A New Paper in Press: A review of genotoxic drugs and checkpoint adaptation

We have a new paper that is published as of today.  This paper reviews the scientific literature about a relatively new topic in cancer cell biology - checkpoint adaptation.  In a few words, checkpoint adaptation is mitosis with damaged DNA.  In this review, we describe how genotoxic cancer drugs, pharmacology, damaged DNA, are linked to checkpoint adaptation.  It is likely that the phenomenon of checkpoint adaptation is more frequent than had been previously reported.  It occurs when cancer cells are treated with pharmacological amounts of genotoxic cancer drugs.  In experiments, if one uses too much of a genotoxic compound (call a supra-pharmacological dose) cells die by other pathways, usually apoptosis.  If one uses too little, the cell repairs the damage.  But if one adds the amount that kills cancer cells without killing healthy cells (a pharmacological dose) then checkpoint adaptation occurs.  We found these "doses" in the scientific literature and report them in this review, to make it easier for others to use them in their experiments.  There are many other important facts brought together in this review.  To receive a copy either contact me, or the first author Lucy Swift, or click on this link:

Checkpoint Adaptation Review - Swift and Golsteyn

 The paper is open access, happy reading.

An image of human cancer cells taken with a microscope.  The rounded objects are cells that are undergoing checkpoint adaptation.  For scale, the bar is 25 um (0.025 mm).  

And the big paper is in press

Our manuscript is accepted in the Biochemical Journal.  It is a too brief moment of satisfaction of completing a project.  A special thanks to the experimentalists who succeeded in converting the complex problem of cell division with damaged DNA into a powerful experimental model. Of the cell lines we tested, HT-29 cells have features that provide a window of the key transition point of entry into mitosis after a checkpoint. 
What's next - we have developed a non-radioisotope assay to measure enzyme activity in mitotic cells; we are testing how to block checkpoint adaptation, and we are looking very closely at the DNA in cancer cells that survive checkpoint adaptation. 
If interested, please feel free to contact us for questions, reagents or a copy of the paper.

Science Education

February is shaping up to be education month.  Working in research has the additional benefit of highlighting areas of science education that need to be strengthened.  On 16 February I gave a lecture at the University of Calgary to students in the Cancer Biology course on the topic of Checkpoint Adaptation.  The textbook version states that cells with damaged DNA will die by apoptosis; everyone is surprised to learn that cells first enter mitosis and that some of these survive. 
This week I'm invited to participate in the Life Science Inspired Teaching Symposium in Toronto.  A leading Canadian science publisher is bringing scientists to the table to discuss the methods of teaching science.  One view is that students live is a noisy and distracting education world, we need to ensure that the science message gets their attention.  The month ends with another Checkpoint Adaptation lecture to the graduating biology class at the U of Lethbridge.  As usual, I will include a slide or two about Louis Pasteur. 

2012

A New Year
We had the pleasure of hosting a French stagiaire in the laboratory and we wish her luck with her studies back in France.  An undergraduate has moved onward to a co-op position after helping set up the video microscopy and winning 1st place in oral presentation of his work.  The video microscopy technique provided insight into the number of cells in population that undergo checkpoint adaptation.  The current team is now working on applying new techniques to measure enzyme activity and DNA damage in treated cancer cells so that we can predict better the mechanisms that drive checkpoint adaptation.

Mitosis or apoptosis (life or death)

Our laboratory has invested much time and effort in developing an experimental model of how human cells can divide even when they have damaged DNA.  The efforts are beginning to pay off.  Recently we found that when cells enter mitosis with damaged chromosomes, they can inactivate apoptosis.  Perhaps this should not be too surprising because mitosis should cause all the alarms to sound (loss of contact, changes in organelles, DNA everywhere).  The rub is to know if cancer cells use this as another mechanism to survive.  We are now examining the pathways that might provide survival.  A new area for us, which was illuminated by our model and a pharmacological approach.

New paper in press

We have a new paper in press in "Life Sciences".  This paper describes novel Chk1 inhibitors that are highly active in kinase assays and in cell-based assays.  We now use Chk1 inhibitors to modify the timing of "checkpoint adaptation."  The paper was a joint effort between the pharmaceutical company Servier Laboratories (France) and our own Mr Philip Kubara (his first paper).

How to see it? - go to the Pubmed website, type "golsteyn chk1" and the link will appear.

Any questions, please feel free to contact me.