Anthracycline Side Effects - Mode of Action

How the anthracyclines cause heart damage – the biochemistry of it all. This post will probably take a few days as I try to get my head around it and then explain it in as simple terms as I can muster.

First off, there is no one mechanism, but it all involves “free radicals” that are widely bandied about in the media, conventional and the full range of complementary medicine as harmful. But what exactly is a free radical? Why is it harmful ? And why to the heart ? And why should anthracyclines contribute to this?

Free radicals

The two major free radicals are known as “superoxide” and “hydroxyl”. I´ll illustrate with the superoxide.

A normal oxygen molecule is constituted of two oxygen atoms and is thus chemically written as O2. Each oxygen atom has a nucleus and six electrons with one pair shared with another normal oxygen atom with six electrons to form a normal O2 molecule. In a superoxide molecule there is a seventh electron unpaired electron and an additional negatively charged elctron (in red in the diagram below). It cannot bind to with its oxygen atom electron neighbour so is “free”, to bind with whoever it likes.


So we have a promiscuous molecule.

The hydroxyl free radical is similar in concept.

They can be called Oxidants.

The superoxide free radical is deployed by the immune system to bind to and damage the DNA of invading micro-organisms, preventing them from replicating and thus finishing them off. But in the same way (see later) it can attack the DNA of the body´s own cells as can the hydroxyl free radicals.

I´ll come back to the free radicals later but will now move onto muscle … don´t we love them! We can walk, talk, run and … breathe because of muscle. Sexy biceps and thighs!


The Heart

There is an essential difference between leg, arm, cheek etc and heart muscle. The former react to stimulation from nerves (i.e. the nerve gives a tiny electric shock to the muscle which makes it move) whilst heart (or cardiac) muscles do it by themselves (more or less) without the help of nerves.

(see diagram below of normal muscle).

You can be totally paralysed with no signals from brain to nerves to muscles but your heart keeps working and you stay (miserably) alive!

However, heart muscle cells, in comparison with the other muscle cells, are distinctly lacking in protection from our promiscuous and aggressive free radicals. This protection is principally in the form of various enzymes – superoxide dismutase (happily known under the acronym SOD), catalase, glutathione peroxidase and glutathione reductase. Unfortunately, heart cells produce a lot less of these enzymes than regular muscle cells.

According to Wikipedia, an infected mouse with SOD production genetically inhibited, can die within 21 days of birth!

Enzymes

Nicotinamide adenine dinuclenotide (NADH) and Nicotinamide adenine dinuclenotide phosphate (NADHP) are enzymes produced in cells from Niacin (or Vitamin B3 – look at the ingredients of your multivitamins) with unique roles concerning energy production and DNA synthesis.

Part of the anthracycline accepts an electron from NADH or NADPH and becomes a free-radical which immediately passes that unpaired electron to molecular oxygen (O2) thus becoming the very harmful, free radical – superoxide.

To make itself more stable the free oxygen radical has to steal an electron from mitochondrial DNA (and I can see I will have to explain the difference between mitochondrial and nuclear DNA). Without that oxygen electron the DNA molecules are damaged and the cells cannot reproduce.

Eventually, this will lead to cell death and as the heart muscle cells don’t have much protection from free reductions.

Anti-oxidants

This is an easy bit. If the anthracycline-induced anti-oxidants or free radicals, are roaming around, then introduce something that acts faster to mop them up before they hit the mitochondrial DNA in heart muscle cells.

Unfortunately, it seems that naturally-produced anti-oxidants, such as vitamins A, C and E (present in foods, drinks and vitamin supplements), are not adequate to this task so stronger anti-oxidant drugs have been introduced.

However, that is but one mechanism by which anthracyclines can damage the heart … (to be continued).

I want to live longer than you ...

... I don't know how.

Fuck off Rob ... you got me onto this, and, yes, we need to go there.

Long term side effects

It seems that most of the long-term side effects are related to radiotherapy, particularly cranial, and bone marrow/stem sell transplants. We haven’t been there (and hopefully won’t) so I won’t talk about it. But if you want to research these side effects, I recommend you start at the Pediatric Oncology Resource Center (link right).

But what Kezia may or may not suffer from are heart problems caused by the anthracycline group of drugs – in her case daunorubicin and doxorubicin.

