Tyrosine kinase inhibitors and topoisomerase inhibitors

 

Tyrosine Kinase Inhibitors (TKIs)

Tyrosine kinases are enzymes that catalyze the phosphorylation of tyrosine residues in proteins, which is crucial for signaling pathways that regulate cell division, growth, and survival. In many cancers, these enzymes are overactive, leading to uncontrolled cell proliferation.

Tyrosine kinase inhibitors (TKIs) are a class of targeted cancer therapies that block the activity of tyrosine kinases, thereby interfering with these signaling pathways and inhibiting cancer cell growth.

• Mechanism of action: TKIs bind to the ATP-binding site of the tyrosine kinase enzyme, preventing ATP from phosphorylating its substrate. This inhibition disrupts the signaling pathway essential for tumor cell proliferation.

• Examples:

  • Imatinib: Used in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST), it targets the BCR-ABL fusion protein.
  • Erlotinib and Gefitinib: Target the epidermal growth factor receptor (EGFR), often overexpressed in non-small cell lung cancer (NSCLC).
  • Sunitinib and Sorafenib: Multi-targeted TKIs used in renal cell carcinoma and hepatocellular carcinoma.

• Side effects: Include fatigue, diarrhea, skin rashes, and liver toxicity, though these vary depending on the specific TKI.

Topoisomerase Inhibitors

Topoisomerases are enzymes involved in the winding and unwinding of DNA, which is essential during DNA replication and transcription. There are two types:

• Topoisomerase I: Relieves torsional stress by making single-strand breaks in the DNA.
• Topoisomerase II: Creates double-strand breaks to manage DNA supercoiling and untangling.

Topoisomerase inhibitors interfere with the ability of topoisomerases to repair these breaks, leading to DNA damage and ultimately cell death, making them effective in cancer treatment.

• Mechanism of action:

  • Topoisomerase I inhibitors: Stabilize the complex formed between DNA and topoisomerase I, preventing the re-ligation of single-strand breaks. Example: Irinotecan and Topotecan, used in colorectal and ovarian cancers.
  • Topoisomerase II inhibitors: Trap the topoisomerase II-DNA complex in a way that prevents re-ligation of double-strand breaks, leading to cytotoxicity. Example: Etoposide and Doxorubicin, used in various solid tumors and hematologic cancers.

• Side effects: Myelosuppression (reduced bone marrow activity), gastrointestinal issues, hair loss, and risk of secondary malignancies like leukemia with prolonged use.

Both TKIs and topoisomerase inhibitors are critical in cancer therapy, each targeting different mechanisms involved in cell growth and survival.