15 replies to this topic

[tiredblood]

I understand that TKIs affect rapidly dividing cells, but exactly what is it doing to the rapidly dividing cells.

 

If I had to guess from my own symptoms, I'd say shrinkage.  Not as in the Seinfeld show shrinkage. :-P

[scuba]

When a CML cell divides (any cell for that matter) a lot of energy is needed to conduct the process. ATP is the energy molecule (adenosine triphosphate) cells need to do this.

 

CML cells, therefore, have ATP binding sites so energy can be provided to conduct cell division (as well  as other cellular functions). TKI's are designed to bind to this site and prevent ATP from binding to the location. The result is cellular division is first interrupted and then apoptosis (cell death) takes place because the CML cell itself recognizes a problem. The cell dies. The exciting breakthrough is that the CML cell ATP pockets are unique in shape - different than normal blood cells - and so a TKI can be designed to fit only that pocket and not any other. This is why TKI's are not chemo. TKI's only fit the ATP pocket of CML cells. Mostly. It's not perfect which is why we have side effects. 

 

Also - when a CML cell is not dividing (stem cell level and other levels), those cells are not affected by the TKI. The ATP binding site is not being used, so the TKI has impact. This is why we have to continue taking our TKI's every day for years. Over time, these quiescent cells divide and a TKI is present to prevent ATP from binding. 

 

CML cells don't shrink. CML cells either lie dormant (quiescent), rapidly divide, or die. When they try to rapidly divide, the TKI binds to their ATP site and stops the division; the CML is unable to cope with no energy and dies. 

[Trey]

The issue is that TKI drugs do not only fit the BCR-ABL ATP binding site in leukemic blood cells.  They also bind to the growth control kinases in other cells where we would prefer they would not, and inhibit "off-target" kinases other than BCR-ABL.  These off-target kinases such as c-Kit, PDGFR, etc, control the growth of such things as skin cells, hair follicles, soft tissues in the mouth, and so on.  Many of the off-target cell functions are in rapidly dividing cells, but not exclusively.  So TKI drugs can alter the growth of other cells beyond just leukemic blood cells. 

[scuba]

The issue is that TKI drugs do not only fit the BCR-ABL ATP binding site in leukemic blood cells.  They also bind to the growth control kinases in other cells where we would prefer they would not, and inhibit "off-target" kinases other than BCR-ABL.  These off-target kinases such as c-Kit, PDGFR, etc, control the growth of such things as skin cells, hair follicles, soft tissues in the mouth, and so on.  Many of the off-target cell functions are in rapidly dividing cells, but not exclusively.  So TKI drugs can alter the growth of other cells beyond just leukemic blood cells. 

 

They do not fit other binding sites anywhere near as well. If they did, then we would have a lot of problems with other tissues. Not just minor side effects we can live with. In fact, TKI's cause these other cells to select against the sub-population that are susceptible and that is why we tend to overcome most side effects with time. And it is ONLY in rapidly dividing cells that this occurs. When a cell is not dividing it is not susceptible.

[August1]

So I had a question on this as well. 

If the TKIs do affect c-Kit, PDGFR, etc., to some degree, does that put us at higher risk for problems or malignancies associated with those cells? For example a lot of us complain of rashes, mouth sores, GI issues which are caused by TKIs. By interfering with the growth of those cells, even to a small degree, does that also increase the risk for bigger problems? Is there any information out there to say, definitively, one way or the other?

 

Take care,

[scuba]

So I had a question on this as well. 

If the TKIs do affect c-Kit, PDGFR, etc., to some degree, does that put us at higher risk for problems or malignancies associated with those cells? For example a lot of us complain of rashes, mouth sores, GI issues which are caused by TKIs. By interfering with the growth of those cells, even to a small degree, does that also increase the risk for bigger problems? Is there any information out there to say, definitively, one way or the other?

 

Take care,

 

No one knows - but probably not. TKI's are toxic foreign chemicals to the body and are treated as such by the liver. Cell death is the result as opposed to DNA mutation. 

 

An interesting side note:

 

http://annonc.oxford...18/10/1750.full

 

A patient tried suicide by Gleevec by taking 6.4 grams (6400 mg) of Gleevec at one time. It did not kill her, but she was very uncomfortable. They reported that 6400 mg is not a lethal dose. I suppose that's good to know.

