Anticancer Drugs

Anticancer Drugs ?

Dr.lokendra Sharma Associate Professor Department of Pharmacology

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

Cell cycle effects of anticancer drugs CCS CCS Drugs CCNS Drugs Chemotherapy Drugs G1 - S

Etoposide

Platinum compounds

S

Antimetabolites

Alkylating agents

G2 – M

Bleomycin Etoposide (Ref Harrison 17th/525)

Anthracyclines Dactinomycin

M

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

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 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 ?



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 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 ?        

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 (GMCSF/G-CSF) – recovery of garnulocytopenia

Drugs used to prevent toxicity of Anti cancer drugs Drug

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 drugs Drug

Mechanism

Indications

Epoetin alpha and darbopoetin alpha

Erythropoietin

Anemia

Filgrastim, pegfilgrastim

G-CSF and

Febrile neutropenia prophylaxis

Sargramostim

GM - CHF

Oprelvekin

IL-11

Thrombocytopenia

Ondansetron

5-HT3 antagonist

Nausea and vomiting

NK – 1 antagonist

Cisplatin induced delayed vomiting

Granisetron Palonosetron Aprepitant

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 Chemotherapy Agent

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 Inhibitors Drug

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 – Tositumomab Y90 – 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 cancers S. No.

Diagnosis

Treatment of choice

1

All

Induction: Vincristine + Prednisolone+Daunorubicin+ Asparaginase+Intrathecal Methotrexate Consolidation: 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 cancers S. 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 chemotherapy Agent

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. 6Mercaptopuine

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 chemotherapy Agent

Cancer (s) where preferred

Delayed toxicity

Antibiotics 1. 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 chemotherapy Agent

Cancer (s) where preferred

Delayed toxicity

Plant Alkaloids 1. Docetaxel

Advance case of carcinoma breast

Neurotoxicity, fluid retention, neutropaenia

2. Etoposide

Carcinoma testis, choriocarcinoma

Alopecia, BMD

3. Paclitaxel

Carcinoma breast, ovary

BMD, peripheral neuritis

4. Vinblastine

HD

Alopecia, BMD, Loss of reflex

5. Vincristine

ALL, NHL

Alopecia, BMD, Peripheral neuritis

6. 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 chemotherapy Agent

Route of admin

Cancer(s) where preferred

Delayed toxicity

Corticosteroids Hydrocortisone Prednisone

Oral Oral

All, CLL, NHL, HL Multiple myeloma

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

Hormones, their antagonists and related agents in cancer chemotherapy Agent

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)

Others GnRH Agonist Goserelin Leuprolide

Carcinoma prostate

None

s.c) s.c.)

Aromatase Nhibitors Aminogulutethimide

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 good Cancer

Treatment of choice

1. Acute lymphocytic leukaemia

Induction: Vincristine + presnisone Maintenance: Methotrexate + Mercaptopurine + Cyclophosphamide

2. Hodgkin’s disease stage I and II Stage III and IV

Radiotherapy Doxorubicin + 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 choice

1. 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 choice

1. Carcinoma lung

Etopise + cisplatin, vinorelbine

2. Carcinoma head and neck

5-fu+cisplatin or cisplatin + paclitaxel

3. Carcinoma adrenal gland

Mitotane

4. Carcinoid tumour

Doxorubicin + cyclophospamide or 5FU + octreotide

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

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

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

– 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, 6TG 6-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 factor b. Amifostine c. Cisplatin d. Methotrexate (b) 2. Topical mitomycin-C is used in a. Sturge-Weber syndrome b. Laryngotracheal stenosis c. Endoscopic angiofibroma d. Skull base osteomyelitis (b)

3. Which group of anticancer drugs Temozolomide belong to a. Oral alkylating agent b. Antitumor Antibiotic c. Antimetabolite d. Mitotic Spindle Inhibitor (a) 4. Methotrexate is used for the management of all of these conditions except a. Rheumatoid arthritis b. Psoriasis c. Sickle cell anemia d. Organ transplantation (c)

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)