First, let’s look at the heart. Four chambers – the right atrium and ventricle, the left atrium and ventricle. Atriums on the top, ventricles on the bottom. The right side receives blood in the atrium. The blood is passed to the right ventricle which pushes it to the lungs to receive oxygen. The blood then passes to the left atrium and then the left ventricle which then pumps it back into the blood system.

The anthracyclines can effect the thickness of the wall of the left ventricle making it thinner (I’ll go into the exact process of how they do this another time – and I really don’t understand why just the left ventricle). Any decrease in the left ventricle’s wall of muscle will both decrease its strength and increase the volume of the ventricular chamber allowing more blood to enter.

Additionally, as one part of ventricular wall is the valve between the atrium and ventricle, the valve tissue will also become thinner. The pumping action of the left ventricle becomes weaker due to less muscle (reduced contractility) and more blood and cannot keep up with pumping rate of the right side. More blood is also left in the heart after each beat (increased afterload). The increased amount of afterload will cause the ventricle to dilate further and the atrium-ventricular valve will fail to close completely.This condition is known as cardiomyopathy.

If the blood cannot be pumped out of the left ventricle, it “backlogs” into the atrium, the small blood vessels of the lungs and finally the right side of the heart causing the typical symptoms of what is known as congestive heart failure.

These symptoms include shortness of beath, chest pain, increasing fatigue, swelling of the ankles and a dry cough.

Epidemiology and risk factors

Much debate here. But the following seem to be badly prognostic in no particular order: a cumulative dosage of anthracyclines above 300 mg/m2 of body surface area (Kezia has received 315 mg/m2), female sex (as they tend to have more fat and anthracyclines are not absorbed in body fat i.e. the anthracyclines will accumulate at higher concentrations in female compared to male muscle including the heart per unit of body surface area), younger age (the heart is growing)- Kezia was just 2 at diagnosis and glucocortisoid treatment as this increases body fat (Kezia is and will be taking dexamethasone until the end of her treatment).

Whether Kezia will develop heart problems has yet to be seen. Heart tissue damage can be instantaneous on administration of anthracyclines but the heart can also recover.

Monitoring

The principal tool for checking the heart is the echocardiogram – similar to the ultrasound of an unborn foetus but of the heart. By this they can measure the thickness of the left ventricle wall.

Our consultant has advised annual checkups until puberty but other medical papers I’ve read advise an annual echocardiogram for life (although they don’t really know as long-term monitoring of childhood cancer patients has only really just begun).

Treatment

If Kezia does develop cardiac problems, there are a host of drugs that can effectively be used as treatments/prophylaxes.

So although, hopefully, I won't live longer than Kezia, I hope I'll lve long enough to alert her and she'll be able to take care of herself.

P.S. Rob, I am sorry for swaering at you. You took me here and it's taken four weeks to get a grip on it, and I appreciate it. Best wishes to Norah, lauren and Fergus.

P.P.S Thanks Patty for the papers - readers, the Ped Onc Resource Center has an excellent page on this.

UKALL 2003 - Daunorubicin and Doxorubicin

These drugs belong to a family of medications called anthracyclines which act directly on cell DNA and prevent the cell from replicating.

Daunorubicin: this is administered during the first Induction phase. It binds to the DNA and intercalates with it i.e. it inserts a molecule of itself in between the DNA molecules. This distorts the DNA, messing with the way it functions and preventing it from replicating.

In the picture above normal DNA is shown on the left and DNA intercalated at three locations (in red) is shown on the right.

Doxorubicin: this is given in the two Delayed Intensification phases (4 and 6). It binds to the DNA and inhibits the enzyme which unwinds the DNA double helix to be read for copying. It stops the enzyme from resealing the double helix thereby stopping replication.

Both drugs are administered by IV drip.

One of the side-effects of both these drugs is feeling sick (nausea) and vomiting. For this the gluco-corticoid (a steroid), Dexamethasone, is given. As well as combatting the side-effect of nausea, Dexamethasone is also used as a first-line treatment drug in later maintenance phases. For this reason, I'll leave its discussion until a later post (as I'm still trying to get my head around how it works!).

Another side-effect of the anthracyclines is hair-loss. In young adults, this can be a major psychological issue (Lucia discusses it in her blog – link on right). However, although it has happened to Kezia, she has not yet developed the self-consciousness for it to be a problem. I think Nanda and I have been more effected – Kezia's hair was so beautiful! However, it will grow back!