Topoisomerase Inhibitors — MCQs

10 questions

Many drugs are used as rescue therapy for preventing the adverse effects of anticancer drugs. Folinic acid is used in:-

A woman presenting with symptoms of urinary tract infection was prescribed a drug that causes tendon rupture and arthropathy. What is the mechanism of action of the drug?

Which enzyme is required for cutting the DNA strand during synthesis?

During the treatment of chronic myeloid leukemia, cytogenetic remission is least likely to occur with which one of the following treatment modalities?

All are true regarding Sunitinib except which of the following?

The use of which of the following helps in reducing the toxicity of doxorubicin to the heart?

Which is the most cardiotoxic anti-cancer drug among the following?

Mechanism of action of Pemetrexed is:-

All of the following are hormonal agents used in treatment of cancer EXCEPT:

Q10

Which local anesthetic is considered the most cardiotoxic?

Topoisomerase Inhibitors Indian Medical PG Practice Questions and MCQs

Question 1: Many drugs are used as rescue therapy for preventing the adverse effects of anticancer drugs. Folinic acid is used in:-

A. Cyclophosphamide toxicity
B. Doxorubicin toxicity
C. Methotrexate toxicity (Correct Answer)
D. Cisplatin toxicity

Explanation: ***Methotrexate toxicity*** - **Folinic acid (leucovorin)** is a reduced folate that bypasses the metabolic block caused by **methotrexate** on dihydrofolate reductase. - It replenishes the body's **folate stores** and protects healthy cells from methotrexate's cytotoxic effects, particularly in the bone marrow and gastrointestinal tract. *Cyclophosphamide toxicity* - **Cyclophosphamide** toxicity, primarily hemorrhagic cystitis, is prevented by **mesna** (2-mercaptoethane sulfonate). - Mesna inactivates the urotoxic metabolite **acrolein** in the urine, preventing bladder damage. *Doxorubicin toxicity* - **Doxorubicin** causes cardiotoxicity, which can be mitigated by the iron-chelating agent **dexrazoxane**. - Dexrazoxane reduces the formation of **free radicals** that contribute to doxorubicin-induced myocardial damage. *Cisplatin toxicity* - **Cisplatin** toxicity, especially nephrotoxicity, is largely prevented by **aggressive hydration** and administration of **diuretics**. - **Amifostine** is another agent that can reduce cisplatin-induced nephrotoxicity, neurotoxicity, and ototoxicity by acting as a cytoprotectant.

Question 2: A woman presenting with symptoms of urinary tract infection was prescribed a drug that causes tendon rupture and arthropathy. What is the mechanism of action of the drug?

A. Ribosomal inhibition
B. Cell wall synthesis
C. Inhibition of folic acid synthesis
D. DNA gyrase inhibition (Correct Answer)

Explanation: ***DNA gyrase inhibition*** - The description of a drug causing **tendon rupture** and **arthropathy** in the context of a urinary tract infection (UTI) suggests a **fluoroquinolone**. - Fluoroquinolones exert their bactericidal effect by inhibiting **bacterial DNA gyrase** (also known as topoisomerase II) and **topoisomerase IV**, thereby preventing DNA replication and repair. *Ribosomal inhibition* - This mechanism is characteristic of antibiotics like **aminoglycosides**, **tetracyclines**, and **macrolides**. - While some of these can treat UTIs, they are not typically associated with **tendon rupture** or **arthropathy** as major side effects. *Cell wall synthesis* - This is the mechanism of action for **beta-lactam antibiotics** (e.g., penicillins, cephalosporins) and **vancomycin**. - These drugs are common for UTIs but do not cause **tendon rupture** or **arthropathy**. *Inhibition of folic acid synthesis* - This mechanism is used by **sulfonamides** and **trimethoprim**, often combined as trimethoprim-sulfamethoxazole. - While effective for UTIs, these drugs are not known to cause **tendon rupture** or **arthropathy**.

Question 3: Which enzyme is required for cutting the DNA strand during synthesis?

A. DNA polymerase
B. DNA ligase
C. Topoisomerase (Correct Answer)
D. Helicase

Explanation: ***Topoisomerase*** - **Topoisomerases** are enzymes essential for DNA replication; they induce temporary **single- or double-strand breaks** in DNA to relieve **supercoiling** ahead of the replication fork. - This cutting and rejoining activity prevents the DNA from becoming excessively tangled and facilitates the unwinding process required for synthesis. *DNA polymerase* - **DNA polymerase** is responsible for **synthesizing new DNA strands** by adding nucleotides, not for cutting the DNA backbone. - It works by moving along the template strand, reading the bases, and then adding complementary nucleotides to the growing DNA strand. *DNA ligase* - **DNA ligase** functions to **join DNA fragments** together by forming phosphodiester bonds, especially in sealing Okazaki fragments during lagging strand synthesis. - Its role is to ligate (join) cut strands, not to initiate cuts in the DNA. *Helicase* - **Helicase** unwinds the DNA double helix into single strands using ATP hydrolysis; it **separates the two strands** but does not cut the phosphodiester backbone. - This enzyme creates the replication fork by disrupting hydrogen bonds between base pairs, making the DNA accessible for replication machinery.