7. All of the following are true regarding ifosfamide EXCEPT a. Metabolised by cytochrome p450 enzymes b. Less neurotoxic than cyclophosphamide c. Chloracetaldehyde is the metabolite of ifosfamide d. It is a nitrogen mustard (b) 8. Alkalinisation of urine ameliorates the toxicity of which of the following drugs? a. Arabinoside-cytosine b. Ifosfamide c. Cisplatin d. Methotrexate (d)

11. Pulmonary fibrosis is seen with a. Bleomycin b. Cisplatin c. Methotrexate d. Actinomycin D (a) 12. Which of the following drug is used in the treatment of estrogen dependent breast carcinoma? a. Tamoxifen b. Methotrexate c. Paclitaxel d. Adriamycin (a)

13. Methotrexate resistance is due to: a. Depletion of Folate b. Overproduction of DHFRase c. Overproduction of Thymidylate kinase d. Decreased DHFRase (b) 14. Hemorrhagic cystitis is caused by a. Cyclophosphamide b. 6 Mercaptopurine c. 5 Fluorouracil d. Busulfan (a)

15. Thalidomide is used in all of the following except a. HIV associated peripheral neuropathy b. HIV associated aphthous (mouth) ulcers c. Behcet syndrome d. Erythema Nodosum Leprosum (a) 16. Most common dose-limiting toxicity of cancer chemotherapy is a. Gastrointestinal toxicity b. Neurotoxicity c. Bone marrow suppression d. Nephrotoxicity (c)

17. Which of the following parameters is not monitored in a patient on methotrexate therapy? a. Liver function tests b. Lung function test c. Eye examination d. Hemogramz (c) 18. All of the following are true about thalidomide except a. Used in pregnancy as anti-emetic but withdrawn due to teratogenicity b. Can be used in multiple myeloma as primary treatment as well as in refractory disease c. Causes euphoria and diarrhea d. 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. 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)

• 21. Drug locally used for tracheal stenosis is a. Mitomycin C b. Doxorubicin c. Bleomycin d. Clindamycin (a) 22. Cetuximab (an EGFR antagonist) can be used in a. Palliation in head and neck cancer b. Anal canal carcinoma c. Gastric carcinoma d. Lung carcinoma (a)

23. Most emetogenic anticancer drug is a. Cisplatin b. Carboplatin c. High dose cyclophosphamide d. High dose methotrexate (a) 24. Cerebellar toxicity is seen with a. Cisplatin b. Cytarabine c. Bleomycin d. Actinomycin D (b)

25. All are alkylating agents, except a. 5-Fluorouracil b. Melphalan c. Cyclophosphamide d. Chlorambucil (a) 26. Which of the following can be given orally? a. Cytosine arabinoside b. Cisplatin c. Doxorubicin d. Mesna (d)

27. In treatment of osteosarcoma, all of the following are used EXCEPT a. High dose methotrexate b. Cyclophosphamide c. Vincristine d. Doxorubicin (c) 28. 'Hand and Foot' syndrome can be caused by a. Cisplatin b. Vincristine c. Capecitabine d. Mitomycin-C (c)

29. Which of the following anti-cancer drugs is cell cycle specific? a. Ifosfamide b. Melphalan c. Vinblastine d. Cyclophosphamide (c) 30. Topical mitomycin-C is used in a. Sturge-Weber syndrome b. Laryngotracheal stenosis c. Endoscopic angiofibroma d. Skull base osteomyelitis (b)

31. Amifostine is protective to all EXCEPT a. Salivary glands b. Skin c. CNS d. GIT (c) 32. Bleomycin toxicity affects which type of cells a. Type-I pneumocytes b. Type-II pneumocytes c. Endothelial cells d. Pulmonary alveolar macrophages (b)

33. SIADH is caused by all EXCEPT a. Vincristine b. Vinblastine c. Actinomycin D d. Cyclophosphamide (c) 34. Imatinib is used in the treatment of? a. Chronic myelomonocytic leukemia b. Myelodysplastic syndrome c. Acute lymphoid leukemia d. Gastro intestinal stromal tumors (d)

35. Sustained neutropenia is seen with? a. Vinblastine b. Cisplatin c. Carmustine d. Cyclophosphamide (c) 36. Rituximab is used in all EXCEPT a. Non Hodgkin lymphoma b. Paroxysomal nocturnal hemoglobinurea c. Rheumatoid arthritis d. Systemic lupus erythematosis (b)