[hannibellemo]

That's one of the more expensive ways to kill yourself that I have heard of! 

[Trey]

A good example of how Gleevec targets other kinases beyond just BCR-ABL is the kinase c-Kit where Gleevec binds strongly.  That is why it is used to treat c-Kit related gastrointestinal stromal tumors (GIST).  But it is also why we have so many side effects such as muscle cramps (not rapidly dividing cells, just dividing ones).  PDGFR is another kinase which Gleevec targets fairly strongly, which is why Gleevec can also be used to treat CEL leukemia where PDGFR is the culprit.  But again, this is an off-target kinase for CML patients, so it induces side effects. 

 

Other TKI drugs like Sprycel cannot treat GIST and CEL leukemia because they do not bind c-Kit and PDGFR as strongly, but it does bind to SRC related kinases which Gleevec does not.  The SRC kinase inhibition causes pleural effusion and other side effects.  The SRC inhibition also allows Sprycel to be used to treat some solid tumors.  So the degree to which the various TKI drugs target and bind to these off-target kinases causes variations in the side effects profiles for each drug.

 

These off-target kinase inhibitions are not the type of issues which cause secondary cancers, just discomfort.  In fact, they allow the CML drugs to be used to treat several non-CML cancers.

 

http://www.gistsuppo...ist/gleevec.php

 

http://www.ncbi.nlm....pubmed/14757533

 

By the way, a cell does not need to be dividing to be susceptible to TKI drugs. 

[MACELPatient]

A good example of how Gleevec targets other kinases beyond just BCR-ABL is the kinase c-Kit where Gleevec binds strongly.  That is why it is used to treat c-Kit related gastrointestinal stromal tumors (GIST).  But it is also why we have so many side effects such as muscle cramps (not rapidly dividing cells, just dividing ones).  PDGFR is another kinase which Gleevec targets fairly strongly, which is why Gleevec can also be used to treat CEL leukemia where PDGFR is the culprit.  But again, this is an off-target kinase for CML patients, so it induces side effects. 

 

Other TKI drugs like Sprycel cannot treat GIST and CEL leukemia because they do not bind c-Kit and PDGFR as strongly, but it does bind to SRC related kinases which Gleevec does not.  The SRC kinase inhibition causes pleural effusion and other side effects.  The SRC inhibition also allows Sprycel to be used to treat some solid tumors.  So the degree to which the various TKI drugs target and bind to these off-target kinases causes variations in the side effects profiles for each drug.

 

These off-target kinase inhibitions are not the type of issues which cause secondary cancers, just discomfort.  In fact, they allow the CML drugs to be used to treat several non-CML cancers.

 

http://www.gistsuppo...ist/gleevec.php

 

http://www.ncbi.nlm....pubmed/14757533

 

By the way, a cell does not need to be dividing to be susceptible to TKI drugs. 

 

You rang?

I've been lucky that I have not had anywhere close to the side effects as some of you around here with CML.  On a rare occasion I will get a muscle cramp.  I get some edema around the eyes and I also have GI issues.

 

As far as I know there are other Inhibitors that are available to me if Gleevec were to ever fail.  It's been a while since I've looked into them.  Doing a couple months on 300mg now and hopefully come mid-August another drop down to 200mg.  I'm concerned about the long term effects of these TKIs in our bodies.

[Trey]

Good to hear Gleevec is still controlling your CEL leukemia well.  The CML TKI drugs Sprycel and Ponatinib also inhibit PDGFR strongly enough to treat the form of CEL you have, so you have options available.

 

http://www.ncbi.nlm....pubmed/21821988

http://www.ncbi.nlm....pubmed/24407160

[tiredblood]

The issue is that TKI drugs do not only fit the BCR-ABL ATP binding site in leukemic blood cells.  They also bind to the growth control kinases in other cells where we would prefer they would not, and inhibit "off-target" kinases other than BCR-ABL.  These off-target kinases such as c-Kit, PDGFR, etc, control the growth of such things as skin cells, hair follicles, soft tissues in the mouth, and so on.  Many of the off-target cell functions are in rapidly dividing cells, but not exclusively.  So TKI drugs can alter the growth of other cells beyond just leukemic blood cells. 

