Anticancer Drugs ?Dr. lokendra Sharma

ProfessorDepartment of Pharmacology

Incharge IT Cell, Directorate of Medical Education

Advances in Cancer Chemotherapy

Treatment options of cancer:?

• No Treatment: Before 1940

• Surgery: before 1955

• Radiotherapy: 1955~1965

• Chemotherapy: after 1965

• Immunotherapy and Gene therapy

Cell Cycle

Cell Cycle Specific Agents

• Antimetabolites

• Bleomycin

• Podophyllin Alkaloids

• Plant Alkaloids

Cell Cycle Non-Specific Agents

• Alkylating Agents

• Antibiotics

•Cisplatin

• Nitrosoureas

ChemotherapyCell cycle effects of anticancer drugsCCS Drugs

CCS Drugs CCNS Drugs

G1 - S Etoposide Platinum compounds

S Antimetabolites Alkylating agents

G2 – M Bleomycin Etoposide(Ref Harrison 17th/525)

AnthracyclinesDactinomycin

M Vinca alkaloidsTaxanesIxabepiloneEstramustine

MitomycinCamptothecins

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 Non-Hodgekin

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

Aim of Therapy – contd.

• Adjuvant therapy:– For mopping up of residual cancer cells including

metastases after Surgery, – Radiation and immunotherapy etc.

• Routinely used now• Mainly in solid tumours

General Principles

Analogous with Bacterial chemotherapy – differences are Selectivity of drugs is limited No or less defence mechanism – Cytokines adjuvant

now All malignant cells must be killed to stop

progemy Subpopulation cells differ in rate of proliferation

and susceptibility to chemotherapy

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 aloneDifferent mechanism of actionDiffering toxicitiesDifferent mechanism of toxicitiesSynergistic biochemical interactionsOptimal schedule by trial and error methodMore importantly on cell cycle specificity

Classification ? According to chemical structure and sources of drugs

– Alkylating Agents, Antimetabolite, Antibiotics, Plant Extracts, Hormones and Others

According to biochemistry mechanisms of anticancer action:– Block nucleic acid biosynthesis– Direct influence the structure and function of DNA– Interfere transcription and block RNA synthesis– Interfere protein synthesis and function– Influence hormone homeostasis

According to the cycle or phase specificity of the drug:– Cell cycle nonspecific agents (CCNSA) & Cell cycle specific agents (CCSA)

Block nucleic acid (DNA, RNA) biosynthesis

Antimetabolites:• Folic Acid Antagonist: inhibit dihydrofolate reductase

(methotrexate)

• Pyrimidine Antagonist: inhibit thymidylate synthetase (fluorouracil) ; inhibit DNA polymerase (cytarabine)

• Purine Antagonist: inhibit interconversion of purine nucleotide (6-mercaptopurine and 6-Thioguanine)

• Ribonucleoside Diphosphate Reductase Antagonist: (hydroxyurea)

Influence :Structure & Function of DNA

• Alkylating Agent: mechlorethamine, cyclophosphamide, ifosfamide, chlorambucil, Mephalan, Busulfan, Nitrosoureas and Thio-TEPA

• Platinum: cis-platinium, carboplatin and imatinib• Antibiotic: bleomycin and mitomycin C• Topoismerase inhibitor: camptothecin analogues

and podophyllotoxin and antibiotics like actinomycin D, daunorubicin and doxorubicin

Sites of Antineoplastic Action ?

PALA = N-phosphonoacetyl-L-aspartate; TMP = thymidine monophosphate.

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 genesMultidrug 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 tooSteep dose response curveLow therapeutic indexParticularly harmful to rapidly multiplying

normal tissues: GI mucosa, Bone Marrow, RE system and gonads and hair cells

Effects are in dose dependent manner

Toxicities ? Bone marrow depression – limits treatment Buccal mucosa erosion – high epithelial turnover

(stomatitis, bleeding gums) GIT: Diarrhoea, shedding of mucosa, haemorrhage Nausea, vomiting – CTZ direct stimulation Skin: alopecia Gonads: oligospermia, impotence, amenorrhoea and

infertility Lymphoreticular system: Lymphocytopenia and inhibition

of lymphocyte function – loss of host defense mechanism – susceptibility to infections

Carcinogenicity Teratogenicity and Hyperuricemia

Distinctive Toxicities of Alkylating Agents ?

Drug Toxicity

Cyclophosphamide Alopecia, Hemorrhage cystitis, SIADH

Ifosfamide Hemorrhagic cystitis, SIADH

Busulfan Pulmonary fibrosis, Hyper pigmentation, Adrenal insufficiency

Procarbazine Secondary leukemias, Disulfiram like reaction, behavioral changes, CNS depression

Cisplatin Emesis, Nephrotoxicity, Peripheral sensory neuropathy, ototoxicity

Countering the Toxicities ? Intermittent therapy Folinic acid rescue Systemic Mesna (sodium-2-mercaptoethane

sulfonate) administration and irrigation by acetylcysteine – detoxify toxic metabolites

Ondansetron Hyperurecaemia: uricosuric agents like allopurinol Platelet and granulocyte transfusion Granulocyte colony stimulating factors (GM-CSF/G-

CSF) – recovery of garnulocytopenia

Drugs used to prevent toxicity of Anti cancer drugsDrug Mechanism Indications

Allopurinol Inhibit xanthine oxidase Prevent hyperuricemia from tumor lysis syndrome

