Alkylating Agents

ALKYLATING AGENTS

Q. 1 Regarding multiple  myeloma which of  the following statements is wrong
 A Malignant neoplasm derived from plasma cells
 B Multiple punched out lesions on radiograms of the skull
 C Multiple hot spots on bone scan
 D Melphalan is used in treatment.
Q. 1 Regarding multiple  myeloma which of  the following statements is wrong
 A Malignant neoplasm derived from plasma cells
 B Multiple punched out lesions on radiograms of the skull
 C Multiple hot spots on bone scan
 D Melphalan is used in treatment.
Ans. C

Explanation:

In Multiple Myeloma, On X-ray lytic lesions are seen. Bone scan is normal. Level of alkaline phosphate in the blood is normal, (despite extensive bone involvement). Generalize body pain is the commonest presentation. Hypercalcaemia, raised ESR, Anemia, are the features. Raised β2 micro globulin is a poor prognostic feature.


Q. 2 Which of the following is the main mechanism by which the mechlorethamine exerts its cell killing?
 A Alkylating DNA, causing cross-links between parallel DNA strands
 B Blocking microtubular assembly and mitosis during M-phase
 C Inhibiting topoisomerase, preventing repair of DNA strand breaks
 D
Intercalating in DNA strands, there by preventing DNA replication by Mrna
Q. 2 Which of the following is the main mechanism by which the mechlorethamine exerts its cell killing?
 A Alkylating DNA, causing cross-links between parallel DNA strands
 B Blocking microtubular assembly and mitosis during M-phase
 C Inhibiting topoisomerase, preventing repair of DNA strand breaks
 D
Intercalating in DNA strands, there by preventing DNA replication by Mrna
Ans. A

Explanation:

Alkylating DNA, causing cross-links between parallel DNA strands

Vincristine and the other vinca alkaloids bind to tubulin and impair microtubular assembly, preventing mitosis (M-phase-specific). Mechlorethamine, like cyclophosphamide (and carmustine and several others), is an alkylating agent. They are called bifunctional alkylating agents because they can covalently bind to DNA in two places (“nucleophilic attack”), thereby forming cross-links between two adjacent strands or between two bases in one strand. This ultimately disrupts DNA and RNA synthesis or may cause strand breakage. Cyclophosphamide (which can be considered the prototype of the alkylating agents) is actually a pro- drug—it requires metabolic activation in order for its effects to occur. Cyclophosphamide (and other alkylating agents) are cell cycle-nonspecific, although their efficacy is greater when cells are not in G0.Bleomycin, dactinomycin, and doxorubicin are good examples of drugs that intercalate in DNA strands. Thus, the altered DNA no longer serves as an adequately precise template for eventual synthesis of more functional DNA and RNA. They are classified as antitumor antibiotics. Etoposide and topotecan are examples of drugs that inhibit topoisomerase 11. The consequence is inhibited ability of affected cells to repair DNA strand breaks. This stops the cell cycle in G2 – The taxoid (e.g., paclitaxel) impairs mitosis, but by stabilizing assembled microtubules rather than by exerting a vinca alkaloid-like inhibition of microtubular assembly.


Q. 3

Which chemotherapeutic agent is pro carcinogenic?

 A Alkylating agents
 B

Antibiotics

 C Monoclonal antibodies
 D

All of the above

Q. 3

Which chemotherapeutic agent is pro carcinogenic?

 A Alkylating agents
 B

Antibiotics

 C Monoclonal antibodies
 D

All of the above

Ans. A

Explanation:

Alkylating agents REF: Robbin’s 7th ed p. 322

Pro carcinogenic chemicals:

  • Alkylating agents
  • Aromatic amines and azo dyes
  • Nitrosoamines and amides

Quiz In Between


Q. 4

Ifosfamide belongs to which group of anticancer drugs‑

 A

Alkylating agents

 B

Antiimetobolites

 C

Mitotic inhibitors

 D

Topoisomerase inhibitors

Q. 4

Ifosfamide belongs to which group of anticancer drugs‑

 A

Alkylating agents

 B

Antiimetobolites

 C

Mitotic inhibitors

 D

Topoisomerase inhibitors

Ans. A

Explanation:

