A 61-year-old woman is brought to the emergency department because of fever, chills, and flank pain for 8 hours. Her temperature is 39.1°C (102.4°F). Physical examination shows right costovertebral angle tenderness. Urine dipstick is positive for nitrites. Urinalysis shows gram-negative rods. The patient is admitted to the hospital and treatment with a drug that directly inhibits bacterial DNA replication is begun. This drug inhibits a protein that is normally responsible for which of the following steps of DNA replication?

Cleaving DNA to relieve supercoils

Excising RNA fragments in 5' to 3' direction

Binding to single-stranded DNA to prevent reannealing

Unwinding DNA at replication fork

A 71-year-old woman presents to her hematologist-oncologist for follow up after having begun doxorubicin and cyclophosphamide in addition to radiation therapy for the treatment of her stage 3 breast cancer. Her past medical history is significant for preeclampsia, hypertension, polycystic ovarian syndrome, and hypercholesterolemia. She currently smokes 1 pack of cigarettes per day, drinks a glass of wine per day, and denies any illicit drug use. The vital signs include: temperature 36.7°C (98.0°F), blood pressure 126/74 mm Hg, heart rate 111/min, and respiratory rate 23/min. On physical examination, the pulses are strong and irregular, she has a grade 3/6 holosystolic murmur heard best at the left upper sternal border, clear bilateral breath sounds, and erythema over her site of radiation. Which of the following statements regarding doxorubicin is true?

Doxorubicin has a maximum lifetime dose, due to the risk of cardiac toxicity

Doxorubicin has a maximum lifetime dose, due to the risk of pulmonary toxicity

Doxorubicin will increase her risk for deep vein thrombosis (DVT) and pulmonary embolism (PE)

Doxorubicin frequently causes an acneiform rash

Doxorubicin frequently causes cystitis

A 54-year-old woman is diagnosed with locally-advanced invasive ductal carcinoma of the breast. She undergoes surgical resection, radiation therapy, and is now being started on adjunctive chemotherapy with cyclophosphamide and doxorubicin. The patient is scheduled for follow up by her primary care provider. Which of the following tests should be performed regularly to monitor her current treatment regimen?

No regular monitoring indicated

Topoisomerase inhibitors Revision – USMLE Pharmacology

Mechanism of Action - Unwinding the Damage

Topoisomerase I and II mechanisms

Topoisomerase I Inhibitors (e.g., Irinotecan, Topotecan):
- Create single-strand nicks in DNA to relieve supercoiling.
- Inhibitors bind to the Topo-I-DNA complex, preventing re-ligation of the nick.
Topoisomerase II Inhibitors (e.g., Etoposide, Teniposide):
- Create transient double-strand breaks.
- Inhibitors stabilize the Topo-II-DNA complex, preventing re-ligation.
Result: Accumulation of DNA strand breaks triggers cell cycle arrest and apoptosis.

⭐ High-Yield: Topoisomerase II inhibitors are cell cycle-specific, acting primarily during the S and G2 phases.

📌 Mnemonic: Topo-I makes 1 cut. Topo-II makes 2 cuts.

Topoisomerase I Inhibitors - The 'Tecan' Team

📌 Mnemonic: Irinotecan & Topotecan inhibit Topoisomerase I ('1 T-can').

Mechanism: Inhibit topoisomerase I, preventing the re-ligation of single-strand breaks in DNA. This leads to the accumulation of DNA damage and triggers apoptosis during the S-phase of the cell cycle.

Drug	Primary Use	Key Toxicities
Irinotecan	Metastatic colorectal cancer (often in FOLFIRI regimen)	Severe Diarrhea (cholinergic, acute; secretory, delayed). Myelosuppression.
Topotecan	Ovarian cancer, Small Cell Lung Cancer (SCLC)	Myelosuppression (dose-limiting neutropenia, thrombocytopenia), alopecia.

Topoisomerase II Inhibitors - Double-Strand Breakers

These agents prevent the re-ligation of double-strand DNA breaks induced by Topoisomerase II, leading to permanent DNA damage and apoptosis.

Agent Class	Mechanism of Action (MOA)	Clinical Use	Key Toxicities
Etoposide, Teniposide	Inhibit Topoisomerase II, causing DNA degradation. Cell cycle-specific for late S & G2 phases.	Solid tumors (testicular, small cell lung), leukemias, lymphomas.	Myelosuppression, alopecia.
Anthracyclines (Doxorubicin, Daunorubicin)	1. Inhibit Topoisomerase II. 2. Generate free radicals via iron-dependent reactions. 3. Intercalate into DNA.	Broad spectrum: solid tumors (breast, ovary), hematologic malignancies (leukemias, lymphomas).	Cardiotoxicity (dose-dependent dilated cardiomyopathy), myelosuppression, alopecia, red urine.

⭐ The lifetime cumulative dose of doxorubicin must be monitored closely. Cardiotoxicity is prevented with dexrazoxane, an iron-chelating agent.

High‑Yield Points - ⚡ Biggest Takeaways

Topoisomerase I inhibitors (Irinotecan, Topotecan) cause single-strand DNA breaks. A key toxicity of Irinotecan is severe diarrhea.

Topoisomerase II inhibitors (Etoposide, Teniposide) induce double-strand DNA breaks. Their dose-limiting toxicity is myelosuppression.

Anthracyclines (e.g., Doxorubicin) also inhibit Topo II; their most feared side effect is irreversible, dose-dependent cardiotoxicity.

Bleomycin induces free radical damage to DNA and is uniquely associated with pulmonary fibrosis.

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