Rasburicase Recombinant urate oxidase Prevent hyperuricemia from lysis

Mesna Neutralizing agent Prevent hemorrhagic cystitis due to ifosfamide and high dose cyclophosphamide

Leucovoring Replete Tetrahydrofolic acid Rescue after high dose methotrexate

Amifostine Prevent radiation induced xerostomia and

Prevent radiation induced xerostomia and cisplatin induced nephrotoxicity

Dexrazoxane Iron chelator Prevent cardiotoxicity due to anthracyclines

Palifermin Keratinocyte growth factor Prevent mucositis following chemotherapy

Pilocarpine Cholinergic agonist Radiation induced xerostomia

Pamidronate and Zolendronate

Bisphosphonates Hypercalcemia of malignancy

Drugs used to prevent toxicity of Anti cancer drugsDrug Mechanism Indications

Epoetin alpha and darbopoetin alpha

Erythropoietin Anemia

Filgrastim, peg-filgrastim

G-CSF and Febrile neutropenia prophylaxis

Sargramostim GM - CHF

Oprelvekin IL-11 Thrombocytopenia

Ondansetron 5-HT3 antagonist Nausea and vomiting

Granisetron

Palonosetron

Aprepitant NK – 1 antagonist Cisplatin induced delayed vomiting

Interfere Protein Synthesis

Antitubulin:

vinca alkaloids (vincristine and vinblastin) and taxanes (paclitaxel and docetaxel)

Bind tubulin, destroy spindle to produce mitotic arrest Influence amino acid supply:

L-asparaginase

.

Some Alkylating Agents used in cancer ChemotherapyAgent Route of

Admin.Cancer where preferred Delayed Toxicity

1. Busulphan Oral CML, PV BMD, bleeding, skin pigmentation adrenal insufficiency, pulmonary fibrosis

2. chlorambucil Oral CLL, PV BMD, bleeding

3. Cyclophosphamide

Oral, i.v All, NHL, PV, Carcinoid tumour, Neurobalstoma

BMD, bleeding, hemorrhagic, cystitis

4. Melphalan Oral Multiple myeloma BMD, Bleeding

5. Mechlorethamine i.v. Hodgkin’s disease BMD, alopecia, Diarrhea oral ulcer leukaemia

6. Cisplatin i.v. CA tests, ovary, cervix, lung, head & neck, thyroid, Melanoma

Renal damage, ototoxicity, neuropathy, BMD

7. Dacarbazine i.v. Melanoma, Hodgkin’s disease BMD

8. Carmustine (BCNU)

i.v. Brain tumours Leukopaenia, thrombocytopaenia

9. Lomustine (CCNU)

Oral Brain tumours Leukopaenia, thrombocytopaenia

10. Thiotepa i.v. CA bladder (early) & Ovary BMD

Tyrosine Kinase InhibitorsDrug Inhibit TK activated Indication

Axitinib VEGFR – 1,2,3 Advanced renal cell carcinoma

Bosutinib Abl –bcr, src CML

Crizotinib c-MET, ALK Non small cell lung carcinoma

Cabozantinib c-MET, VEGFR-2 Medullary carcinoma thyroid

Dasatinib abl -bcr CML

Erlotinib EGFR Non small cell lung carcinoma Pancreatic carcinoma

Geftinib abl-bcr, c- KIT, PDGF Non small cell lung carcinoma

Imatinib her-2/neu, erb-B2 CML GIST

Lapatinib abl-bcr Breast carcinoma

Nilotinib VEGFR-1,2,3 PDGFR α β c-KIT

CML

Pazopanib abl-bcr Advanced renal cell carcinoma

Tyrosine Kinase Inhibitors

Drug Inhibit TK activated Indication

Regorafenib VDGFR2, TIE2 Colorectal carcinoma GIST

Ruxolitinib JAK 1,2 Myelofibrosis

Sorafenib VEGFR, PDGFR RAF Renal cell carcinoma Hepatocellular carcinoma

Sunitinib VEGFR, PDGFR c- KIT, FLT-3 RET Renal cell carcinoma, Pancreatic neuroendocrine tumors GIST

Tofacitinib JAK Rheumatoid arthritis

Vandetanib VEGFR, EGFR Medullary carcinoma thyroid

Vemurafenib BRAF Maliganant melaonma

Monoclonal Antibodies S. No.

Monoclonal antibody Targeted against

Indication Comments

1 Rituximab CD - 20 Non hodgkin lymphoma

2 Alemtuzumab CD - 52 Low grade lymphomas and CLL

3 Trastuzumab HER 2/neu Breast Carcinoma Can cause cardiotoxicity

4 Cetuximab and panitumumab

EGFR EGFR – positive metastatic colorectal carcinoma

Cause rash, Hypomagnesemia and tnterstitial lung disease

5 Bevacizumab VEGF Metastatic colorectal carcinoma

Combined with 5 - FU

6 Gemtuzumab CD-33 CD-33 Positive AML Linked to calicheamicin

7 I131 – TositumomabY90 – Ibritumomab tiuxetan

CD-20 Relapsed lymphomas Conjugated with radioisotopes

8 Denileukin diftitox - Recurrentcutaneous T-cell lymphoma

Recombinant IL – 2 plus diphtheria toxin

Therapy of choice for various cancersS. No. Diagnosis Treatment of choice

1 All Induction: Vincristine + Prednisolone+Daunorubicin+ Asparaginase+Intrathecal MethotrexateConsolidation: Hyper-CVAD alternated with cytarabine+Methotrexate