Alkylating agents [Ref: KDT 6 th/e p. 822; Goodman & Gilman 111h/e p. 1328]

  • Ifosfamide belongs to alkylating agent.
  • It is an analogue of cyclophosphamide.
  • It is used in combination for germ cell testicular cancer and is widely used to treat pediatric and adult sarcomas. Adverse effect of If osfamide:-
  • Ifosfamide has virtually the same toxicity profile as cyclophosphamide although it causes greater platelet suppression, neurotoxicity, nephrotoxicity and in the absence of mesna, urothelial damage.
  • When it is used in high doses (myeloablative doses) it causes severe neurological toxicity.
  • When it is used in nonmyeloablative or low doses it causes severe urinary tract abnormalities. Intravenous mesna is given together with ifosfamide to prevent urinary tract adverse effects.

Q. 5

Sustained neutropenia is seen with ?

 A

Vinblastin

 B

Cisplatin

 C

Carmustine

 D

None of the above

Q. 5

Sustained neutropenia is seen with ?

 A

Vinblastin

 B

Cisplatin

 C

Carmustine

 D

None of the above

Ans. C

Explanation:

Carmustine [Ref. Goodman Gilman 1 lth/e p 1330]

Myelosuppression leading to neutropenia, thrombocytopenia and anemia is seen with most of the anticancer drugs.

  • The characteristic feature of myclosuppression produced by carmustine is that it causes delayed myelosuppression that is prolonged too

According to Goodman Gilman

“It causes profound and delayed myelosuppression with recovery 4-6 weeks after a single dose. The myelosuppression leads to leukopenia and thrombocytopenia (may be prolonged)”

More on Carmustine:

  • Carmustine belongs to nitrosoureas class of anticancer drugs
  • They have an important role in the treatment of brain tumours.
  • It is highly lipophilic and thus it readily crosses the blood brain barrier.

Other adverse effects of carmustine

  • Delayed renal damage
  • Reversible liver damage
  • Leukemia
  • Myocardial ischemia

Q. 6

Cyclophosphamide is?

 A

Alkylating agent

 B

Antitumor antibiotic

 C

Monoclonal antibody

 D

Antimetabolites

Q. 6

Cyclophosphamide is?

 A

Alkylating agent

 B

Antitumor antibiotic

 C

Monoclonal antibody

 D

Antimetabolites

Ans. A

Explanation:

Ans. is ‘a’ i.e., Alkylating agent

Quiz In Between


Q. 7

All are alkylating agents, except

 A

5-FU

 B

Melphalan

 C

Cyclophosphamide

 D

Chlorambucil

Q. 7

All are alkylating agents, except

 A

5-FU

 B

Melphalan

 C

Cyclophosphamide

 D

Chlorambucil

Ans. A

Explanation:

Ans. is ‘a’ i.e., 5 Fluorouracil


Q. 8

Sterility is caused by –

 A

Vinca alkaloids

 B

Alkylating agents

 C

Antimetabolites

 D

Actinomycin D

Q. 8

Sterility is caused by –

 A

Vinca alkaloids

 B

Alkylating agents

 C

Antimetabolites

 D

Actinomycin D

Ans. B

Explanation:

Ans. is ‘b’ i.e., Alkylatings agents

Alkylating agents may contribute to sterility by the following effects :

  • Azoospermia in males
  • Amenorrhea and ovarian atrophy in females

Specific toxicity of important alkylating agents.

o Cyclophosphamide          —> Cystitis, alopecia, SIADH

o Ifosfamide                     —> Cystitis, SIADH, neurotoxicity

o Cisplatin                       —>  Nephrotoxicity, peripheral neuropathy, ototoxicity, vomiting.

o Busulfan                       —> Adrenal insufficiency, hyperpigmentation,pu/monaryfibrosis.

o Procarbazine                 —> Disulfiram like reaction, secondary leukemias, CNS effects.