39. Which of the following anticancer drug is excreted by lungs? a. 5-Fluorouracil b. Cyclophosphamide c. Doxorubicin d. Cisplatin (a) 40. Which of the following drugs is used for the treatment of refractoty histiocytosis? a. High dose methotrexate b. High dose cytarabine c. Cladribine d. Fludarabine (c)

41. Thalidomide, used for multiple myeloma, is a. Associated with diarrhea b. Characterized by enantiomeric intercon-versions c. Metabolized extensively by hepatic CYP system d. 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. Daunorubicin b. Hydroxyurea c. Cytarabine d. Tretinoin (d)

43. Mechanism of action of paclitaxel is a. Topoisomerase inhibition b. Increases the polymerization of tubulin c. Inhibits protein synthesis d. Alkylation of DNA (b) 44. Which antineoplastic drug is a peptide? a. Bleomycin b. Asparteme c. Valinomycin d. Dactinomycin (a)

45. Leucovorin is used to decrease the toxicity of a. Methotrexate b. Mercaptopurine c. Thio-TEPA d. Cytosine arabinoside (a) 46. All-trans-retinoic acid is used in treatment of a. Acute promyelocytic leukemia b. A.L.L. c. CML d. Transient myeloproliferative disorder (a)

47. Treatment of choice for chronic myeloid leukemia is a. Imatinib b. Hydroxyl-urea c. Interferon-alpha d. Cytarabine (a) 48. Which of the following anticancer drugs can cause hypercoagulable state? a. 5-FU b. L-asparaginase c. Melphalan d. Carmustine (b)

49. Anticancer drug causing SIADH as an adverse effect is a. Vincristine b. Paclitaxel c. Dacarbazine d. Cyclophosphamide (a) 50. Which of the following anticancer drugs acts by hypomethylation? a. Gemcitabine b. 5-FU c. Decitabine d. Homoharringotonine (c)

51. High dose methotrexate is used for the treatment of a. Osteosarcoma b. Rhabdomyosarcoma c. Retinoblastoma d. Ewing's sarcoma (a) 52. Which of the following drugs is topoisomerase 1 inhibitor? a. Doxorubicin b. Irinotecan c. Etoposide d. Vincristine (b)

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)

61. Which of the following is an anti-metabolite? a. Methotrexate b. Cyclosporine c. Etoposide d. Vinblastine (a) 62. Mechanism of action of imatinib mesylate is a. Increase in metabolism of P glycoprotein b. Blocking the action of P glycoprotein c. Blocks the action of chimeric fusion protein of bcrabl d. 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. 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)

65. The drug imatinib acts by the inhibition of a. Tyrosine kinase b. Glutathione reductase c. Thymidylate synthetase d. Protein kinase (a) 66. The new drug pemetrexed useful in breast cancer belongs to which of the following category of the drugs? a. Antitumor agent b. Alkylating agent c. Hormonal agent d. Antimetabolite (d)

71. Sodium 2-mercapto ethane sulfonate is used as a protective agent in a. Radiotherapy b. Cancer chemotherapy c. Lithotripsy d. Hepatic encephalopathy (b) 72. Pulmonary fibrosis is a common complication after treatment with a. 6-Mercaptopurine b. Vincristine c. Bleomycin d. Adriamycin (c)

73. A patient receiving allopurinol requires dose reduction of a. 6-Meracaptopurine b. Cyclophosphamide c. 6-Thioguanine d. Climetidine (a) 74. Which of the following are alkylating agents? a. Cyclophosphamide b. Ifosfamide c. Methotrexate d. Vincristine (a)

75. Anticancer drugs of plant origin is/are a. Vincristine b. Isotretinoin c. Bleomycin d. Methotrexate (a, b) 76. Alkylating agents are a. Vincristine b. Actinomycin-D c. Chlorambucil d. 5-Fluorouracil e. Cyclophosphamide (c, e)

77. Which of the following drugs are anticancer antibiotics? a. Vancomycin b. Actinomycin D c. Bleomycin d. Mithramycin e. Vincristine (b, c, d) 78. Metaphase arrest is caused by a. Griseofulvin b. Vincristine c. Paclitaxel d. Colchicine e. Etoposide (b, c, d)