2 AML Cytarabine+Daunorubicin/Idarubicin

3 CML Imatinib

4 CLL FCR or Fludarabine

5 Hairy cell leukemia Cladribine

6 Hodgkin disease ABVD

7 Non hodgkin lymphoma

CHOP-R

8 Multiple Myeloma Bortezomib+Dexamethasone+Lenalidomide

9 Waldenstrom macroglobulinemia

FCR

10 Polycthemia vera Hydroxyurea

Therapy of choice for various cancersS. No. Diagnosis Treatment of choice

11 Non small cell lung cancer

Cisplatin + Vinorelbine ± Bevacizumab

12 Small cell lung cancer

Cisplatin + Etoposide

13 Mesothelioma Cisplatin + Pemetrexed

14 Head and neck cancer Cisplatin + 5-FU

Some antimetabolites used in cancer chemotherapyAgent Route

of admin.

Cancer (s) where preferred

Delayed toxicity

1. Cytarabine i.v. AML BMD, nausea, Vomiting stomatitis ataxia (cerevellar)

2. 5- Fluorouracil i.v. Carcinoma head & neck, Stomach colon, breast

BMD, Oral and GI ulceration, nausea, diarrhoea, neurotoxicity, *hand and foot syndrome

3. 6- Mercaptopuine

Oral All BMD, Hyperuricaemia, immunosuppression, hepatotoxicity

4. Methotrexate Oral All, choriocarcinoma, osteogenic sarcoma

BMD, vomiting, oral & GI ulcers hepatotoxicity (acute & chronic)

5. Thioguanine Oral AML BMD, Hyperuricaemia

Some natural products in cancer chemotherapyAgent Cancer (s) where preferred Delayed toxicity

Antibiotics1. Bleomycin Carcinoma testis, malignant

effusion (intracavity)Alopecia, oedema of hand, pulomonary fibrosis, stomatitis

2. Dactinomycin Wilm’s tumour Alopecia, BMD, Stomatitis, Oral ulcer

3. Daunorubicin AML Alopecia, BMD, Cardiomyopathy

4. Doxorubicin HL, NHL, neuroblastoma, Carcinoma thyroid, stomach, carcinoid tumouir, sarcomas, osteogenic sarcoma

Alopecia, BMD, Cardiomyopathy, stomatitis

5. Mitomycin Carcinoma stomach Thrombocytopaenia, leukopaenia

6. Streptozotocin (sreptozocin)

Insulinoma Renal damage, hypoglycaemia, hyperglycaemia, liver damage, BMD, fever eosinophilia, nephrogenic diabetes insipidus

Some natural products in cancer chemotherapyAgent Cancer (s) where

preferredDelayed toxicity

Plant Alkaloids1. Docetaxel Advance case of

carcinoma breastNeurotoxicity, fluid retention, neutropaenia

2. Etoposide Carcinoma testis, choriocarcinoma

Alopecia, BMD

3. Paclitaxel Carcinoma breast, ovary BMD, peripheral neuritis4. Vinblastine HD Alopecia, BMD, Loss of reflex5. Vincristine ALL, NHL Alopecia, BMD, Peripheral

neuritis6. Vinorelbine Carcinoma lung BMD, fatigue, constipation,

hyporeflexia paresthesia

Miscellaneous agents including monoclonal antibodies in cancer chemotherapy

Agent Route of admin. Cancer(s) where used 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 CML, AML (blast crisis)

BMD

4. Mitotane Oral Adrenocortical carcinoma

Adrenal insufficiency, diarrhoea, lethargy, skin rash (transient)

5. Mitoxantrone Oral Aml BMD, cardiotoxicity, alopecia

6. Imatinib Oral CML (chronic phase) & blast crisis

Fluid retention (periorbital and ankle oedema), diarrhoea, myalgia

7. Trastuzumab i.v. Carcinoma breast (metaastatic)

BMD, cardiomyopathy, pulm. Toxicity, cardiac failure

Hormones, their antagonists and related agents in cancer chemotherapyAgent Route of admin Cancer(s) where

preferredDelayed toxicity

CorticosteroidsHydrocortisonePrednisone

OralOral

All, CLL, NHL, HL Multiple myeloma

Fluid retention,Hypertension, diabetes mellitus, susceptibility to infection, moon face

AndrogensTestosterone

i.m. Premenopausal breast cancer (oestrogen receptor positive)

Fluid retention masculinization

OestrogensDiethylstilboesterol

Ethinyloestradiol

OralOral

Carcinoma prostate,Postmenopausal breast cancer (oestrogen receptors negative)

Feminization, Fluid retention

ProgestinsHydroxyprogesteroneMedroxyprogesterone

i.m.Oral

Carcinoma endometrium

None

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, triptorelinaromatase inhibitor: Letrozole and

anastrazole

Hormones, their antagonists and related agents in cancer chemotherapyAgent Route of admin Cancer(s) where

preferredDelayed toxicity

AntiandrogenFlutamide

Oral Carcinoma prostate None

AntiandrogenTamoxifen

Oral Carcinoma breast (early stage, metastatic after surgery)

None

Others GnRH AgonistGoserelin Leuprolide

s.c)s.c.)

