Introduction to Topoisomerase I Inhibitors

For DNA replication and cellular division to occur, topoisomerase I is required. It is an enzyme that creates and helps repair strands of DNA. In cancer cells, it has been shown that there is an increased activity of topoisomerases. This is why topoisomerase inhibitor medications have been used in many cancer therapies. Mainly topoisomerase I is responsible for relaxing supercoiled double strands of DNA, which then allows for replication to occur. The most common topoisomerase I inhibitor medications are irinotecan and topotecan.

In 1996, irinotecan and topotecan were approved for use in the United States. Camptothecin is another topoisomerase I inhibitor, and irinotecan and topotecan were originally derived from it. Camptothecin was isolated from the Camptotheca acuminata, which is a Chinese tree. Since its discovery, several analogues with improved efficacy and reduced toxicity profiles have been developed.

Mechanism of Action of Topoisomerase I Inhibitors

Topoisomerase I inhibitors work by stabilizing the temporary complex formed between topoisomerase I and DNA during replication. Normally, the enzyme creates a single-strand break to relieve torsional stress and then repairs the break. Irinotecan and topotecan prevent this repair process, resulting in DNA damage, replication arrest, and ultimately cancer cell death. Because rapidly dividing cancer cells rely heavily on DNA replication, they are particularly susceptible to these agents.

Clinical Uses of Irinotecan and Topotecan

Depending on the drug, indications can vary. Commonly, they are used in advanced colorectal, ovarian, and small-cell lung cancer. There are multiple regimens, and dose administration is dependent on the specific regimen cycle it is being used for. Irinotecan has been used with other therapies, such as 5-fluorouracil (5-FU) and leucovorin (LV). Hepatic adjustments may be seen with irinotecan because it is metabolized by the liver. Compared to topotecan, it is renally eliminated, which may result in possible renal adjustments in patients. Moreover, dosage and administration can sometimes vary based on the regimen, body weight, and other patient-specific factors.

Pharmacogenomics and UGT1A1 Testing

An important advancement in irinotecan therapy is the increasing use of pharmacogenomic testing. Irinotecan is converted to its active metabolite, SN-38, which is subsequently metabolized by the UGT1A1 enzyme. Patients carrying certain UGT1A1 variants, particularly UGT1A1*28/*28, may have reduced metabolism of SN-38 and an increased risk of severe neutropenia and diarrhea. Clinical guidelines increasingly support consideration of UGT1A1 genotyping in select patients receiving irinotecan-containing regimens.

What are the differences and similarities between liposomal irinotecan and irinotecan?

• Liposomal form of irinotecan has a lipid bilayer
• SN-38 is an active metabolite of both medications
• The lipid bilayer prolongs irinotecan half-life, and it prevents it from converting to its active metabolite quicker
• The liposomal form is used for treatment in patients with metastatic adenocarcinoma of the pancreas
• These are not interchangeable medications

Additional Considerations for Liposomal Irinotecan

Liposomal irinotecan continues to play an expanding role in pancreatic cancer treatment. Recent clinical studies, including the NAPOLI-3 trial, have evaluated liposomal irinotecan-containing regimens in earlier treatment settings for metastatic pancreatic adenocarcinoma. Healthcare professionals should recognize that dosing, administration, and toxicity management differ from conventional irinotecan formulations.

Adverse Effects and Toxicity Management

There are many chemotherapeutic medications that have extensive side effect profiles or adverse reactions associated with them. It is important to distinguish that there are acute and delayed adverse reactions. To overcome these acute and delayed adverse reactions, patients are pre-medicated. For example, the most notable toxicity seen with irinotecan is diarrhea, which is usually delayed. To overcome this, some patients will receive loperamide. Another example associated with irinotecan is its acute cholinergic syndrome, which can be treated with atropine. Overall, not all patients will be pre-medicated with the same regimens because there are patient-specific factors to account for prior to selecting treatments that mitigate and prevent adverse effects seen with these chemotherapeutic medications. The noticeable toxicities in topoisomerase I inhibitors are typically hematologic and gastrointestinal.

Common Monitoring Parameters

Patients receiving irinotecan or topotecan should undergo routine monitoring throughout therapy. Common monitoring parameters include:

• Complete blood count (CBC)
• Liver function tests
• Renal function
• Frequency and severity of diarrhea
• Signs and symptoms of infection
• Hydration status
• Performance status

Pharmacists play a critical role in educating patients and identifying toxicities early to improve outcomes and reduce treatment-related complications.

Emerging Developments in Topoisomerase I Inhibition

Research involving topoisomerase I inhibition continues to evolve. Several antibody-drug conjugates (ADCs), including trastuzumab deruxtecan and sacituzumab govitecan, utilize topoisomerase I inhibitor payloads to selectively deliver therapy to cancer cells. These newer therapies have expanded the role of topoisomerase I inhibition beyond traditional irinotecan and topotecan treatment approaches and represent an important area of growth in oncology.

Irinotecan and topotecan have been used for a long time. It is important to notice that even though these medications are in the same drug class, they are not interchangeable. These medications are utilized for many different cancer types, such as advanced colorectal, ovarian, and small-cell lung cancer. Overall, staying up to date with new findings and the most current literature is important to ensure that patients receive the best-individualized therapy.

Original Author: Dagmara Zajac

Editorial Update (June 2026): Elizabeth Rodriguez

RxPharmacist Team

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