Question 4: During the treatment of chronic myeloid leukemia, cytogenetic remission is least likely to occur with which one of the following treatment modalities?

A. imatinib mesylate
B. Interferon-alpha
C. Bone marrow transplantation
D. Hydroxyurea (Correct Answer)

Explanation: ***Hydroxyurea*** - **Hydroxyurea** (hydroxycarbamide) is a cytoreductive agent that can control cell counts in **chronic myeloid leukemia (CML)** but it does not specifically target the **BCR-ABL fusion gene**. [1] - Its mechanism of action involves inhibiting **ribonucleotide reductase**, which prevents DNA synthesis and thus reduces cell proliferation, but it does not lead to **cytogenetic remission**. [1] *imatinib mesylate* - **Imatinib mesylate** is a **tyrosine kinase inhibitor (TKI)** that specifically targets the **BCR-ABL fusion protein**. [1] - It is highly effective in achieving **hematological and cytogenetic remission** in most CML patients. [1] *Interferon-alpha* - **Interferon-alpha** is an immunomodulatory agent that was formerly a standard treatment for **CML** before TKIs. [1] - It can induce **cytogenetic remissions** in a significant proportion of patients, though less frequently and with more side effects than TKIs. [1] *Bone marrow transplantation* - **Allogeneic hematopoietic stem cell transplantation (HSCT)**, or bone marrow transplantation, offers the only potential cure for CML. - It involves replacing the patient's diseased bone marrow with healthy donor cells, leading to sustained **cytogenetic and molecular remission** in a high percentage of patients. [1]

Question 5: All are true regarding Sunitinib except which of the following?

A. It inhibits tyrosine kinase receptors
B. It is excreted primarily in urine (Correct Answer)
C. It is used for the treatment of GIST
D. It is used for renal cell carcinoma

Explanation: ***It is excreted primarily in urine*** - **Sunitinib** is predominantly metabolized in the **liver** by CYP3A4 and primarily excreted in the **feces**, not urine. - Its major active metabolite, N-desethyl sunitinib, is also primarily eliminated via the fecal route. *It inhibits tyrosine kinase receptors* - **Sunitinib** is a **multitargeted receptor tyrosine kinase (RTK) inhibitor**. - It blocks several RTKs involved in tumor growth, angiogenesis, and metastatic progression, such as **VEGFR, PDGFR, KIT, and FLT3**. *It is used for the treatment of GIST* - **Sunitinib** is approved for the treatment of **imatinib-refractory** or **imatinib-intolerant gastrointestinal stromal tumors (GIST)**. - Its mechanism in GIST involves inhibiting KIT and PDGFR, which are often mutated and constitutively active in this cancer. *It is used for renal cell carcinoma* - **Sunitinib** is a standard first-line treatment for **advanced renal cell carcinoma (RCC)**. - Its efficacy in RCC is primarily due to its inhibition of VEGFR, which targets the high vascularity characteristic of kidney tumors.

Question 6: The use of which of the following helps in reducing the toxicity of doxorubicin to the heart?

A. Dexrazoxane (Correct Answer)
B. Amifostine
C. Carboplatin
D. Flucytosine

Explanation: ***Dexrazoxane*** - **Dexrazoxane** is a **cardioprotective agent** that chelates intracellular iron, thereby reducing the formation of **free radicals** responsible for doxorubicin-induced cardiotoxicity. - It is specifically approved for reducing the incidence and severity of **cardiomyopathy** associated with doxorubicin use, particularly in patients who have received a high cumulative dose. *Amifostine* - **Amifostine** is a **cytoprotective agent** used to reduce the incidence of nephrotoxicity associated with platinum-based chemotherapy (e.g., cisplatin) and to reduce xerostomia in patients undergoing radiation therapy for head and neck cancer. - Its primary mechanism involves scavenging **free radicals** and detoxifying reactive metabolites in normal tissues, but it is not specifically indicated for doxorubicin-induced cardiotoxicity. *Carboplatin* - **Carboplatin** is a **platinum-based chemotherapy agent** similar to cisplatin, primarily used in the treatment of various cancers, including ovarian, lung, and head and neck cancers. - It causes myelosuppression and nephrotoxicity as major side effects but is a **chemotherapeutic drug itself**, not a protective agent against other chemotherapies. *Flucytosine* - **Flucytosine** is an **antifungal medication** used to treat severe systemic fungal infections, often in combination with amphotericin B. - Its mechanism involves interfering with fungal DNA and RNA synthesis, and it has no known role in mitigating the toxicity of doxorubicin.

Question 7: Which is the most cardiotoxic anti-cancer drug among the following?