Carcinoma prostate None

Aromatase NhibitorsAminogulutethimide

Oral Metastatic breast cancer

None

Peptide hormone Inhibitor

s.c. Carcinoid tumour None

Choice of drug in some malignancies where the response of chemotherapy is very goodCancer Treatment of choice

1. Acute lymphocytic leukaemia Induction: Vincristine + presnisoneMaintenance: Methotrexate + Mercaptopurine + Cyclophosphamide

2. Hodgkin’s disease stage I and IIStage III and IV

RadiotherapyDoxorubicin + bleomycin+vinblastine+dacarbazine

3. Non Hodgkin’s disease Cyclophosphamide + doxorubicin + vincristine + prednisolone

4. Choriocarcinoma Methotrexate + folic acid or cisplatin + etoposide

5. Cancer testis Bleomycin + cisplatin+ etoposide

6. Wilm’s tumour Surgery + radiotherapy followed by vincristine + dactinomycin

Choice of drug in some malignancies where the response of chemotherapy is good

Cancer Treatment of choice1. Acute myeloid leukaemia Cytarabine + idarubicin/daunorubicin

2. Chronic lymphocytic leukaemia

Chlorambucil + prednisone (if indicated) + fludarabine or cytarabine alone or in combination with other drugs

3. Chronic myelogenous leukaemia

Busulfan or interferon, imatinib (bone marrow transplatation in selected patients)

4. Multiple myeloma Melphalan + prednisone

5. * Carcinoma breast stage 1 Tomoxifen after breast surgery

6. Endometrial carcinoma Progestins or tamoxifen

7. Carcinoma cervix Radiation + cisplatin (localized), cisplatin/carboplatin (metastatic)

8. Carcinoma prostate GnRh agonist or oestrogen + androgen anatagonist (flutamide)

Choice of drug in some malignancies where the response of chemotherapy is average

Cancer Treatment of choice

1. Carcinoma breast stage II to IV

Cyclophosphamide + methotrexate + 5-FU or Transtuzumab + prednisone + antioestrogen

2. Carcinoma ovary Cisplatin or carboplatin + paclitaxel + interferom

3. Carcinoma thyroid Radioidine (I131), doxorubicin, cisplatin

4. Carcinoma stomach 5-FU + doxorubicin + mitomycin

5. Carcinoma colon 5-FU + leucovorin + irinotecan

6. Osteogenic sarcoma Doxorubicin or methotrexate with leucovorin after surgery

7. Melanoma Dacarbazine, cisplatin, interferon

Choice of drug in some malignancies where the response of chemotherapy in unsatisfactory

Cancer Treatment of choice1. Carcinoma lung Etopise + cisplatin, vinorelbine2. Carcinoma head and neck

5-fu+cisplatin or cisplatin + paclitaxel

3. Carcinoma adrenal gland

Mitotane

4. Carcinoid tumour Doxorubicin + cyclophospamide or 5-FU + octreotide

5. Polycythaemia vera Busulfan, chlorambucil or cyclophospamide

Alkylating AgentsMechanism 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

Nitrogen Mustards – contd.

• Chlorambucil: orally, active against lymphoid tissues (Ch. Lymphatic leukaemia and non-Hodgkin's lymphoma)

• Busulfan: orally, active against CML• Carmustine: IV, effective against brain tumors and

Hodgkin's lymphoma• Dacarbazine: Different from other alkylating agents –

action against RNA and protein synthesis– Used Melanoma and Hodgkin's lymphoma

AntimetabolitesFolic acid Antagonists: MTXPurine Antagonists: 6MP and 6TGPyrimidine Antagonists: 5FU and cytarabineGeneral 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 , good oral absorption– CSF entry - intrathecal

• Indications:– Choriocarinoma - was the first demonstration of curative

chemotherapy

– Tumors of head and neck

– Breast cancer

– Acue lymphatic leukemia

– Meningeal metastases of a wide range of tumors

Purine Antagonists – 6MP, 6TG6-Mercapapurine (6-MP) and others• Exact mechanisms uncertain – inhibit purine base

synthesis• Used in childhood Acute lymphatic Leukaemia for

maintenance and remission• combination MTX choriocarcinoma• Metabolized xanthine oxidase (inhibited by

allopurinol) and allopurinol dose has to be adjusted to ½ or 1/4th

• Well tolerated, mild myelosuppression , hepatotoxicity on long term administration

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

• Indications: solid tumors, especially breast, colorectal, and gastric tumors and squamous cell tumors of the head and neck

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

1. Which of the following is a radioprotector?a. Colony stimulating factorb. Amifostinec. Cisplatind. Methotrexate

(b)2. Topical mitomycin-C is used ina. Sturge-Weber syndromeb. Laryngotracheal stenosisc. Endoscopic angiofibromad. Skull base osteomyelitis

(b)

3. Which group of anticancer drugs Temozolomide belong toa. Oral alkylating agentb. Antitumor Antibioticc. Antimetabolited. Mitotic Spindle Inhibitor

(a)4. Methotrexate is used for the management of all of these conditions excepta. Rheumatoid arthritisb. Psoriasisc. Sickle cell anemiad. Organ transplantation

(c)

5. Which of the following drug is used for the is treatment of sickle cell anemia?a.Hydroxyureab. Cisplatinc. Paclitaxeld. Carboplatin

(a)6. Use of tamoxifen in carcinoma of breast patients does not lead to the following

side effectsa. Thromboembolic eventsb. Endometrial carcinomac. Cataractd. Cancer in opposite breast

(d)

7. All of the following are true regarding ifosfamide EXCEPTa. Metabolised by cytochrome p450 enzymesb. Less neurotoxic than cyclophosphamidec. Chloracetaldehyde is the metabolite of ifosfamided. It is a nitrogen mustard

