestrogen
receptors negative)
Feminization, Fluid
retention
i.m.
Oral
Carcinoma
endometrium
None
Ethinyloestradiol
Progestins
Hydroxyprogesterone
Medroxyprogesterone
Influence hormone
homeostasis
Estrogens and estrogen antagonistic drug
(EE, SERM-tamoxifene)
Androgens and androgen antagonistic
drug (flutamide and bicalutamide)
Progestogen drug (hydroxyprogesterone)
Glucocorticoid drug (prednisolone and
others)
Gonadotropin-releasing hormone
inhibitor: nafarelin, triptorelin
aromatase inhibitor: Letrozole and
anastrazole
Route of admin
Cancer(s) where
preferred
Delayed toxicity
Antiandrogen
Flutamide
Oral
Carcinoma prostate
None
Antiandrogen
Tamoxifen
Oral
Carcinoma breast
None
(early stage, metastatic
after surgery)
Carcinoma prostate
None
s.c)
s.c.)
Aromatase Nhibitors
Aminogulutethimide
Oral
Metastatic breast
cancer
None
Peptide hormone
Inhibitor
s.c.
Carcinoid tumour
None
Treatment of choice
Radiotherapy
Doxorubicin +
bleomycin+vinblastine+dacarbazine
4. Choriocarcinoma
5. Cancer testis
6. Wilms tumour
Cytarabine + idarubicin/daunorubicin
2. Chronic lymphocytic
leukaemia
3. Chronic myelogenous
leukaemia
4. Multiple myeloma
Melphalan + prednisone
6. Endometrial carcinoma
Progestins or tamoxifen
7. Carcinoma cervix
8. Carcinoma prostate
Treatment of choice
2. Carcinoma ovary
3. Carcinoma thyroid
4. Carcinoma stomach
5. Carcinoma colon
6. Osteogenic sarcoma
7. Melanoma
Treatment of choice
1. Carcinoma lung
3. Carcinoma adrenal
gland
Mitotane
4. Carcinoid tumour
5. Polycythaemia vera
Busulfan, chlorambucil or
cyclophospamide
Alkylating Agents
Mechanism of Action:
Nitrogen mustards inhibit cell reproduction
binding irreversibly nucleic acids (DNA)
After alkylation, DNA is unable to replicate
no synthesize proteins and essential cell
metabolites
Consequently, cell reproduction inhibited cell
eventually dies inability maintain metabolic
functions.
Nitrogen Mustards
Mechlorethamine:
Uses: IV
MOPP (Mechlorethamine oncovine-prednisolone and
procarbazine) in Hodgekin`s lymphoma and disease
ADRs: Severe Vomiting, myelo and immunosuppression
Extravasation severe local toxicity
Cycolphosphamide:
Transformed active aldophosphamide and
phospharamide
orally
Used Hodgkin's lymphoma, breast and ovary cancers
Ifosphamide longer half life and used mainly testicular
tumour
Antimetabolites
Folic acid Antagonists: MTX
Purine Antagonists: 6MP and 6TG
Pyrimidine
Antagonists:
5FU
cytarabine
and
General Characteristics:
Antimetabolites S phase-specific drugs
structural analogues of essential metabolites and
that interfere with DNA synthesis.
Myelosuppression dose-limiting toxicity
Methotrexate Folate
Antagonist
MOA:
Structures MTX and folic acid similar
MTX actively transported mammalian cells and
inhibits dihydrofolate reductase
the enzyme that normally converts dietary folate
to the tetrahydrofolate form required for thymidine
and purine synthesis
Leucovorin rescue:
Administered as a plan in MTX therapy
Leucovorin (Folinic acid) is directly converted to
tetrahydrofolic acid - production of DNA cellular
protein inspite of presence of MTX
Used to rescue bone marrow and GIT mucosal cells
Methotrexate contd.
Kinetics:
orally/IM /IV intrathecally
absorption
CSF entry - intrathecal
Indications:
good
oral
Antimetabolites (Pyrimidine
Antagonists) - 5 FU
MOA:
Fluorouracil analogue of thymine
Converted to 5-fluoro-2deoxy-uridine
monophosphate (5-FdUMP)
5-FdUMP inhibits thymidylate synthase and
blocks conversion of deoxyuridilic acid to
deoxythymidylic acid failure of DNA
synthesis
Antibiotics
Anthracyclines (doxorubicin and dau norubicin),
Dactinomycin, Bleomycin, and mitomycin
Anthracyclines:
Enters themselves into DNA and causes DNA break
Activates TopoisomeraseII and cause break in DNA
strands
Generates excess free radicals causing production of
superoxide damage to DNA
Known to damage cardiac cells also (unique)
Resistance developes due to increased eflux of drug
Uses: Doxo- Breast, ovary, lung, [prostate and acute
lymphatic leukaemia
Dauno- ALL and AML
5. Which of the following drug is used for the is treatment of sickle cell anemia?
a.Hydroxyurea
b. Cisplatin
c. Paclitaxel
d. Carboplatin
(a)
6. Use of tamoxifen in carcinoma of breast patients does not lead to the following
side effects
a. Thromboembolic events
b. Endometrial carcinoma
c. Cataract
d. Cancer in opposite breast
(d)
19. Which of the following drug acts by inhibiting tyrosine kinase activated by
EGF receptor as well as HER2?