Q. 9

Which of the following is not an adverse effect of cyclophosphamide –

 A

Cystitis

 B

Alopecia

 C

Hypoglycemia

 D

GIT disorder

Q. 9

Which of the following is not an adverse effect of cyclophosphamide –

 A

Cystitis

 B

Alopecia

 C

Hypoglycemia

 D

GIT disorder

Ans. C

Explanation:

Ans. is ‘c’ i.e., Hypoglycemia

Toxicity of Cyclophosphamide

o Bone marrow suppression (relative platelet sparing)                          o Pulmonary toxicity               o Cardiac (at higher doses)

o Cystitis                                                                                        o Infertility                             o GI Toxicity

o Alopecia                                                                                      o Teratogenesis                      o SIADH


Quiz In Between

Q. 10

Cyclophosphamide can cause?

 A

Hemorragic cystitis

 B

Hand-foot syndrome

 C

Radiation Recall

 D

Cardiomyopathy

Q. 10

Cyclophosphamide can cause?

 A

Hemorragic cystitis

 B

Hand-foot syndrome

 C

Radiation Recall

 D

Cardiomyopathy

Ans. A

Explanation:

Ans. is ‘a’ i.e., Haemorrhagic cystitis

“Haemorrhagic cystitis can develop in patients receiving cyclophosphamide or ifbsphamide”.


Q. 11

Sodium 2-mercapto ethane sulfonate (mesna) is used as a protective agent in –

 A

Radiotherapy

 B

Cancer chemotherapy

 C

Lithotripsy

 D

Hepatic encephalopathy

Q. 11

Sodium 2-mercapto ethane sulfonate (mesna) is used as a protective agent in –

 A

Radiotherapy

 B

Cancer chemotherapy

 C

Lithotripsy

 D

Hepatic encephalopathy

Ans. B

Explanation:

Ans. is ‘b’ i.e., Cancer chemotherapy

o Mesna is used to block the cystitis caused by Cyclophosphamide and Ifophosphamide. o Note — Acetylcysteine can also be used for this purpose.

Folinic acid AllopurinolLithium carbonate Ondensetron

Other drugs used for toxicity amelioration in cancer therapy

For preventing methotrexate toxicity

To prevent hyperuricemia caused by rapid destruction of cells during cancer chemotherapy It has stimulant effect on bone marrow, so used during myelosuppresive drug therapy. For controlling cytotoxic drug induced vomiting.


Q. 12

Mesna is given with cyclophosphamide to

 A

Increase absroption

 B

Decrease excretion

 C

Amolierate haemorrhagic cystitis

 D

Decrease metabolism

Q. 12

Mesna is given with cyclophosphamide to

 A

Increase absroption

 B

Decrease excretion

 C

Amolierate haemorrhagic cystitis

 D

Decrease metabolism

Ans. C

Explanation:

Ans. is ‘c’ i.e., Ameliorate haemorrhagic cystitis

Quiz In Between


Q. 13

Cyclophosphamide is used in all except –

 A

Burkitt’s lymphoma

 B

Hodgkin’s

 C

Choriocarcinoma

 D

Ovarian Ca

Q. 13

Cyclophosphamide is used in all except –

 A

Burkitt’s lymphoma

 B

Hodgkin’s

 C

Choriocarcinoma

 D

Ovarian Ca

Ans. C

Explanation:

Ans. is ‘c’ i.e., Choriocarcinoma

Cyclophosphamide is used in

o Acute leukemias              o Wilm’s tumour

o CLL & CML                    o Prostate carcinoma

o Multiple myeloma           o Breast carcinoma

o Ewing’s sarcoma              o Ovarian carcinoma

o Small cell lung cancer

o Carcinoma cervix

o Hodgkin’s disease


Q. 14

All are true about cyclophosphamide except –

 A

Causes immunosuppression

 B

Causes local irritation

 C

Well absorbed orally

 D

Alkylating agent

Q. 14

All are true about cyclophosphamide except –

 A

Causes immunosuppression

 B

Causes local irritation

 C

Well absorbed orally

 D

Alkylating agent

Ans. B

Explanation:

Ans. is ‘b’ i.e., Causes local irritation

o The drug is not a vesicant, and produces no local irritation.

o Cyclophosphomide is an alkylating agent, absorbed well orally and is used as immunossuppressant in many refractory autoimmune diseases.


Q. 15

The most important target of action of chlorambucil is –

 A

Myeloid tissue

 B

Lymphoid tissue

 C

Neural tissue

 D

Skin

Q. 15

The most important target of action of chlorambucil is –

 A

Myeloid tissue

 B

Lymphoid tissue

 C

Neural tissue

 D

Skin

Ans. B

Explanation:

Ans. is ‘b’ i.e., Lymphoid tissue

o Chlorambucil is a very slow acting alkylating agent especially active on lymphoid tissue; myeloid tissue is largely spared.