(b)8. Alkalinisation of urine ameliorates the toxicity of which of the following drugs?a. Arabinoside-cytosineb. Ifosfamidec. Cisplatind. Methotrexate

(d)

11. Pulmonary fibrosis is seen witha. Bleomycinb. Cisplatinc. Methotrexated. Actinomycin D

(a)12. Which of the following drug is used in the treatment of estrogen

dependent breast carcinoma?a. Tamoxifenb. Methotrexatec. Paclitaxeld. Adriamycin (a)

13. Methotrexate resistance is due to:a. Depletion of Folateb. Overproduction of DHFRasec. Overproduction of Thymidylate kinased. Decreased DHFRase

(b)14. Hemorrhagic cystitis is caused bya. Cyclophosphamideb. 6 Mercaptopurinec. 5 Fluorouracild. Busulfan

(a)

15. Thalidomide is used in all of the following excepta. HIV associated peripheral neuropathyb. HIV associated aphthous (mouth) ulcersc. Behcet syndromed. Erythema Nodosum Leprosum

(a)16. Most common dose-limiting toxicity of cancer chemotherapy isa. Gastrointestinal toxicityb. Neurotoxicityc. Bone marrow suppressiond. Nephrotoxicity

(c)

17. Which of the following parameters is not monitored in a patient on methotrexate therapy?

a. Liver function testsb. Lung function testc. Eye examinationd. Hemogramz

(c)18. All of the following are true about thalidomide excepta. Used in pregnancy as anti-emetic but withdrawn due to teratogenicityb. Can be used in multiple myeloma as primary treat ment as well as in refractory

diseasec. Causes euphoria and diarrhead. Can be used in erythema nodosum leprosum

(c)

19. Which of the following drug acts by inhibiting tyrosine kinase activated by EGF receptor as well as HER2?

a. Imatinibb. Geftinibc. Erlotinibd. Lapatinib

(d)20. Tyrosine kinase inhibitors are first line treatment ina. Gastrointestinal stromal tumorsb. Receptor mediated neuroendocrine tumorsc. Breast cancerd. Renal cell carcinoma

(a)

• 21. Drug locally used for tracheal stenosis isa. Mitomycin Cb. Doxorubicinc. Bleomycind. Clindamycin

(a)22. Cetuximab (an EGFR antagonist) can be used ina. Palliation in head and neck cancerb. Anal canal carcinomac. Gastric carcinomad. Lung carcinoma

(a)

23. Most emetogenic anticancer drug isa. Cisplatinb. Carboplatinc. High dose cyclophosphamided. High dose methotrexate

(a)24. Cerebellar toxicity is seen witha. Cisplatinb. Cytarabinec. Bleomycind. Actinomycin D

(b)

25. All are alkylating agents, excepta. 5-Fluorouracilb. Melphalanc. Cyclophosphamided. Chlorambucil

(a)26. Which of the following can be given orally?a. Cytosine arabinosideb. Cisplatinc. Doxorubicind. Mesna

(d)

27. In treatment of osteosarcoma, all of the following are used EXCEPTa. High dose methotrexateb. Cyclophosphamidec. Vincristined. Doxorubicin

(c)28. 'Hand and Foot' syndrome can be caused bya. Cisplatinb. Vincristinec. Capecitabined. Mitomycin-C

(c)

29. Which of the following anti-cancer drugs is cell cycle specific?a. Ifosfamideb. Melphalan c. Vinblastined. Cyclophosphamide

(c)30. Topical mitomycin-C is used ina. Sturge-Weber syndromeb. Laryngotracheal stenosisc. Endoscopic angiofibromad. Skull base osteomyelitis

(b)

31. Amifostine is protective to all EXCEPTa. Salivary glandsb. Skinc. CNSd. GIT

(c)32. Bleomycin toxicity affects which type of cellsa. Type-I pneumocytesb. Type-II pneumocytesc. Endothelial cellsd. Pulmonary alveolar macrophages

(b)

33. SIADH is caused by all EXCEPTa. Vincristineb. Vinblastinec. Actinomycin Dd. Cyclophosphamide

(c)34. Imatinib is used in the treatment of?a. Chronic myelomonocytic leukemiab. Myelodysplastic syndromec. Acute lymphoid leukemiad. Gastro intestinal stromal tumors

(d)

35. Sustained neutropenia is seen with?a. Vinblastineb. Cisplatinc. Carmustined. Cyclophosphamide

(c)36. Rituximab is used in all EXCEPTa. Non Hodgkin lymphomab. Paroxysomal nocturnal hemoglobinureac. Rheumatoid arthritisd. Systemic lupus erythematosis

(b)

39. Which of the following anticancer drug is excreted by lungs?a. 5-Fluorouracilb. Cyclophosphamidec. Doxorubicind. Cisplatin

(a)40. Which of the following drugs is used for the treatment of refractoty

histiocytosis?a. High dose methotrexateb. High dose cytarabinec. Cladribined. Fludarabine

(c)

41. Thalidomide, used for multiple myeloma, isa. Associated with diarrheab. Characterized by enantiomeric intercon-versionsc. Metabolized extensively by hepatic CYP systemd. Safe for use in pregnant females

(b)42. A patient on treatment for leukemia, develops chest pain, pulmonary infiltrates

and pleural effusion. The likely causeis.a. Daunorubicinb. Hydroxyureac. Cytarabined. Tretinoin

