Chemotherapy and heart disease risk.
Jacob Schor, ND
October 10, 2007
Lauran Neergaard, an Associated Press medical writer, wrote an article a few days back, “Chemotherapy boosts heart disease risk.” which was published in papers all over the country. Numerous people have emailed asking about it.
Here's a link to it: http://news.yahoo.com/s/ap/20071008/ap_on_he_me/healthbeat_breast___heart
My initial reaction was, ‘So, what else in new?' Actually this an interesting turn of events. Before delving into the details of Lauran's article, let me give you some background.
The article is about anthracyclines, a class of chemotherapy drugs. This class of drugs include doxorubicin (Adriamycin) and daunorubicin. These drugs are naturally produced by a fungus called Streptomyces . There are several derivatives synthesized from these starter drugs including epirubicin and idarubicin. Though the article focused on breast cancer, oncologists prescribe these drugs for a range of cancers including leukemia, lymphoma, carcinomas and sarcomas. These drugs are also the foundation of most breast cancer treatment protocols.
All of the anthracyclines drugs cause dose dependent cardiac toxicity. Too much drug and you poison the heart. These drugs cause both acute and chronic cardiotoxicity. Acute poisoning occurs in the first 24 hours and can be seen almost immediately on EKG. These acute changes usually go away. Chronic cardiotoxicity is a much greater concern. Patients develop irreversible damage and congestive heart failure that does not respond to conventional drug treatments. Doxorubicin, the most commonly used of the anthracyclines, is also the most toxic.
Damage to the heart may not be noticeable immediately. Cardiomyopathy can show up in the first month after chemo or any time up to six or months later. There have been reports of delayed toxicity up to 20 years after therapy. Cardiac cells do not grow and divide, though their organelles do regenerate over time.
The earliest and most prominent sign of anthracycline cardiotoxicity is damage to the mitochondria inside the heart cells. This damage only occurs in the heart mitochondria and not in the mitochondria of other tissues. Though the AP story title makes the link between these drugs sound like a new discovery, the process is well understood.
Anthracycline cardiotoxicity is due to oxidative stress from the generation of reactive oxygen species (ROS) like hydrogen peroxide. These ROS chemicals generate lipid peroxides, or in simpler words, make fats in the tissues go rancid. This is why these drugs are good at killing cancer cells. Anthracycline induced oxidative stress is ten times higher in the heart than in other tissue. Why the heart?
The mitochondria inside heart cells are built differently than mitochondria in other cells. There is not a simple way to say this. Cardiac mitochondria have an NADH dehydrogenase enzyme on the outer surface of their inner membranes along with another copy of this enzyme facing the inner matrix. In the mitochondria of cells other than cardiac cells, the anthracyclines cannot get all the way in to the inner core of the mitochondria. These drugs are hydrophilic, water loving, and they move across the inner mitochondrial membranes which are made of fat. In mitochondria of cardiac cells, this enzyme, NADH dehydrogenase, makes anthracycline cardiotoxic. This enzyme reduces anthracyclines to its semiquinone that self oxidizes to dihydroquinone (note: if I've lost you, don't worry, it will make sense in a second) which then forms a doxorubicin aglycone. These aglycones are lipophilic and can easily move across the inner membrane to the inside of the organelle.
These aglycones knock a chemical called coenzyme Q-10 off the inner membrane where it normally acts as an antioxidant. Now it starts getting complicated. Let me skip to the end of the story. When the Co Q-10 gets displaced in the cardiac mitochondria, the anthracycline metabolites go to work injuring the inside of the mitochondria through oxidative damage. Remember that mitochondria are almost separate entities living with in our cells. They have their own DNA, passed down from your mother. The cardiac mitochondria cannot keep up with the DNA damage caused by the drug metabolites.
Co Q (ubiquinone) is part of the energy generating systems of all animals, plants, and most aerobic organisms. The number “10” refers to the number of isoprene units attached. Most mammals have 10 units, thus we usually call ubiquinone, Co Q-10. The concentration of Co Q-10 in the heart is 5 times that of the liver and 10 tines that of the kidney, pancreas and spleen. [i]
It turns out that administering Co Q-10 prior to treatment with anthracyclines prevents the damage to cardiac mitochondria. Giving Co Q-10 after chemotherapy does not reverse the damage. These anthracycline drugs create irreversible damage to the cardiac mitochondria. In rat experiments, administering moderate doses of Co Q-10 for several days prior to doxorubicin administration delayed death from heart failure. In rabbit experiments, doxorubicin causes similar heart damage as in humans. Giving the bunnies Co Q-10 before the chemo, protected their hearts from damage.
In humans with lung cancer being treated with doxorubicin, Co Q-10 started a few days prior, appeared quite protective against cardiac toxicity.
There are a number of studies along this vein, but I'm getting distracted here. Suffice to say, the mitochondria inside cardiac cells are built differently and this makes them more susceptible to damage from anthracycline drugs. Co Q-10, a chemical that normally is protective, is inactivated by the drugs. Supplemental Co Q-10 appears protective. L-carnitine may be even more protective. [ii] Some research suggests using both Co Q-10 and carnitine combined. [iii]
Now back to this week's AP story.
Dennis Slamon from UCLA has taken a controversial position saying that anthracyclines are only useful in women with breast cancer that are Her-2 positive. These women account for only about one fifth of all breast cancer cases. Slamon gets even more specific saying that only Her-2 positive women with an overactive Topo-II gene will benefit from taking anthracyclines. Only about 8 percent of breast cancer patients have this particular hand of cards.