Quiz In Between


Q. 16

Melphalan is used in –

 A

Multiple myeloma

 B

Wilm’s tumour

 C

Neuroblastoma

 D

Retinoblastoma

Q. 16

Melphalan is used in –

 A

Multiple myeloma

 B

Wilm’s tumour

 C

Neuroblastoma

 D

Retinoblastoma

Ans. A

Explanation:

Ans. is ‘a’ i.e., Multiple myeloma

o Melphalan is an anticancer (alkylating) agent which is most effective in multiple myeloma.


Q. 17

Busulfan toxicity does not include –

 A

Hyperpigmentation

 B

Toxic carditis

 C

Hyperuricemia

 D

Pulmonary fibrosis

Q. 17

Busulfan toxicity does not include –

 A

Hyperpigmentation

 B

Toxic carditis

 C

Hyperuricemia

 D

Pulmonary fibrosis

Ans. B

Explanation:

Ans. is ‘b’ i.e., Toxic carditis

o Adverse effects of busulfan —> Myelosuppression, hyperuricemia, pulmonary fibrosis, sterility, impotence, amenorrhea, addison’s disease like syndrome (asthenia and hypotension).

o High dose causes veno-occlusive disease of liver, seizures, hemorrhagic cystitis, alopecia, cataract.

About option ‘a’ – In addison’s disease there is hyperpigmentation (Busulfan causes addison’s disease like syndrome).


Q. 18

Which is chemotheraputic agent that must be included in treatment of ovarian carcinoma –

 A

Methotrexate

 B

Cyclophosphamide

 C

Flourouracil

 D

Procarbazine

Q. 18

Which is chemotheraputic agent that must be included in treatment of ovarian carcinoma –

 A

Methotrexate

 B

Cyclophosphamide

 C

Flourouracil

 D

Procarbazine

Ans. B

Explanation:

Ans. is ‘b’ i.e., Cyclophosphamide

Drugs used for ovarian carcinoma

o First line –p Cisplatin, Carboplatin, Paclitaxel, Cyclophosphamide, doxorubicin.

o Second line —> Melphalan, chlorambucil, 5-Fu, Methotrexate, Vincristine, Topotecan.

Quiz In Between


Q. 19

Peripheral neuropathy may occur with the use of all the following except –

 A

Vincristine

 B

Cisplatin

 C

L-Asparaginase

 D

Procarbazine

Q. 19

Peripheral neuropathy may occur with the use of all the following except –

 A

Vincristine

 B

Cisplatin

 C

L-Asparaginase

 D

Procarbazine

Ans. C

Explanation:

Ans. is ‘c’ i.e., L-Asparaginase

Drug causing peripheral necropathy

Amiodarone                 Demeclocycline          Isoniazid

Chloramphenicol         Disopyramide             Methysergide

Chloroquine                 Ethambutol                 Metronidazole

Cisplatin                     Ethionamide               Vincristine

Clioguinol                   Glutethemide              Tricyclic antidepressant

Clofibrate                    Hydralazine                Tolbutamide

Paclitaxol                  Chlorpropamide

Mustine                     Nalidixic acid                Nitrofurantoin

Perhexiline                 Phenelzine                  Phenytoin

Streptomycin             Procarbazine               Polymyxin, colistin

Stavudine                   Didanosine               Zalcitabine


Q. 20

All of the following statements about treatment of typical CLL are true, except :

 A

Treatment should be initiated as soon as diagnosis is established

 B

Chlorambucil and Fludarabine are the most commonly used agents

 C

Fludarabine is preferred in the young and Chlorambucil is preferred in the elderly

 D

Young patients are candidates for Bone marrow transplantation

Q. 20

All of the following statements about treatment of typical CLL are true, except :

 A

Treatment should be initiated as soon as diagnosis is established

 B

Chlorambucil and Fludarabine are the most commonly used agents

 C

Fludarabine is preferred in the young and Chlorambucil is preferred in the elderly

 D

Young patients are candidates for Bone marrow transplantation

Ans. A

Explanation:

Answer is A (Treatment should be initiated as soon as diagnosis is established)

It is not essential to initiate treatment as soon as a diagnosis of CLL is established.