(d)

43. Mechanism of action of paclitaxel isa. Topoisomerase inhibitionb. Increases the polymerization of tubulinc. Inhibits protein synthesisd. Alkylation of DNA

(b)44. Which antineoplastic drug is a peptide?a. Bleomycinb. Aspartemec. Valinomycind. Dactinomycin

(a)

45. Leucovorin is used to decrease the toxicity ofa. Methotrexateb. Mercaptopurinec. Thio-TEPAd. Cytosine arabinoside

(a)46. All-trans-retinoic acid is used in treatment ofa. Acute promyelocytic leukemiab. A.L.L.c. CMLd. Transient myeloproliferative disorder

(a)

47. Treatment of choice for chronic myeloid leukemia isa. Imatinibb. Hydroxyl-ureac. Interferon-alphad. Cytarabine

(a)48. Which of the following anticancer drugs can cause hypercoagulable state?a. 5-FUb. L-asparaginasec. Melphaland. Carmustine

(b)

49. Anticancer drug causing SIADH as an adverse effect isa. Vincristineb. Paclitaxelc. Dacarbazined. Cyclophosphamide

(a)50. Which of the following anticancer drugs acts by hypomethylation?a. Gemcitabineb. 5-FUc. Decitabined. Homoharringotonine

(c)

51. High dose methotrexate is used for the treatment ofa. Osteosarcomab. Rhabdomyosarcomac. Retinoblastomad. Ewing's sarcoma

(a)52. Which of the following drugs is topoisomerase 1 inhibitor?a. Doxorubicinb. Irinotecanc. Etoposided. Vincristine

(b)

53. All of the following anticancer agents cause bone marrow suppression EXCEPT

a. Chlorambucilb. Daunorubicinc. Doxorubicind. Flutamide

(d)54. All the following are hormonal agents used against breast cancer EXCEPTa. Letrozoleb. Exemestanec. Taxold. Tamoxifen

(c)

55. Which is the most active single chemotherapeutic agent in the treatment of leiomyosarcoma?

a. Adriamycinb. Daunorubicinc. Methotrexated. Cisplatin

(a)56. Gemcitabine is effective ina. Head and neck cancersb. Pancreatic cancerc. Small-cell lung cancerd. Soft tissue sarcoma

(b)

57. All of the following statements about methotrexate are correct EXCEPTa. Folinic acid enhances the action of methotrexateb. Methotrexate inhibits dihydrofolate reductasec. Non-proliferative cells are resistant to methotrexated. Methotrexate is used in the treatment of psoriasis

(a)58. Mesna is given with cyclophosphamide toa. Increase absorptionb. Decreased excretionc. Ameliorate hemorrhagic cystitisd. 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. Vinblastineb. Bleomycinc. Mithramycind. Adriamycin

(b)60. Arsenic is useful in the treatment ofa. Acute promyelocytic leukemiab. Myelodysplastic syndromec. Transient myeloproliferative disorderd. All of the above

(a)

61. Which of the following is an anti-metabolite?a. Methotrexateb. Cyclosporinec. Etoposided. Vinblastine

(a)62. Mechanism of action of imatinib mesylate isa. Increase in metabolism of P glycoproteinb. Blocking the action of P glycoproteinc. Blocks the action of chimeric fusion protein of bcr abld. Non-competitive inhibition of ATP binding site

(c)

63. Which of the following drugs is associated with untoward side effect of renal tubular damage?

a. Cisplatinb. Streptozocinc. Methysergided. Cyclophosphamide

(a)64. Which of the following chemotherapeutic agents is associated with secondary

leukemia?a. Vinblastineb. Paclitaxelc. Cisplatind. Bleomycin

(c)

65. The drug imatinib acts by the inhibition ofa. Tyrosine kinaseb. Glutathione reductasec. Thymidylate synthetased. Protein kinase

(a)66. The new drug pemetrexed useful in breast cancer belongs to which of the

following category of the drugs?a. Antitumor agentb. Alkylating agentc. Hormonal agentd. Antimetabolite

(d)

71. Sodium 2-mercapto ethane sulfonate is used as a protective agent ina. Radiotherapyb. Cancer chemotherapyc. Lithotripsyd. Hepatic encephalopathy

(b)72. Pulmonary fibrosis is a common complication after treatment witha. 6-Mercaptopurineb. Vincristinec. Bleomycind. Adriamycin

(c)

73. A patient receiving allopurinol requires dose reduction ofa. 6-Meracaptopurineb. Cyclophosphamidec. 6-Thioguanined. Climetidine

(a)74. Which of the following are alkylating agents?a. Cyclophosphamideb. Ifosfamidec. Methotrexated. Vincristine

(a)

75. Anticancer drugs of plant origin is/area. Vincristineb. Isotretinoinc. Bleomycind. Methotrexate

(a, b)76. Alkylating agents area. Vincristineb. Actinomycin-Dc. Chlorambucild. 5-Fluorouracile. Cyclophosphamide

(c, e)

77. Which of the following drugs are anticancer antibiotics?a. Vancomycinb. Actinomycin Dc. Bleomycind. Mithramycine. Vincristine

(b, c, d)78. Metaphase arrest is caused bya. Griseofulvinb. Vincristinec. Paclitaxeld. Colchicinee. Etoposide

(b, c, d)