79. The mechanism of anticancer action of fluorouracil is a. Cross linking of double stranded DNA and the resulting inhibition of DNA replication and transcription b. Cytotoxicity resulting from a metabolite that interferes with the production of dTMP c. Irreversible inhibition of dihydrofolic acid reductase d. Selective action on DNA polymerase (b) 80. A cell cycle specific anticancer drug that acts mainly in the M phase of the cycle is a. Cisplatin b. Etoposide c. Methotrexate d. Paclitaxel (d)

81. Maintenance of high urinary pH is important during methotrexate treatment because a. Bladder irritation is reduced b. It decreases renal tubular secretion of methotrexate c. Leucovorin toxicity is increased in a dehydrated patient d. Methotrexate is a weak acid (d) 82. All of the following statements about methotrexate are true Except a. It is cell cycle specific and kills in the S phase b. Its toxicity primarily affects bone marrow and epithelial structures c. Folic acid reverses its toxic effects d. It is the drugs of choice for choriocarcinoma (c)

83. Mechanism of action of vincristine in the treatment of All is a. Inhibition of topoisomerase II to cause breaks in DNA strands b. Alkylation and cross linking DNA strands c. Inhibition of DNA mediated RNA synthesis d. Inhibition of polymerization of tubulin to form microtubules (d) 84. All of the following statements about vincristine are true EXCEPT a. It acts by inhibiting mitosis b. Its prominent adverse effect is peripheral neuropathy c. It does not suppress bone marrow d. It is a drug of choice for solid tumors (d)

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)

87. Which of the following drugs is not used in prostate carcinoma? a. Finasteride b. Diethylstilbesterol c. Testosterone d. Flutamide (c) 88. Pentostatin acts by inhibiting a. RNA dependent DNA polymerase b. Aldolase c. Adenosine deaminase d. Adenylyl cyclase (c)

89. Hand and foot syndrome is an adverse effect of a. 5-Fluorouracil b. Bleomycin c. Etoposide d. Actinomycin D (a) 90. Side effects of cisplatin include all of the following EXCEPT a. Nausea and vomiting b. Nephrotoxicity c. Blindness d. Ototoxicity (c)

91. Most common side effect of 5-fluoracil is a. G.I. toxicity b. Bone marrow depression c. Cardiotoxicity d. Neurotoxicity (a) 92. Sterility is caused by a. Vinca alkaloids b. Alkylating agents c. Antimetabolites d.Actinomycin Ds (b)

99. Neoadjuvant chemotherapy is used in all except a. Esophageal carcinoma b. Breast carcinoma c. Thyroid carcinoma d. Non- small cell carcinoma of lung (c) 100.Which of the following anticancer drugs can cross blood brain barrier? a. Cisplatin b. Nitrosourea c. Vincristine d. Vinblastine (b)

101. Which of the following drugs produce significant nephrotoxicity? a. Cisplatin b. Carboplatin c. Vinblastine d. Vincristine (a) 102. Phocomelia is due to teratogenic effects of a. Thailidomide b. Chlopromazine c. Methotrexate d. Carbamzepine (a)

103. Folinic acid counteracts the toxicity of a. Doxorubicin b. Methotrexate c. Cyclophosphamide d. Fluorouracil (b) 104. Which of the following antineoplastic and immunosuppressant drugs is a dihydrofolate reductase inhibitor? a. Methotrexate b. Adriamycin c. Vincristine d. Cyclophosphamide (a)

105. Toxicity of nitrogen mustards can be decreased by a. Amifostine b. Folinic acid c. GM-CSF d. MESNA (c) 106. Which one of the following alkaloids is used as anticancer agent? a. Vincristine b. Papaverine c. Ephedrine d. Atropine (a)

107. The antimalignancy drug which is potentially cardiotoxic is a. Doxorubicin b. Bleomycin c. Fluorouracil d. Dacarbazine (a) 108. The drug of choice in choricarcinoma is a. Methotrexate b. Actinomycin –D c. Vincristine d. 6-thioguanine (a)

109. “Stocking and glove” neuropathy is seen in a. Vinblastine b. Paclitaxel c. Etoposide d. Mitroxantrone (b) 110Drug that is radioprotective is a. Paclitaxel b. Vincristine c. Etoposide d. Amifostine (d)