‘An unusual feature of CLL compared to other leukemias is that making the diagnosis is not necessarily an indication to initiate treatment’ – DeVita

Treatment need not be initiated as soon as diagnosis of CLL is established

Early stage asymptomatic disease requires no treatment. CLL may be diagnosed in an asymptomatic patient and have a prolonged course. Meta-analysis has shown no survival advantage of initiating treatment in early stage disease. Active monitoring should however be pursued and treatment initiated only if and when the patient meets established ‘criteria for treatment’.

Criteria for treatment

  • Progressive marrow failure
  • Massive(>10cm)/progressive lymphadenopathy
  • Massive (>6cm)/progressive splenomegaly
  • Progressive lymphocytosis (doubling time <6 months)
  • Systemic symptoms;
  • Weight loss >10%in 6 months fever>38° C for >2 weeks extreme fatigue or night sweats
  • Autoimmune cytopenias (this may only require treatment of the autoimmune component not necessarily the leukaemia)

Chlorambucil and Fludarabine are the most commonly used agents.

The most common treatment for CLL are Chlorambucil or Fludarabine alone or in combination.

Chlorambucil

  • Can be administered orally and has few side effects
  • Less active than Fludarabine and usually unsuccessful in achieving remission
  • Most common agent chosen for treatment of elderly patients requiring therapy. (Majority of elderly patients have significant comorbid conditions associated with aging and may have an indolent disease)

Fludarabine

  • Administered intravenously and has significant side effects (Significant immune suppression)
  • More active agent and by far the only drug associatedwith a significant incidence of complete remission
  • Preferred agent for treatment of young patientsrequiring therapy Fludarabine is often used incombination with Cyclophosphamide (FC).Following theresults of LRF CC4 Trial many now consider FC to be thegold standard first Line treatment of CLL in the young

Young patients are candidates for Bone marrow transplanatation

Bendamustine is an alkylating agent structurally related to nitrogen mustards that is highly effective and is vying with fludarabine as the primary treatment of choice.

Rituximab (AntiCD20) and Alemtuzumab (anti CD52) may also be used.

`Young patients with CLL can be candidates for Allogenic bone marrow transplantation. Allogenic bone marrow transplantation can be urative but is associated with a significant treatment related mortality rate’ – Harrison

 

 


Q. 21

Busulfan may cause:        

September 2007

 A

Cystitis

 B

Pulmonary fibrosis

 C

Loss of hair

 D

Peripheral neuropathy

Q. 21

Busulfan may cause:        

September 2007

 A

Cystitis

 B

Pulmonary fibrosis

 C

Loss of hair

 D

Peripheral neuropathy

Ans. B

Explanation:

Ans. B: Pulmonary Fibrosis

Toxicity of busulphan may include:

  • Interstitial pulmonary fibrosis
  • Hyperpigmentation
  • Seizures
  • Hepatic (veno-occlusive disease)
  • Wasting syndrome.

Phenytoin may be used concurrently to prevent the seizures.

Levetiracetam, has shown efficacy for the prophylaxis against busulfan-induced seizures. Benzodiazepines can also be used for busulfan-induced seizures.

Quiz In Between


Q. 22

Anticancer drug also used in RA, produces acrolein in urine that leads to hemorrhagic cystitis

 A

Cyclophosphamide

 B

Busulfan

 C

Procarbazine

 D

Mesna

Q. 22

Anticancer drug also used in RA, produces acrolein in urine that leads to hemorrhagic cystitis

 A

Cyclophosphamide

 B

Busulfan

 C

Procarbazine

 D

Mesna

Ans. A

Explanation:

Cyclophosphamide

IMPORTANT POINTS ON HEMORRHAGIC CYSTITIS:

  • Drugs causing:
    • Cyclophosphamide
    • Ifosfamide
  • Metabolite responsible:
    • Acrolein – In Cyclophosphamide
    • Chloracetaldehyde – In Ifosfamide
  • Treatment:
    • Mesna.