79. The mechanism of anticancer action of fluorouracil isa. Cross linking of double stranded DNA and the resulting inhibition of DNA

replication and transcriptionb. Cytotoxicity resulting from a metabolite that interferes with the production of dTMPc. Irreversible inhibition of dihydrofolic acid reductased. Selective action on DNA polymerase

(b)80. A cell cycle specific anticancer drug that acts mainly in the M phase of the cycle isa. Cisplatinb. Etoposidec. Methotrexated. Paclitaxel

(d)

81. Maintenance of high urinary pH is important during methotrexate treatment because

a. Bladder irritation is reducedb. It decreases renal tubular secretion of methotrexatec. Leucovorin toxicity is increased in a dehydrated patientd. Methotrexate is a weak acid

(d)82. All of the following statements about methotrexate are true Excepta. It is cell cycle specific and kills in the S phaseb. Its toxicity primarily affects bone marrow and epithelial structuresc. Folic acid reverses its toxic effectsd. It is the drugs of choice for choriocarcinoma

(c)

83. Mechanism of action of vincristine in the treatment of All isa. Inhibition of topoisomerase II to cause breaks in DNA strandsb. Alkylation and cross linking DNA strandsc. Inhibition of DNA mediated RNA synthesisd. Inhibition of polymerization of tubulin to form microtubules (d)84. All of the following statements about vincristine are true EXCEPTa. It acts by inhibiting mitosisb. Its prominent adverse effect is peripheral neuropathyc. It does not suppress bone marrowd. It is a drug of choice for solid tumors

(d)

85. All of following statements about are true about mercaptopurine EXCEPTa. It is metabolized by xanthine oxidaseb. It does not cause hyperuricemiac. Its dose should be reduced when allopurinol is given concurrentlyd. It is an active metabolite of azathioprine

(b)86. Which of the following immunosuppressants is not used for the treatment of

cancers?a. Cyclophosphamideb. Cyclosporinec. Methotrexated. 6-Mercaptopurine

(b)

87. Which of the following drugs is not used in prostate carcinoma?a. Finasterideb. Diethylstilbesterolc. Testosteroned. Flutamide

(c)88. Pentostatin acts by inhibitinga. RNA dependent DNA polymeraseb. Aldolasec. Adenosine deaminased. Adenylyl cyclase

(c)

89. Hand and foot syndrome is an adverse effect ofa. 5-Fluorouracilb. Bleomycinc. Etoposided. Actinomycin D

(a)90. Side effects of cisplatin include all of the following EXCEPTa. Nausea and vomitingb. Nephrotoxicityc. Blindnessd. Ototoxicity

(c)

91. Most common side effect of 5-fluoracil isa. G.I. toxicityb. Bone marrow depressionc. Cardiotoxicityd. Neurotoxicity

(a)92. Sterility is caused bya. Vinca alkaloidsb. Alkylating agents c. Antimetabolitesd.Actinomycin Ds

(b)

99. Neoadjuvant chemotherapy is used in all excepta. Esophageal carcinomab. Breast carcinomac. Thyroid carcinomad. Non- small cell carcinoma of lung

(c)100.Which of the following anticancer drugs can cross blood brain barrier?a. Cisplatinb. Nitrosoureac. Vincristined. Vinblastine

(b)

101. Which of the following drugs produce significant nephrotoxicity?a. Cisplatinb. Carboplatinc. Vinblastined. Vincristine

(a)102. Phocomelia is due to teratogenic effects ofa. Thailidomideb. Chlopromazinec. Methotrexated. Carbamzepine

(a)

103. Folinic acid counteracts the toxicity ofa. Doxorubicinb. Methotrexatec. Cyclophosphamided. Fluorouracil

(b) 104. Which of the following antineoplastic and immunosuppressant drugs is a

dihydrofolate reductase inhibitor?a. Methotrexateb. Adriamycinc. Vincristined. Cyclophosphamide

(a)

105. Toxicity of nitrogen mustards can be decreased bya. Amifostineb. Folinic acidc. GM-CSFd. MESNA

(c)106. Which one of the following alkaloids is used as anticancer agent?a. Vincristineb. Papaverinec. Ephedrined. Atropine

(a)

107. The antimalignancy drug which is potentially cardiotoxic isa. Doxorubicinb. Bleomycinc. Fluorouracild. Dacarbazine

(a)108. The drug of choice in choricarcinoma isa. Methotrexateb. Actinomycin –Dc. Vincristined. 6-thioguanine

(a)

109. “Stocking and glove” neuropathy is seen ina. Vinblastineb. Paclitaxelc. Etoposided. Mitroxantrone

(b)110Drug that is radioprotective isa. Paclitaxelb. Vincristinec. Etoposided. Amifostine

(d)

111. Hemorrhagic cystitis is caused bya. Cyclophosphamideb. Ifosfamidec. Vincristined. Adriamycin

(b)112. Which of the following anti-cancer drug is cell cycle specific?a. Cyclophosphamideb. Vincristinec. Nitrogen mustardd. Doxourubicin

(b)

113. Which of the following anticancer drug is not ‘S’-phase specific?a. Methotrexateb. Meracaptopurinec. Ifosfamided. Thiouanine

(c)114. All are alkylating agents excepta. Cyclophosphamideb. Lomustinec. Busulfand. Zalcitabine

(d)

115. Chemotherapy is not useful ina. Chondrosarcomab. Wilm’s tumorc. Choriocarcinomad. All

(a)116. Cisplatin does not causea. Cardiomyopathyb. Nephrotoxicityc. Neuropathyd. Tinnitus