111. Hemorrhagic cystitis is caused by a. Cyclophosphamide b. Ifosfamide c. Vincristine d. Adriamycin (b) 112. Which of the following anti-cancer drug is cell cycle specific? a. Cyclophosphamide b. Vincristine c. Nitrogen mustard d. Doxourubicin (b)

113. Which of the following anticancer drug is not ‘S’-phase specific? a. Methotrexate b. Meracaptopurine c. Ifosfamide d. Thiouanine (c) 114. All are alkylating agents except a. Cyclophosphamide b. Lomustine c. Busulfan d. Zalcitabine (d)

115. Chemotherapy is not useful in a. Chondrosarcoma b. Wilm’s tumor c. Choriocarcinoma d. All (a) 116. Cisplatin does not cause a. Cardiomyopathy b. Nephrotoxicity c. Neuropathy d. Tinnitus (a)

117. Cyclophosphamide can cause a. Hemorrhagic cystitis b. Cardiomyopathy c. Neuropathy d. Convulsions (a) 118. Which of the following is not an early adverse effect of methotrexate? a. Hepatic fibrosis b. Myelosupression c. Nausea d. Stomatitis (a)

119. Which of the following is not an antineoplastic antibiotic? a. Actinomycin D b. Doxorubicin c. Bleomycin d. Spiramycin (d) 120. All cause myelosuppression except a. Docetaxel vincristine b. Vincristine c. Methotrexate d. Irrnotecan (b)

121. Leucovorin rescue is related to a. Methotrexate toxicity b. Cyclophosphamide toxicity c. Oncovin toxicity d. Cisplatin toxicity (a) 122. Which of the following causes peripheral neuritis? a. Methotrexete b. Vincristine c. Busulfan d. Cyclophosphamide (b)

123. The drug of choice for chronic myeloid leukemia, is a. Chlorambucil b. Busulfan c. Vincristine d. Procarbazine (b) 124. Proliferation independent agents include all the following except a. Vincristine b. Carmustine c. Melphalan d. Cyclophosphamide (a)

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)

127. Rituximab is used in a. Hodgkin,s disease b. Acute myeloid leukemia c. Non-Hodgkin lymphoma d. Multiple myeloma (c) 128. Allopurinol potentiates action of a. Azathioprine b. Busulfan c. Actinomycin d. Procarbazine (a)

129. Alkylating agengts include a. Doxorubicin b. Cholorambucil c. Vinblastine d. Busulfan e. Methotrexate (b, d)

69. Sterile hemorrhagic cystitis is caused by a. Busulfan b. Ketoprofen c. Methicillin d. 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. Anthracycline b. Alkylating agent c. Platinum compound d. Bisphosphonates (a)

67. Which of the following statements is FALSE regarding vincristine? a. It is an alkaloid b. Its use is associated with neurotoxicity c. It does not cause alopecia d. 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. Vincristine b. Dactinomycin c. Cyclophosphamide d. 6- Mercaptopurine (b)

37. Ifosfamide belongs to which group of anticancer drugs? a. Alkylating agents b. Antimetabolites c. Mitotic inhibitors d. 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 containing no human component. b. It is a monoclonal antibody produced by injecting her-2 antigen c. It is a polyclonal antibody d. It is a monoclonal antibody containing only human component (b)

93. Which of the following is a common side effect of cisplatin a. Diarrhea b. Vomiting c. Pulmonary fibrosis d. 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. Bleomycin b. Cytarabine c. Mercaptopurine d. 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. 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 patient’s 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 patient’s symptoms? a. Restrictive cardiomyopathy b. Hypertrophic cardiomyopathy c. Dilated cardiomyopathy d. 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 drugs 1. Leukovorin/citrovorum factor folinic acid 2. Xanthine oxidase inhibitor allopurinol 3. Colony stimulating factor for Neutrophils filgrastim & sargramostim, For RBCs darbopoetin –α & erythropoietin. 4. Thiophosphate cytoprotectants amifostine 5. Acrolein conjugator, mesna, acetylcysteine 6. Iron chelator, Dexrazoxane 7. Thrombopoietic factor, Oprelvekin, Thrombopoietin.

thanks