Anticancer Topoisomerase Inhibitors

Topoisomerase inhibitors are important drugs used alongside other medicines in the treatment of a wide range of cancers. Here, we review the fundamental pharmacology – classes, indications, mechanism, side effects, and clinical factors – you need to know about anticancer topoisomerase inhibitors.

First, we need to ask: what are “topoisomerases?”

Topoisomerases are enzymes required for cell replication and growth. They break and rejoin DNA strands, helping in new cell formation. These enzymes control DNA structural changes by catalyzing the breakage and rejoining of the DNA phosphodiester backbone during the normal cell cycle. Topoisomerases also play a role in DNA replication, transcription, repair and chromatin assembly by forming a temporary single or doubled strand breaks in DNA.

There are two main kinds of topoisomerase enzyme: type I and type II.

Topoisomerase I breaks one strand of the DNA helix to relax the molecule ahead of the replication fork, hence decreasing torsional strain, while topoisomerase II breaks both strands of DNA and helps in the uncoiling phase. This let the strands pass through one another to control the supercoiling process. After cutting DNA strands, cell repair or replication takes place and the strands are coiled back.

Camptothecin was isolated from a Chinese tree and showed antileukemic activity by targeting topoisomerase I. Campthotecin and its derivates exert actions only on topoisomerase I, while podophyllotoxin derivatives target topoisomerase II. Topoisomerase I is extracted from the bark of Campthoteca accuminata tree. Topoisomerase II is extracted from podophyllotoxin present in American mayapple.

Classes and indications

Let’s now take a few moments to review these two drug classes in more detail – and what primary indications they are used to treat.

Topoisomerase I inhibitors

  • Irinotecan – colorectal cancer
  • Topotecan – acute myeloid leukemia, prostate cancer

Topoisomerase II inhibitors

  • Etoposide – small cell lung cancer, testicular cancer
  • Doxorubicin: acute myeloid leukemia, acute lymphoblastic leukemia, breast cancer, stomach cancer, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, neuroblastoma, soft and bone sarcoma, small cell lung cancer, Wilm’s tumor, thyroid cancer, bladder cancer
  • Mitoxantrone – prostate cancer, acute myeloid leukemia (mitoxantrone is also used in the treatment of relapsing multiple sclerosis)
  • Teniposide – acute lymphoblastic leukemia in children
  • Valrubicin – BCG-resistant bladder cancer (valrubicin)
  • Epirubicin – breast cancer
  • Daunorubicin – leukemia – both acute lymphocytic and non-lymphocytic
  • Idarubicin – acute myeloid leukemia

Mechanism of action

Topoisomerase inhibitors inhibit the action of enzymes called topoisomerases, enzymes responsible for cell growth.

These medicines kill cancerous cells by blocking the resealing step of DNA replication – interrupting the essential cellular processes of DNA replication, RNA transcription and DNA damage repair. Inducing DNA damage is a powerful means to induce apoptosis – or, programmed cell death.

Topoisomerase I inhibitors are S phase-specific drugs. Since topoisomerase relieves torsional strain in DNA, topoisomerase inhibitors bind to the enzyme-DNA complex and prevent religation of single-strand breaks.

Topoisomerase II inhibitors block cell division in the late S and G2 phases of the cell cycle – binding to the enzyme-DNA complex, making it susceptible to irreversible double-strand breaks.

Side effects

As potent anticancer drugs, topoisomerase inhibitors are associated with a wide range of potential side effects, some of which include:

  • Myelosuppression – neutropenia, anemia, thrombocytopenia, increased risk of both infections and septic shock
  • Interstitial lung disease – more common with topotecan
  • Alopecia – because they target newly dividing cells
  • Mucositis
  • Fatigue
  • Loss of appetite
  • Increased risk of other cancers – including leukemias

More specifically:

  • Etoposide and teniposide are associated with life-threatening arrhythmias and hypotension.
  • Irinotecan can cause severe diarrhea because of is anticholinesterase inhibitory activities.
  • Irinotecan is also linked to severe hepatotoxicity.
  • Epirubicin is associated with swelling, rapid weight gain (notably in the face and midsection), and dark urine.

Clinical considerations

When it comes to the clinical pharmacology of anticancer topoisomerase inhibitors, here are some key points to consider:

  • Doxorubicin has a black box warning for myocardial damage. Risk of cardiotoxicity increases if given with trastuzumab.
  • Risk of cardiotoxicity with anthracycline anticancer drugs is reduced if patients are co-administered dexrazoxane. Dexrazoxane is a derivative of EDTA and works to chelates iron and reduce the number of metal ions complexed with anthracycline and, from this, reducing the generation of cardiotoxic superoxide radicals.
  • Doxorubicin should be avoided with other anthracyclines because their combination can predispose patients to acute myelogenous leukemia and myelodysplastic syndrome.
  • Mitoxantrone can cause congestive heart failure, therefore it should be avoided in patients with established heart disease.
  • Epirubicin can cause severe heart failure, therefore it should be avoided in patients with prior myocardial events or established cardiovascular disease.
  • Doxorubicin is a potent vesicant, and can cause tissue necrosis.
  • Live vaccines should be avoided whilst taking these medicines as they increase the risk of severe infection.

That concludes our review of anticancer topoisomerase inhibitors; important medicines used alongside other drugs in the treatment of a wide range of cancers.

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