(a)

117. Cyclophosphamide can causea. Hemorrhagic cystitisb. Cardiomyopathyc. Neuropathyd. Convulsions

(a)118. Which of the following is not an early adverse effect of methotrexate?a. Hepatic fibrosisb. Myelosupressionc. Nausead. Stomatitis

(a)

119. Which of the following is not an antineoplastic antibiotic?a. Actinomycin Db. Doxorubicinc. Bleomycind. Spiramycin

(d)

120. All cause myelosuppression excepta. Docetaxel vincristineb. Vincristinec. Methotrexated. Irrnotecan

(b)

121. Leucovorin rescue is related toa. Methotrexate toxicityb. Cyclophosphamide toxicityc. Oncovin toxicityd. Cisplatin toxicity

(a)122. Which of the following causes peripheral neuritis?a. Methotrexeteb. Vincristinec. Busulfand. Cyclophosphamide

(b)

123. The drug of choice for chronic myeloid leukemia, is a. Chlorambucilb. Busulfanc. Vincristined. Procarbazine

(b)124. Proliferation independent agents include all the following excepta. Vincristineb. Carmustinec. Melphaland. Cyclophosphamide

(a)

125. People with high risk for development of breast cancer should be treated by prophylactic admini-stration of

a. Tamoxifenb. Aminoglutethimidec. Diethyistibesterold. Flutamide

(a)126. Which of the following is widely used in the management of carcinoma breast?a. Actinomycin Db. Bleomycinc. Doxorubicind. Dacarbazine

(c)

127. Rituximab is used ina. Hodgkin,s diseaseb. Acute myeloid leukemiac. Non-Hodgkin lymphomad. Multiple myeloma

(c)128. Allopurinol potentiates action ofa. Azathioprineb. Busulfanc. Actinomycind. Procarbazine

(a)

129. Alkylating agengts includea. Doxorubicinb. Cholorambucilc. Vinblastined. Busulfane. Methotrexate

(b, d)

69. Sterile hemorrhagic cystitis is caused bya. Busulfanb. Ketoprofenc. Methicillind. Cyclophosphamide

(d)70. A 50 year old woman, Hema has been diagnosed with locally advanced breast cancer

and recommended for chemotherapy. She has five years history of myocardial infarction and congestive heart failure. Which antineoplastic drug should be best avoided?

a. Anthracyclineb. Alkylating agentc. Platinum compoundd. Bisphosphonates

(a)

67. Which of the following statements is FALSE regarding vincristine?a. It is an alkaloidb. Its use is associated with neurotoxicityc. It does not cause alopeciad. It is a useful drug for induction of remission in acute lymphoblastic leukemia

(c)68. A patient with cancer developed extreme degree of radiation toxicity. Further history

revealed that the dose adjustment of a particular drug was missed during the course of radiotherapy. Which of the following drugs required a dose adjustment during radiotherapy in order to prevent radiation toxicity?

a. Vincristineb. Dactinomycinc. Cyclophosphamided. 6- Mercaptopurine

(b)

37. Ifosfamide belongs to which group of anticancer drugs?a. Alkylating agentsb. Antimetabolitesc. Mitotic inhibitorsd. Topoisomerase inhibitors

(a)38. A 56 year old female presented with breast carcinoma and she was prescribed

herceptin (trastuzumab). Which of the following statements regarding this drug is true?

a. It is an antibody produced entirely from mouse con taining no human component.b. It is a monoclonal antibody produced by injecting her-2 antigenc. It is a polyclonal antibodyd. It is a monoclonal antibody containing only human component

(b)

93. Which of the following is a common side effect of cisplatina. Diarrheab. Vomitingc. Pulmonary fibrosisd. Alopecia

(b)94. The antimetabolite ‘X’ inhibits DNA polymerse and is one of the most active drugs in the

treatment of leukemia. Although myelo-suppression is done limiting, the drug may also cause cerebellar dysfunction, including ataxia and dysarthria. Which of the following can be ‘X’?

a. Bleomycinb. Cytarabinec. Mercaptopurined. Methotrexate

(b)

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. Dacarbazineb. Procarbazinec. Melphaland. 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 excepta. N-acetylcysteineb. Slow rate of infusionc. Chloride dieresisd. 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 patient’s condition?

a. Folinic acidb. Mesnac. Dexazoxaned. 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 patient’s symptoms?

a. Restrictive cardiomyopathyb. Hypertrophic cardiomyopathyc. Dilated cardiomyopathyd. Pericardial fibrosis

(c)

• It is important to remember that antimetabolites such as cytarabine, 5-FU do not cause acute toxicity

• Most of the hormones and hormone antagonist do not cause acute toxicity

• All alkylating agents such as chlorambucil cyclophosphamide, melphalan etc cause nausea and vomiting as acute toxicity.

• Most of the natural products such bleomycin vincristine and vinbalstine etc used for cancer chrmotherapy cause nausea and vomiting as acute toxicity

Substances used to reduce the toxicity of anticancer drugs1. Leukovorin/citrovorum factor folinic acid2. Xanthine oxidase inhibitor allopurinol3. Colony stimulating factor for Neutrophils filgrastim &

sargramostim, For RBCs darbopoetin –α & erythropoietin.

4. Thiophosphate cytoprotectants amifostine5. Acrolein conjugator, mesna, acetylcysteine6. Iron chelator, Dexrazoxane7. Thrombopoietic factor, Oprelvekin, Thrombopoietin.

thanks