A. Cyclophosphamide
B. Tamoxifen
C. Imatinib
D. Anthracyclines (Correct Answer)

Explanation: ***Anthracyclines*** - **Anthracyclines** (e.g., doxorubicin, daunorubicin) are notorious for causing **dose-dependent cardiotoxicity**, leading to **irreversible dilated cardiomyopathy** and **heart failure**. - Their cardiotoxic effect is primarily due to the generation of **reactive oxygen species** and interference with cardiac topoisomerase IIβ. *Cyclophosphamide* - Cyclophosphamide can cause cardiotoxicity, particularly at **high doses**, manifesting as **hemorrhagic myocardial necrosis** or **pericarditis**. - However, its cardiotoxicity is generally considered **less frequent and severe** than that of anthracyclines. *Tamoxifen* - Tamoxifen is primarily associated with an **increased risk of thromboembolic events** and **endometrial cancer**. - While some cardiac effects like **QT prolongation** can occur, it is not considered a primary cardiotoxic agent leading to cardiomyopathy. *Imatinib* - Imatinib, a **tyrosine kinase inhibitor**, has been linked to **cardiac dysfunction** including heart failure in some patients. - However, the incidence and severity of cardiotoxicity with imatinib are **lower** compared to anthracyclines, which are broadly cardiotoxic.

Question 8: Mechanism of action of Pemetrexed is:-

A. Topoisomerase inhibitor
B. Dihydrofolate reductase inhibitor
C. Dopamine agonist
D. Thymidylate synthase inhibitor (Correct Answer)

Explanation: ***Thymidylate synthase inhibitor*** - **Pemetrexed** is a **multi-targeted antifolate agent** that primarily inhibits **thymidylate synthase (TS)**, the key enzyme responsible for synthesizing thymidine monophosphate, an essential building block for DNA synthesis. - While pemetrexed also inhibits **dihydrofolate reductase (DHFR)** and **glycinamide ribonucleotide formyltransferase (GARFT)**, its **primary and most clinically significant mechanism** is TS inhibition, making it particularly effective in mesothelioma and non-small cell lung cancer. - This multi-targeted action enhances its cytotoxic effects compared to single-target antifolates. *Dihydrofolate reductase inhibitor* - While pemetrexed does inhibit **DHFR** as part of its multi-targeted mechanism, this is a **secondary action**, not its primary mechanism. - Classical DHFR inhibitors include **methotrexate** and **trimethoprim**, which specifically target this enzyme. - In exam contexts, pemetrexed is best classified by its **primary target: thymidylate synthase**. *Topoisomerase inhibitor* - **Topoisomerase inhibitors** target enzymes that control DNA topology during replication and transcription. - Examples include **irinotecan** and **topotecan** (topoisomerase I inhibitors) and **etoposide** (topoisomerase II inhibitor). - This is not the mechanism of action for pemetrexed. *Dopamine agonist* - **Dopamine agonists** activate dopamine receptors and are used in neurological conditions like Parkinson's disease (e.g., **pramipexole**, **ropinirole**). - This mechanism is completely unrelated to anticancer agents and folate metabolism.

Question 9: All of the following are hormonal agents used in treatment of cancer EXCEPT:

A. Cabergoline
B. Leuprolide
C. Irinotecan (Correct Answer)
D. Anastrozole

Explanation: ***Irinotecan*** - **Irinotecan** is a **chemotherapeutic agent** that acts as a **topoisomerase I inhibitor**, interfering with DNA replication and repair. - It works through a **cytotoxic mechanism** directly killing cancer cells, rather than modulating hormonal pathways. *Cabergoline* - **Cabergoline** is a **dopamine agonist** primarily used to treat **prolactinomas**, which are prolactin-producing pituitary tumors. - While it treats a tumor, its mechanism is **hormonal modulation** by reducing prolactin secretion, not direct cytotoxicity. *Anastrozole* - **Anastrozole** is an **aromatase inhibitor** used in estrogen receptor-positive breast cancer. - It works by **blocking the conversion of androgens to estrogens**, thereby reducing estrogen levels that fuel cancer growth. *Leuprolide* - **Leuprolide** is a **GnRH agonist** used in prostate cancer, breast cancer, and other hormone-sensitive conditions. - It initially stimulates, then continuously downregulates, the **pituitary gland's production of LH and FSH**, leading to reduced testosterone or estrogen levels.

Question 10: Which local anesthetic is considered the most cardiotoxic?

A. Procaine
B. Prilocaine
C. Ropivacaine
D. Bupivacaine (Correct Answer)

Explanation: ***Bupivacaine*** - **Bupivacaine** is an amide-type local anesthetic associated with significant **cardiotoxicity** due to its high lipid solubility and slow dissociation from cardiac sodium channels. - This can lead to severe **arrhythmias** and myocardial depression, making it particularly dangerous in systemic overdose. *Procaine* - **Procaine** is an ester-type local anesthetic with a relatively low potential for cardiotoxicity. - Its rapid metabolism by **plasma pseudocholinesterase** limits systemic exposure and reduces the risk of cardiac effects. *Prilocaine* - **Prilocaine** is an amide-type local anesthetic that is generally less cardiotoxic than bupivacaine. - Its primary concern is the potential to cause **methemoglobinemia** at higher doses, a side effect not directly related to cardiotoxicity. *Ropivacaine* - **Ropivacaine** is an amide-type local anesthetic developed as an alternative to bupivacaine with a reduced cardiotoxicity profile. - It exhibits a more favorable **therapeutic index** for cardiac effects due to its chemical structure and faster dissociation from cardiac sodium channels.

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