Thanks, Trey.   I should have been more specific in my original post that I was speaking of cells other than the leukemic cells.

 

More specifically, I'm curious as to how the C-Kit, PDGFR, etc. affect/alter the growth of such cells such as skin and hair follicle cells, etc.

[Trey]

First a little about tyrosine kinases which TKI drugs inhibit.  Tyrosine kinases are signalling enzymes in all types of cells in the body.  In blood cells the ABL tyrosine kinase controls cell proliferation in an orderly manner.  When it becomes the BCR-ABL combination (CML leukemic cells) the ABL is stuck in the "on" position, meaning the cell is told to continually divide instead of dividing only occasionally.  So it is a cancer.  Our CML TKI drugs inhibit the BCR-ABL by turning it off, so the cell does not divide.  It often becomes confused and dies.

 

When we ingest a TKI drug it goes throughout the blood and most tissues.  Because no TKI drug is perfectly targeted (i.e., just for BCR-ABL) certain other tyrosine kinases mistake the drug for their own signal component and they attach to it.  This is because of molecular similarity to the enzyme they were looking for.  Sometimes the affinity is strong, and other times it is weak.  Depending on what tissue is involved, and the strength of the affinity, the TKI drug can cause the cell to alter its actions, possibly not divide, or possibly do something else weird such as make hair curly.  Not a lot is known about these off-target kinase inhibitions except that patients report them as a problem, and therefore they are called side effects. 

 

When you ask: "I'm curious as to how the c-Kit, PDGFR, etc. affect/alter the growth of such cells such as skin and hair follicle cells, etc." let me clarify that the c-Kit, PDGFR, etc are normal human cellular enzymes which signal cells to accomplish certain normal tasks.  But when they mistake the TKI drug as a signal component and attach to it, this can alter their intended purposes and send mixed signals, or refuse to send signals, or whatever.  The result can be changes in the cells they send signals to. 

 

Drug companies doubted that TKI drugs would work, and Gleevec was almost not put into clinical trials because most people thought it would shut down off-target kinases in such a way that would seriously harm the patient.  To the surprise of most people, that did not happen.  But all TKI drugs inhibit more than just BCR-ABL, and they are all different.  This allows for some amount of selection of side effects.

 

https://en.wikipedia...Tyrosine_kinase

[kat73]

Trey, something I've wondered about for so long:  Many times you have spoken about side effects lessening with time as the body adapts.  I don't understand the mechanism of that adaptation.  If the cells find a way to fulfill their function by a work-around the TKI's, then wouldn't leukemic cells logically be able to do the same?  And yet they don't - the TKI hits 'em, messes with their ability to keep turned on, and they die or (I love it) get "confused."  Can you enlighten us as to HOW the body adapts over time and side effects lessen, without a similar compromise happening in leukemic cells? 

[scuba]

Trey wrote, 

"Our CML TKI drugs inhibit the BCR-ABL by turning it off, so the cell does not divide.  It often becomes confused and dies."

 

This is not true. TKI drugs do not turn off bcr-abl cells. What they do is bind to the ATP pocket in the bcr-abl cells that prevents the cell from getting the energy it needs to divide and it dies as a result. It doesn't get "confused" - it doesn't have a brain. It dies from lack of energy. Once a cell is committed to the G1 phase (cell division) - it needs a lot of energy for the requisite biosynthesis. This is why rapidly dividing cells die off when starved of ATP. When a cell is quiescent (non-dividing) its energy requirements are MUCH lower and it can get energy from alternate non-ATP pathways. CML stem cells survive TKI's because in the quiescent phase they don't need ATP - but when they do divide they too get nailed by a TKI.

[Trey]

Kat,

The body adapts and finds alternate ways.  I would use an analogy to explain, but have just been told above they are not precise enough for some people who would prefer I write a book to answer every posting simply to satisfy those who disdain analogies.

 

Silliness aside, the fact is many side effects do lessen in intensity or go away over time.  That is a happy fact for which we are grateful.

[DebDoodah22]

I hope one of the subsiders is brain fog or at least fatigue.