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Inhibitors of topoisomerases as anticancer drugs: problems and prospects

B S Dwarakanath1, Divya Khaitan, Rohit Mathur

  • 1Institute of Nuclear Medicine and Allied Sciences, Brig S K Mazumdar Marg, Delhi 110054, India. bsd@inmas.org

Indian Journal of Experimental Biology
|September 2, 2004
PubMed

Insights

DNA topoisomerase inhibitors are vital anticancer drugs, but tumor resistance and normal tissue toxicity limit their use. This review explores strategies to enhance the efficacy of these crucial topoisomerase-targeting therapies.

Area of Science:

  • Molecular Biology
  • Pharmacology
  • Oncology

Background:

  • DNA topoisomerases are essential enzymes that manage DNA topology during cellular processes.
  • Topoisomerase poisons, such as camptothecin (Topoisomerase I inhibitor) and etoposide (Topoisomerase II inhibitor), are established anticancer agents used in treating leukemias.
  • Current limitations include tumor resistance and off-target cytotoxicity, hindering their broader therapeutic application.

Purpose of the Study:

  • To review the mechanisms underlying cytotoxicity development in topoisomerase poison-based anticancer drugs.
  • To outline strategies for overcoming resistance and normal tissue toxicity associated with these therapies.
  • To enhance the clinical efficacy of topoisomerase inhibitors for cancer treatment.

Main Methods:

  • Literature review of existing research on DNA topoisomerases and their inhibitors.
  • Analysis of mechanisms driving tumor resistance to topoisomerase poisons.
  • Exploration of novel approaches to mitigate non-specific tissue cytotoxicity.

Main Results:

  • Identified key pathways contributing to resistance against camptothecin and etoposide.
  • Highlighted strategies such as drug delivery systems and combination therapies to improve efficacy.
  • Discussed methods to reduce off-target effects, enhancing the therapeutic window.

Conclusions:

  • Topoisomerase inhibitors remain promising anticancer agents, particularly for leukemia.
  • Overcoming drug resistance and reducing cytotoxicity are critical for successful therapeutic development.
  • Further research into novel strategies is essential to maximize the clinical benefit of these drugs.

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