Oncology-Topoisomerase Inhibitors

Oncology-Topoisomerase Inhibitors

I. Topoisomerases: The Basics

• Function: Topoisomerases are nuclear proteins crucial for managing DNA topology (shape and structure). They regulate DNA supercoiling, a process essential for replication, transcription, and recombination.
• Types: Eukaryotes possess two main types:
  • Topoisomerase I (Topo I): Cleaves and rejoins one strand of DNA, relaxing supercoils.
  • Topoisomerase II (Topo II): Cleaves both strands of DNA, allowing another DNA duplex to pass through the break.

II. Topoisomerase I Inhibitors

• Camptothecin (CPT) and Derivatives: CPT, derived from the Camptotheca acuminata tree, stabilizes the covalent complex between Topo I and DNA, preventing relegation and leading to DNA damage.
  • Limitations of CPT: High toxicity initially hindered its widespread use.
  • Licensed Derivatives: Irinotecan (CPT-11) and Topotecan are currently used clinically. They differ in administration schedules and toxicity profiles.
• Side Effects (common to both Irinotecan and Topotecan): Neutropenia, diarrhea (early or late onset), thrombocytopenia, anemia, alopecia, nausea, and vomiting.
• Clinical Pharmacology:
  • Absorption and Distribution: Both are administered intravenously (IV), and Topotecan can also be absorbed orally (30-50% bioavailability). Both distribute widely throughout the body, including the cerebrospinal fluid (CSF).
  • Metabolism and Excretion: Topotecan undergoes minimal metabolism and is primarily renally excreted. Its clearance is directly related to creatinine clearance. Irinotecan (CPT-11) is a prodrug; it's converted to the active form, SN-38, by carboxylesterases. SN-38 is eliminated via glucuronidation and biliary excretion. Liver dysfunction necessitates dose adjustments.

III. Topoisomerase II Inhibitors

• Etoposide and Teniposide: These drugs inhibit Topo II's ability to rejoin cleaved DNA, resulting in:
  • High levels of double-stranded DNA breaks.
  • Increased mutations.
  • Illegitimate recombination.
  • Apoptosis (programmed cell death).
• Pharmaceutical Properties: Poor water solubility necessitates formulation with excipients (e.g., polysorbate for etoposide, Cremophor EL for teniposide). Etoposide can be given orally or IV; teniposide is IV only.
• Clinical Use: Widely used in adult and pediatric cancers. Etoposide is more commonly used in first-line treatments, especially for small-cell lung cancer (SCLC) and germ cell tumors. Teniposide is not licensed in the UK.
• Toxicity: Similar toxicity profiles for both, including neutropenia, alopecia, mucositis, infusion-related blood pressure changes, and hypersensitivity reactions.
• Clinical Pharmacology:
  • Absorption: Etoposide absorption is non-linear, with reduced bioavailability at higher doses.
  • Protein Binding: Both are highly protein-bound; low albumin levels increase free drug concentration and toxicity.
  • Metabolism and Excretion: Both are extensively metabolized, with etoposide exhibiting faster elimination than teniposide. Etoposide clearance shows a linear relationship with creatinine clearance.

IV. Key Differences Summarized:

Feature	Topoisomerase I Inhibitors (e.g., Irinotecan, Topotecan)	Topoisomerase II Inhibitors (e.g., Etoposide, Teniposide)
Target Enzyme	Topoisomerase I	Topoisomerase II
Mechanism	Stabilizes Topo I-DNA complex, preventing relegation	Inhibits DNA relegation, causing double-stranded breaks
Key Side Effects	Neutropenia, Diarrhea	Neutropenia, Alopecia, Mucositis
Metabolism	Topotecan: Renal; Irinotecan: Hepatic (SN-38)	Extensive hepatic metabolism