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

mIBG – We are back on!

This entry is part 3 of 3 in the series "Radiation" --

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.
 
MetaIodoBenzylGuanidine

MetaIodoBenzylGuanidine


[Prologue]

For those avid followers of all of the science that I have introduced during all of this, you will recognize that this post is a rehash, but an exciting rehash.

Early on, Liam was initially slated to participate in a mIBG (MetaIodoBenzylGuanidine) trial.  The trial wasn’t supposed to happen until after the induction period of chemotherapy.  The catch is that only 80-85% of neuroblastomas absorb mIBG.  This is why fairly soon after diagnoses, while there is still a lot of cancer in concentrated pockets throughout the body, an mIBG scan is given to see if the particular variety of neuroblastoma picks it up. This is done with [123]- mIBG (see below.)

When this scan was performed on Liam back in September, there had been problems and the scan was not performed right away.  The doctors and hospital staff were having difficulty stabilizing Liam.  In fact, that first session in the hospital lasted over 21 days.  He had been started on  a fantastic chemotherapy drug called Topotecan (which is a TopoIsomerase I inhibitor that is so darn cool, it deserves its own post and I will not discuss it here.)  The problem was that Liam was spiraling out of control while he was on it. He started having trouble breathing, and he ended up with a plural effusion (yep… that was a bad couple of days. Click here for the post from that day).  After all was said and done, the mIBG scan was pushed off until he was admitted for chemo round 2.

When the [123] mIBG scan was finally performed, it came back negative. We were bummed, but the chemo seemed to be going so well that we really didn’t give it much thought. Liam was feeling better.

After 6 rounds of chemotherapy, a follow up PET scan was performed. No cancer showed up on the scan. He had a remarkable response, and we thought we were doing pretty well.  In reviewing all that had happened over the course of 6 rounds of chemo, I wondered if most of the cancer had vanished just after the first round of chemotherapy.  If it did, it would have skewed the mIBG test to a negative result.

Looking back at the sudden improvement after round 1- the plural effusion (now believed to be caused by cancer dying his lungs) and all of the immediate weight loss (now believed to be the cancer dying in his abdomen)…. he looked normal for the first time in months; I contend that the Topotecan chemotherapy made most of the cancer disappear quickly.  His response even astonished his doctors.

Now that the cancer has come back,  it was suggested by the doctors at CookChildren’s that we look one more time at the mIBG.  So, we did, and it gave a positive response to mIBG.  It can clearly be seen in the left tibia and the pelvis.

mIBG Liam 24July2015

123-mIBG Scan of Liam on 24July2015. His neuroblastoma has soaked up the mIBG compound, and due to its radioactivity is exposing the film. His trouble spots in his left leg and pelvis can clearly be seen.

So what does this mean? It means that we now have a really awesome tool in our tool chest to fight this. It won’t cure the neuroblastoma, but hopefully we can knock it down and coupled with other therapies, we can get this disease under control for Liam.  This is an option that a week ago we did not have.

[End of Prologue]

So, how does it work? It turns out that Neuroblastoma has a strong affinity for mIBG in about 85% of cases.[1] In a very high percentage, the Neuroblastoma cells will take this compound up while the normal cells will not. This is called ‘selectivity’. (i.e. the Neuroblastoma soaks this compound up selectively over normal cells).  mIBG in itself, however, doesn’t do anything. It is taken into the cell, and then is excreted from the cell at a later time.  This means that the Neuroblastoma cells are not sensitive to the compound. 

A clever and ingenious pupil of chemistry can already see what to do next.  Swapping out the Iodine atom on this compound with the radioactive version  makes this molecule very useful.


[123]-Iodine

123 Iodine will decay by electron capture to form 123 Tellurium which will then emit a Gamma ray with an energy of 159 keV. This is useful for imaging.  This is like having an x-ray performed, but rather than having an x-ray source shining high energy light through Liam, the light will be generated inside him!  Since this radioactive atom is attached to a compound which is only selective to Neuroblastoma, Gamma rays (like x-rays) will be generated only at the Neuroblastoma sites.  With the correct detector, the Neuroblastoma will light up like a Christmas tree.


[131]-Iodine

If 131 Iodine is used, different results will be observed.  131 Iodine decays in the follow two manners (statistically a 90% Beta(-) Decay and a 10% Gamma decay):

(Beta(-) Decay ~90%) {^{131}_{53}\mathrm{I}} \rightarrow \beta + \bar{\nu_e} + {^{131}_{54}\mathrm{Xe}^*}  + 606 keV 

(Gamma Decay ~10%) {^{131}_{54}\mathrm{Xe}^*}  \rightarrow {^{131}_{54}\mathrm{Xe}} + \gamma  + 364 keV

The Beta(-) decay produces a very energetic electron and an Antineutrino which have a tissue penetration of about 0.6 to 2 mm. This is enough energy to destroy cells. (i.e. a cell sized atomic bomb) So in essence, this gives a pathway for the mIBG, which is very selective to the Neuroblastoma, to blow up the cells (and leave the good cells alone).


This mIBG scan that was performed today only involved 123 Iodine for gamma ray imaging (see above images). This indicates all of the places that the Neuroblastoma is, with a few exceptions. There are false readings in some of the places like the thyroid (which regulates Iodine containing compounds).    In the coming weeks, it’ll be time to bring out the [131] Iodine and give this cancer the radioactive punch it deserves.

  1. According to NationWideChildrens.org “…Roughly 80-85% of neuroblastomas will absorb MIBG. There are really 2 ways in which MIBG treatment is used. In both methods, the MIBG chemical is attached to an iodine molecule that has been made radioactive. The radioactivity can be either a low-dose or a high-dose…. ”

The PET Scan, a Chemist’s View

This entry is part 2 of 3 in the series "Radiation" --

Liam had a Positron Emission Tomography (PET) scan on 19Sept2014. For this the radioactive tracer is Fludeoxyglucose (18F) or (18F-FDG) for short. For those of you crazy chemistry people out there (like Jenn and myself), check this out:

a)Fludeoxyglucose b) β+ Decay of a proton emits a positron (and changes Fluorine to Oxygen); Since a positron is the antimatter equivalent of an electron, when it finds the closest electron it will annihilate. The matter will cease to exist, and it will turn into energy in the form of light (gamma rays). The two gamma rays produced each will have 511 keV of energy. c) With a little acid, the product will be glucose and continue through the energy cycle in the cell. Until the radioactive decay, the molecule is stuck. There is no chemistry available to the cell to process the glucose with substituted Fluorine, once the F gets converted to a hydroxyl, the chemistry can proceed as normal (With a heavy, but stable Oxygen atom)

The 18F-FDG looks just like the glucose molecule except for a heavy fluorine in place of the  2′ hydroxyl group.  Since all cells use glucose as a power source, the PET scan exploits the fact that cancer cells require more energy, and they will take up more of the compound than normal cells. The areas of the body emitting large amounts of gamma radiation are likely to have concentrations of cancer cells.

For those of you (and I know who you are) who would like even more information, here are some links that I found helpful when I was coming up to speed on the technique:

Fludeoxyglucose (18F)

Positron Emmision Tomography

A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications (scroll down to figure 13)

Decay scheme of 18F