WK3 - Cancer chemotherapy - Topoisomerase II

What is intercalation?

The drug slides between DNA base pairs (like sliding a coin between pages of a book). It physically distorts the DNA structure.

What is the main mechanism of anthracyclines (doxorubicin)?

They intercalate into DNA AND inhibit Topoisomerase II. This creates the "cleavable complex" – a permanent DNA break.

What is the cleavable complex?

A permanent complex made of DNA + drug + Topoisomerase II. Normally Topo II cuts DNA, passes another strand through, and reseals the cut. The drug traps Topo II after it cuts, so the DNA cannot be resealed.

Why does the cleavable complex kill cancer cells?

The trapped cleavable complex causes permanent double-strand DNA breaks. These breaks accumulate and trigger apoptosis (cell death).

What are the main anthracycline drugs?

Doxorubicin, Daunorubicin, Epirubicin, Idarubicin.

What is the main toxicity of anthracyclines and why?

Cardiotoxicity (heart damage). Occurs because the drug contains a quinone ring that undergoes redox cycling, producing reactive oxygen species (ROS). Heart cells have low levels of detoxifying enzymes.

What is the main mechanism of resistance to anthracyclines?

Increased expression of P-glycoprotein (P-gp). This is a drug efflux pump that pumps the drug out of the cell before it can work.

Which Topoisomerase II inhibitor is used for testicular and small cell lung cancer?

Etoposide (VP-16).

Which Topoisomerase II inhibitor causes blue urine?

Mitoxantrone.

What is the difference between Topoisomerase I and Topoisomerase II?

Topo I cuts ONE strand of DNA (single-strand breaks). Topo II cuts BOTH strands of DNA (double-strand breaks).

Which drug inhibits Topoisomerase I?

Camptothecin (and its derivatives like irinotecan, topotecan).

What is the difference between a Topo I inhibitor and a Topo II inhibitor in how they kill cells?

Both trap the enzyme after DNA cutting, preventing resealing. Topo I inhibitors cause single-strand breaks. Topo II inhibitors cause double-strand breaks.

What is the role of Topoisomerase II in normal cells?

It untangles knots in DNA during replication. It cuts both strands, passes another DNA segment through the break, then reseals the cut.

How does doxorubicin kill cancer cells (summary)?

1) Intercalates into DNA. 2) Inhibits Topoisomerase II. 3) Forms cleavable complex (DNA + drug + Topo II). 4) Causes permanent double-strand DNA breaks. 5) Apoptosis.

What is the quinone ring and why is it important?

A chemical structure in anthracyclines that undergoes redox cycling. It generates reactive oxygen species (ROS), which cause cardiotoxicity.

What is redox cycling?

The quinone ring accepts electrons to form semiquinone radicals. These radicals react with oxygen to produce superoxide and hydrogen peroxide (reactive oxygen species).

Why are heart cells especially sensitive to anthracycline toxicity?

Heart cells have low levels of detoxifying enzymes (like superoxide dismutase) that normally neutralise reactive oxygen species.

What is P-glycoprotein (P-gp)?

A drug efflux pump that transports chemotherapy drugs out of the cell. Overexpression of P-gp is a major resistance mechanism for anthracyclines.

What is the difference between doxorubicin and daunorubicin?

Doxorubicin has an OH group (more cardiotoxic). Daunorubicin has H instead of OH (less cardiotoxic, used mainly for leukaemia).

What is etoposide used for?

Testicular cancer and small cell lung cancer. It is a Topoisomerase II inhibitor (not an anthracycline).

Complete the sentence: "The cleavable complex is made of DNA + drug + ___________ .",Topoisomerase II

What is the difference between intercalation and crosslinking?

Intercalation = drug slides between DNA bases (reversible). Crosslinking = drug forms covalent bonds connecting DNA strands (irreversible).