Nitrogen mustards:

1. Cyclophosphamide:

  • Powerful vesicant
  • Prodrug – Activated by hepatic biotransformation to aldophosphamide.
    • Acrolein – One of its degradation products.
    • Responsible for hemorrhagic cystitis – Characteristic adverse effect.
  • Use: DOC for Wegener’s granulomatosis.
  • Adverse effects:
    • Hemorrhagic cystitis (Characteristic) – Treated by mercapto ethane sulfonic acid (mesna).
    • May cause cardiac dysfunction, pulmonary toxicity & syndrome of inappropriate ADH secretion.

2. Ifosfamide:

  • Produces chloracetaldehyde & acrolein as metabolites.
  • Adverse effects:
    • HIGHER risk of neurotoxicity & hemorrhagic cystitis.
    • Chloracetaldehyde – Responsible for nephrotoxic.

Q. 23

Anticancer drug with disulfuram like action –

 A

Procarbazine

 B

Nitrosurea

 C

5 FU

 D

Methotrexate

Q. 23

Anticancer drug with disulfuram like action –

 A

Procarbazine

 B

Nitrosurea

 C

5 FU

 D

Methotrexate

Ans. A

Explanation:

Ans. is ‘a’ i.e., Procarbazine

Disulfiram like reaction

  • Certain drugs when taken concurrently with alcohol produce disulfiram like actions.
  • That means these drugs produce similar distressing symptoms as disulfiram, when taken with alcohol → flushing, burning sensation, throbbing headache, prespiration, unesasiness, tightness in chest, vomiting, dizziness, visual disturbances, mental confusion, postural fainting and circulatory collapse.

The drugs causing Disulfiram like actions

  1. Chlorpropramide            
  2. Animal charcol
  3. Cephalosporins (Cefoperazone, moxalactam, cefamandole) 
  4. Griseofulvin
  5. Metronidazole         
  6. Procarbazine
  7. Citrated calcium carbamide  
  8. Tinidazine
  9. Cynamide

Q. 24

Alkylating agents are all except ‑

 A

Buslfan

 B

Carmustine

 C

Dacarbazine

 D

Etoposide

Q. 24

Alkylating agents are all except ‑

 A

Buslfan

 B

Carmustine

 C

Dacarbazine

 D

Etoposide

Ans. D

Explanation:

Ans. is `d’ i.e., Etoposide

Quiz In Between


Q. 25

Nitrosoureas used in the treatment of cancer are‑

 A

Carmustine

 B

5FU

 C

Methotrexate

 D

Cisplatin

Q. 25

Nitrosoureas used in the treatment of cancer are‑

 A

Carmustine

 B

5FU

 C

Methotrexate

 D

Cisplatin

Ans. A

Explanation:

Ans. is ‘a’ i.e., Carmustine

Nitrosoureas

  • Nitrosoureas (Lomustine and carmustine) are highly lipid soluble alkylating agents – cross blood – brain barrier → Effective in meningeal leukaemias and brain tumours.
  • Nitrosoureas are highly lipid soluble and can cross blood brain barrier used in brain tumors like gliomas.
  • Because they cross BBB, most common adverse effects are nausea, vomiting and other CNS effects.
  • Bone marrow depression is peculiarly delayed, taking nearly 6 weeks to develop. → delayed neutropenia
  • Nitrosoureas can cause visceral fibrosis and renal damage.

Q. 26

Mode of excretion of cyclophosphamide is ‑

 A

Lung

 B

Liver

 C

Kidney

 D

Skin

Q. 26

Mode of excretion of cyclophosphamide is ‑

 A

Lung

 B

Liver

 C

Kidney

 D

Skin

Ans. C

Explanation:

Ans. is ‘c’ i.e., Kidney 

  • Cyclophosphomide is primarily metabolized (80%) and metabolites are excerted in urine.
  • 10 to 20% is excreted unchanged in urine and 4% is excreted in bile.

Q. 27

Mode of excretion of cyclophosphamide is ‑

 A

Lung

 B

Liver

 C

Kidney

 D

Skin

Q. 27

Mode of excretion of cyclophosphamide is ‑

 A

Lung

 B

Liver

 C

Kidney

 D

Skin

Ans. C

Explanation:

Ans. is ‘c’ i.e., Kidney 

Quiz In Between



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