Topotecan

This entry is part 1 of 1 in the series "NB Chemotherapy" --

WARNING: Science Content


As with all my posts, I try to include some thought provoking science, as well as interesting water cooler talk.  Good luck.
 

Topotecan

Prerequisite Reading

Some DNA Basics

DNA Replication and Torsional Strain


Introduction

Liam’s Rounds 1 and 2

The first chemotherapy drugs in Liam’s treatment were topotecan and cyclophosphamide. He received two five-day treatments with these drugs.  The first was during Aug 2014 and the second was in Sept. 2014 (separated by four weeks).

The drugs are given together for a combined treatment that offers a synergistic effect.  In his case, they proved to be very effective.  His cancer could not be found in a PET scan after just one round. (This doesn’t mean that his cancer wasn’t present, just that the much of the solid mass tumors were no longer taking up glucose … in other words – dead or dying.)

 Focus

Even though chemotherapy drugs are often given in pairs to give a compounded blow to the cancer, in these blog posts I will explain the mechanism of each drug individually so that it can be digested by the audience.

Fig 1. Topotecan

Topotecan

Topotecan is a topoisomerase I inhibitor which is derived from a plant called the Asian “Happy Tree” (Camptotheca acuminata).[1]  Topoisomerase I, discussed in a previous blog post,  is an enzyme that relieves torsional strain ahead of the advancing DNA replication fork. Without this torsional strain relief, the DNA is too strained to be able to separate into two strands.

A chemical mechanism for how topotecan inhibits topoisomerase I is proposed in the Proceedings of the National Academy of Sciences. [2]  The authors suggest that as the one side of the DNA is pulled apart by topoisomerase I, the topotecan molecule wedges (intercalates) between the +1 and −1 bases of the duplex DNA, and is further stabilized by six different protein contacts while the DNA is open. (Think of jamming a zipper, and then sewing the thing that is lodged in the zipper in place.)

Ribbon Diagram of regular Topoisomerase I breaking one side of the DNA

Fig 2 – Ribbon Diagram of regular Topoisomerase I breaking one side of the DNA, used by permission [3] PNAS, 99, 24, pp. 15387- 15392

The intercalation of topotecan causes a shift of the downstream bases by ~3.6 Angstroms (defining the displacement that this monkey wrench causes in the system). Figures 2 and 3 show ribbon diagrams of both the regular process and the process that is poisoned by topotecan.

Ribbon Diagram of Topoisomerase I with Topotecan interfering with the process.

Fig 3 – Ribbon diagram of topoisomerase I with topotecan interfering with the process, used by permission [4] PNAS, 99, 24, pp. 15387- 15392

An article in Nature [5] provides evidence that topisomerase I is inhibited (poisoned) more readily when the forming supercoil has a positive coiling direction. Topotecan has the effect of being a monkey wrench in the topoisomerase I process.

In slightly easier to understand terms, the topotecan is just the perfect shape with just the right bonding attachments to act like something getting stuck in a zipper.  Eventually, with enough vibrations and thrashing about, the topotecan will get unstuck, but cancer is impatient with the process and typically triggers the apoptosis alarm (cell death trigger) before it can work the topotecan out of the zipper.

License Number  3681730918315, 8/4/2015, NATURE PUBLISHING GROUP LICENSE

Fig 4 – Cover art that shows a good overall picture of the topotecan poisoning process. Reprinted and adapted by permission from Macmillan Publishers Ltd: Nature, 448, 213-217, copyright 2007

 

 

  1. http://chemocare.com/chemotherapy/drug-info/Topotecan.aspx 
  2. PNAS, 99, 24, pp. 15387- 15392 (26 Nov. 2002), “The mechanism of topoisomerase I poisoning by a camptothecin analog”PNAS Cover
  3.  Anyone may, without requesting permission, use original figures or tables published in PNAS for noncommercial and educational use (i.e., in a review article, in a book that is not for sale) provided that the original source and the applicable copyright notice are cited. http://www.pnas.org/site/aboutpnas/rightperm.xhtml
  4. See note 3
  5.  Nature 448, pp. 213-217 (12 July 2007), “Antitumour drugs impede DNA uncoiling by topoisomerase INature Artwork

DNA Replication and Torsional Strain

This entry is part 2 of 2 in the series "DNA" --

WARNING: Science Content


As with all my posts, I try to include some thought provoking science, as well as interesting water cooler talk.  Good luck.
 

A Schematic / Block Diagram

DNA_replication_en.svg

Many enzymes work together in the replication of DNA. The focus of this post will be on the topoisomerase enzymes and their function. In another upcoming post, I will introduce topoisomerase inhibitors. It is important to understand what is going on with these enzymes and how the topoisomerase enzymes work to relieve torsional strain during DNA replication.  

Torsional Strain

When DNA is at equilibrium and not under any torsional strain, one full rotation of the double helix contains 10.6 base pairs.  When it is replicated, the entire DNA strand has to be divided into two new strands. This separation introduces a significant amount of torsional strain in the DNA coil. (Think of that handset cord on your desk phone that is completely tangled up because of all of the rotations of the handset over time.) This process of DNA entanglement is called supercoiling.  The only way to relieve the strain is to break the DNA, pass a segment through, and put it back together.  The topoisomerase enzymes do just that. They relieve the mounting torsional strain before the strain becomes so great that the replication process is halted. Still confused? Take a look at this video.