If these drugs are really only effective for 8% of breast cancers, why give them to the other 92%? Especially when we know how toxic they are. Estimates put cardiac toxicity at anywhere between 10-50% of people who are treated with these drugs.
There is a good reason why Neergaard's article is creating a stir. The rest of the article is devoted to quotes from various authorities, saying the standard lines, like “not enough data yet.” Still, this information may change the way many of us look at using anthracyclines and researchers will be looking for tests to predict the efficacy of using these drugs in other cancers. This is all good and is moving the practice of oncology forward, though Neegaard found a few practitioners to quote in her article that are not eager to change the way they see things.
Her-2 positive women should still use doxorubicin and take co Q-10 and carnitine along with it. For the majority of women with breast cancer who are not Her-2 positive, other chemotherapy drugs may be more appropriate and not come with the risk.
Coenzyme q10 for prevention of anthracycline-induced cardiotoxicity.
Jonsson Comprehensive Cancer Center , David Geffen School of Medicine, University of California , Los Angeles , CA 90095-1778 , USA . firstname.lastname@example.org
Preclinical and clinical studies suggest that anthracycline-induced cardiotoxicity can be prevented by administering coenzyme Q10 during cancer chemotherapy that includes drugs such as doxorubicin and daunorubicin. Studies further suggest that coenzyme Q10 does not interfere with the antineoplastic action of anthracyclines and might even enhance their anticancer effects. Preventing cardiotoxicity might allow for escalation of the anthracycline dose, which would further enhance the anticancer effects. Based on clinical investigation, although limited, a cumulative dose of doxorubicin of up to 900 mg/m2, and possibly higher, can be administered safely during chemotherapy as long as coenzyme Q10 is administered concurrently. The etiology of the dose-limiting cardiomyopathy that is induced by anthracyclines can be explained by irreversible damage to heart cell mitochondria, which differ from mitochondria of other cells in that they possess a unique enzyme on the inner mitochondrial membrane. This enzyme reduces anthracyclines to their semiquinones, resulting in severe oxidative stress, disruption of mitochondrial energetics, and irreversible damage to mitochondrial DNA. Damage to mitochondrial DNA blocks the regenerative capability of the organelle and ultimately leads to apoptosis or necrosis of myocytes. Coenzyme Q10, an essential component of the electron transport system and a potent intracellular antioxidant, appears to prevent damage to the mitochondria of the heart, thus preventing the development of anthracycline-induced cardiomyopathy.
PMID: 15911925 [PubMed - indexed for MEDLINE]
Differences between carnitine derivatives and coenzyme Q10 in preventing in vitro doxorubicin-related cardiac damages.
Istituto di Clinica Medica Generale e Terapia Medica IV, Università degli Studi di Firenze, Italia.
Anthracycline derivatives are among the most effective and widely used antiblastic drugs. Irreversible and dose-dependent cardiotoxic side effects, however, severely limit their prolonged use. This study sought to establish whether carnitine derivatives or coenzyme Q10 could provide protection against doxorubicin-related cardiac damage. Rat heart slices were incubated for 60 min in a Warburg apparatus at 38 degrees C with 4 mM L-carnitine or 1 mM propionyl carnitine or 15 microM coenzyme Q10 to which 25 microM doxorubicin was added. Cellular oxygen uptake and 14C-leucine incorporation were measured. Carnitine derivatives significantly reduced (p less than 0.001) the metabolic cardiac impairment due to doxorubicin. Incubation for 60 min with a mixture of L-carnitine and doxorubicin improved cellular respiration, oxygen uptake being only 9% less than that of the controls, and an even greater reversal characterized the propionyl carnitine mixture for which the recovery of endogenous cellular respiration was almost complete (93%). Coenzyme Q10 instead provided no significant protection against doxorubicin-induced inhibition. The incorporation of 14C-leucine followed a similar pattern; the addition of carnitine derivatives to doxorubicin served to restore cellular protein synthesis almost totally (from 76 to 97%), whereas coenzyme Q10 produced no significant increment, probably due to the low permeability of the cell membrane to exogenous coenzyme Q10. Thus, levo and propionyl carnitine even more appear to be promising agents in the prevention of doxorubicin-related cardiac toxicity.
PMID: 3368201 [PubMed - indexed for MEDLINE]
Synergic and complementary effects of L-carnitine and coenzyme Q on long-chain fatty acid metabolism and on protection against anthracycline damage.
Institute of Biological Chemistry, School of Medicine , University of Pisa , Italy .
Exogenous L-carnitine and coenzyme Q are used to protect the heart against anthracycline damage and to enhance energy metabolism in the heart and in the muscle. Though their metabolic function is well known and their effects on anthracycline damage have been largely studied, their combined action has not been investigated. Therefore we have used partially CoQ-depleted bovine mitochondria to evaluate the synergic action of CoQ and carnitine on palmitoylCoA oxidation, as an experimental model in which either CoQ or L-carnitine may be the limiting factor in the oxidation of activated fatty acids. The protective effect exerted by the combined use of L-carnitine and CoQ against damage by the anthracycline derivative doxorubicin has been compared to the protection exerted by each compound alone. The effect was evaluated by assessing oxygen consumption and 14C-leucine incorporation in rat heart slices. The results obtained suggest that the administration of an association of L-carnitine and CoQ exerts a stronger protection against anthracycline damage and induces a greater utilization of fatty acids as compared to the effects of each compound alone.
PMID: 2276901 [PubMed - indexed for MEDLINE]