DNA-interactive anticancer agents - Topoisomerase inhibitors

Question 1

How do Topoisomerase inhibitors work?

Answer 1

Topoisomerase inhibitors inhibit the enzymes responsible for winding and unwinding of DNA, hence inhibiting transcription and protein synthesis

Question 2

whats the difference between Topoisomerase I and Toposiomerase II

Answer 2

Topoisomerase I enzymes

Breaks only one strand of DNA and attaches the free phosphate residue of the broken strand to a tyrosine residue on the enzyme. Complex then rotates, relieving the supercoiled tension of DNA and two ends are resealed.

• Topoisomerase II enzymes*
• Cleaves both strands simultaneously, passing a complete duplex strand through the cut followed by resealing of both strands

Humans express two genetically distinct forms of Topo II known as Topo II-α and Topo II-β

Question 3

How do Topoisomerase I inhibitors work, give an example. How do you administer. Side effects etc

Answer 3

The drug binds to Topo I DNA complex which prevents re-ligation of strands leading to DNA single strand breaks and cell death

E.g Topotecan exhibits selectivity due to faster cell proliferation in tumor cells vs normal cells.

• Cell cycle specific – S phase
• IV: metastatic ovarian cancer (second line)
• Side effects:
• Dose limiting myelosuppression
• GI effects

Alopecia

Question 4

How do Topoisomerase II inhibitors work? gvie an example

Answer 4

E.g Etoposide Inhibits the ability of Topo II-α and Topo II-β to reseal the cleaved DNA duplexes leading to lethal strand breaks.

• Oral (double dose of IV)/ slow IV
• 3-5 days at intervals of 21 days
• Small cell carcinoma

Side effects:

• Alopecia
• Myelosuppression
• GI effects