a. Imatinib
b. Geftinib
c. Erlotinib
d. Lapatinib
(d)
20. Tyrosine kinase inhibitors are first line treatment in
a. Gastrointestinal stromal tumors
b. Receptor mediated neuroendocrine tumors
c. Breast cancer
d. Renal cell carcinoma
(a)
53. All of the following anticancer agents cause bone marrow suppression
EXCEPT
a. Chlorambucil
b. Daunorubicin
c. Doxorubicin
d. Flutamide
(d)
54. All the following are hormonal agents used against breast cancer EXCEPT
a. Letrozole
b. Exemestane
c. Taxol
d. Tamoxifen
(c)
55. Which is the most active single chemotherapeutic agent in the treatment of
leiomyosarcoma?
a. Adriamycin
b. Daunorubicin
c. Methotrexate
d. Cisplatin
(a)
56. Gemcitabine is effective in
a. Head and neck cancers
b. Pancreatic cancer
c. Small-cell lung cancer
d. Soft tissue sarcoma
(b)
57. All of the following statements about methotrexate are correct EXCEPT
a. Folinic acid enhances the action of methotrexate
b. Methotrexate inhibits dihydrofolate reductase
c. Non-proliferative cells are resistant to methotrexate
d. Methotrexate is used in the treatment of psoriasis
(a)
58. Mesna is given with cyclophosphamide to
a. Increase absorption
b. Decreased excretion
c. Ameliorate hemorrhagic cystitis
d. Decrease metabolism
(c)
59. A 35 yr old patient is having carcinoma lung with a past history of lung
disease. Which of the following drugs should not be given?
a. Vinblastine
b. Bleomycin
c. Mithramycin
d. Adriamycin
(b)
60. Arsenic is useful in the treatment of
a. Acute promyelocytic leukemia
b. Myelodysplastic syndrome
c. Transient myeloproliferative disorder
d. All of the above
(a)
63. Which of the following drugs is associated with untoward side effect of renal tubular
damage?
a. Cisplatin
b. Streptozocin
c. Methysergide
d. Cyclophosphamide
(a)
64. Which of the following chemotherapeutic agents is associated with secondary
leukemia?
a. Vinblastine
b. Paclitaxel
c. Cisplatin
d. Bleomycin
(c)
85. All of following statements about are true about mercaptopurine EXCEPT
a. It is metabolized by xanthine oxidase
b. It does not cause hyperuricemia
c. Its dose should be reduced when allopurinol is given concurrently
d. It is an active metabolite of azathioprine
(b)
86. Which of the following immunosuppressants is not used for the treatment of
cancers?
a. Cyclophosphamide
b. Cyclosporine
c. Methotrexate
d. 6-Mercaptopurine
(b)
125. People with high risk for development of breast cancer should be treated by
prophylactic admini-stration of
a. Tamoxifen
b. Aminoglutethimide
c. Diethyistibesterol
d. Flutamide
(a)
126. Which of the following is widely used in the management of carcinoma breast?
a. Actinomycin D
b. Bleomycin
c. Doxorubicin
d. Dacarbazine
(c)
95. Which of the following antineoplastic drugs should not be administered to a chronic
alcoholic patient due to risk of development of disulfiram like reaction?
a. Dacarbazine
b. Procarbazine
c. Melphalan
d. Hydroxyurea
(b)
96 Roopa devi, a 65 year old female with overian cancer is being treated with cisplatin based
chemotherapy. All of the following are used to limit the toxicity of cisplatin except
a. N-acetylcysteine
b. Slow rate of infusion
c. Chloride dieresis
d. Amifostine
(a)
97. Roopmati, A 56 year old femal with lymph node positive breast cancer was treated with systemic
chemotherapy. Four weeks later, she developed frequent urination, suprapublic pain, dysuria and
hematuria. Which of the following could have prevented this patients condition?
a. Folinic acid
b. Mesna
c. Dexazoxane
d. Amifostine
(b)
98. Sunder, a ypung male was diagnosed as suffering from acute myeloid leukemia. He was started on
induction chemotherapy with doxorubicin based regiments. Induction regimen was successful. Two
months later, he presents to opd with swelling of both the feet and breathlessness on climbing the stairs.
He also complains the he had to wake up many times because of breathlessness. Which of the following is
most likely responsible for this patients symptoms?
a. Restrictive cardiomyopathy
b. Hypertrophic cardiomyopathy
c. Dilated cardiomyopathy
d. Pericardial fibrosis
(c)
thanks