Circadian rhythm and bioavailabilty

November 11 2007 post. Last week I came across and had just enough time to glance at an interesting article on the effectiveness of chemotherapy drugs administered at different times of the day when my computer crashed. (Don’t you hate it when that happens?) I lost the page reference and so far haven’t been able to find it again. Sigh. The gist, however, was that malignant cells are more susceptible to certain chemo drugs at different times of day. The reason I found this idea fascinating is because I wonder if it applies to curcumin and other non toxic substances. Well, why wouldn’t it? I clearly remember Prof. Aggarwal telling me that the best time to take curcumin is early in the morning. He didn’t say why, but I will ask him again, and I will see if I can come up with an answer on my own (not today, though, I have run out of time!). Also, one of my blog readers takes some of her supplements, I forget the details, late at night when cancer cells may be more vulnerable. I confess that this sounded a bit nuts to diffident and sceptical me when I first read about it, but is now beginning to make sense.

So even though this topic wasn’t on my to-be-researched-in-a-hurry list and I meant to post on an entirely different issue today, I woke up thinking that I would like to take a quick poke at it. It’s a grim day in Florence, so we are staying inside, a perfect day to do research. Well, truth be told, I should be straightening up the house, blablabla but that can wait. ;-)

The first reference I found this morning was a well-written article in the online magazine Slate. I confess that this was the first time I’d ever heard the term circadian rhythm, no, not even in connection with jet lag, which is a typical example of disruption of our internal clock. The Slate article wasn’t the same one that I lost last week but it covers similar points, i.e. the best time of day to take a given medication (see: http://tinyurl.com/267jrs). Even something that we imbibe almost without thinking, i.e. aspirin, is best taken in the evening, when it will do less damage to the stomach lining than in the morning. Did you know that? I didn’t.

The article continues: Despite this evidence of variation, drug research is almost always done during daylight hours, when the humans leading the studies are awake and alert. And in the animal testing stage, it’s almost always done with mice and rats, which are nocturnal €”the middle of our day is the middle of their night. This can lead to gross misestimations of the effectiveness and toxicity of a drug intended for humans. How about that for a shocker? What if certain toxic or undesirable side effects from drugs, perhaps even from curcumin itself (some of my correspondents have reported diarrhea and stomach upsets, for instance), could be AVOIDED simply by modifying our supplement/drug-taking schedules? Why, that is absolutely BRILLIANT! And WHY doesn’t the FDA focus on such crucial issues? Well, the Slate article provides the obvious answer to that question: money!

I quote again from the article, a good easy read, I highly recommend it: Modern drug development generally assumes that the body maintains a stable internal state. To that end, many prescription drugs are designed to be taken in equal amounts at regular intervals to keep a patient’s drug levels steady. The problem is that a growing body of research suggests that our bodies are not constant. Instead, nearly every physiological process oscillates with our internal circadian rhythms. The body’s temperature, immune function, and hormone levels all partly depend on whether it’s night or day, or sometime in between. Meanwhile, many diseases also have daily rhythms, with symptoms more severe at certain times. The body’s sensitivity to time of day means that a drug proven safe to take in the morning may not be safe at night, or that a dose that works at 8 p.m. may be too small at 8 a.m. This would seem to support my friend Ana’s feeling that she should take her curcumin dose once a day instead of twice a day. Perhaps her circadian rhythm is telling her something. Okay, that sounds completely unscientific, but please read the above-mentioned article before jumping to conclusions.

I had the time this morning to find a couple of related and interesting studies. The first one, see full text: http://tinyurl.com/2anhv6, published in Cancer Research in 2003, is titled The Days and Nights of Cancer Cells. Need I say more? The second study, see full text: http://tinyurl.com/yp76f3, published in Cancer Research in 1977 (1977!), examines how leukaemic mice reacted to the administration of cyclophosphamide (Cytoxan) and 1-f3-D-anabinofuranosylcytosine (ara-C, for short) at different times of day. It turns out that giving these drugs at different times of day produced different effects in terms of animal weight, toxic reactions and survival. For example, more mice (94% compared to 44%!) survived when Cytoxan was given to them in the late afternoon/early evening, leading to the conclusion that the optimal time to administer cyclophosphamide is around the transition from rest to activity (between 5 p.m. and 8 p.m. for mice kept in light from 6 a.m. to 6 p.m., alternating with 12 hr of darkness). For ara-C, however, the best time was 8 AM. For both drugs taken together, apparently the best time was 11 AM: after 75 days, in fact, 28% of the mice treated with both drugs at 11 AM were still alive. The study also tells us that drug toxicity was affected by circadian rhythms: mice that received Cytoxan in the evening had significantly fewer toxic reactions than those on the morning schedule, for instance.

In conclusion, and speaking of mice (poor dears!), I wish research would focus on important matters such as these instead of developing mutant mice that aren’t afraid of cats (did you hear THAT bit of recent news? A few days ago, it made the Italian national news, for crying out loud talk about research money going down the bloody drain ! Ahhh, che pazienza che ci vuole!!!).

February 11 2009 update: Don (Myeloma Hope blog) has recently been discussing chronotherapy, or chrono-modulated therapy, in which the chemo is administered at the time of day that takes advantage of a person’s biorhythms to maximize the benefit and minimize the side effects of the drug (see http://myelomahope.blogspot.com/2009/02/plateau-continued.html).

It just so happens that I just finished reading a Science Daily article (http://tinyurl.com/dykr6y) linking the disruption of the circadian clock, the internal time-keeping mechanism that keeps the body running on a 24-hour cycle, to the slowing down of cancer growth. Coincidentally, more than a year ago I wrote a post about our complex internal ticking system (see my November 11, 2007 post; great set of comments, too). The subject is of huge interest to me, since it would be absolutely fantastic to figure out the best time of day to take supplements…

At any rate, a team of University of North Carolina researchers discovered that genetically altering one of four essential “clock” genes actually suppressed cancer growth in a mouse model commonly used to investigate cancer. A group of mice with a mutated p53 gene (p53 is a tumour suppressor under normal circumstances) lived longer, 50% longer!, when the researchers fiddled around with their internal clocks. Their experiment showed that the mutation of this clock gene reactivates the intracellular signals that can eliminate cancerous cells. Well, well…

So the idea would be to slow down the rate of cancer progression by altering the internal clock of those who possess the p53 mutation. And, since this mutation is present in about 50% of human cancers, that would be quite an impressive number of patients. Hmmm, question: how do we find out if we have a mutated p53 gene?

At any rate, The findings could enable clinicians to reset the internal clock of each cancer cell to render it more vulnerable to attack with chemotherapeutic drugs. Reset e-a-c-h cancer cell? Uhmmm…hey, Scotty, beam me up!

Seriously now, more research is needed (I know, I know, I say that a lot, then I get totally sidetracked into researching heaps of other things…oh well…). I have begun compiling a list of circadian studies…at this rate, with all the studies I have to read, let’s see, uhm, I will have to live at least another 120 years…hey, I wonder if I can reset that part of my biological ticker…!

One thought on “Circadian rhythm and bioavailabilty

  1. Ruthie

    I am very much enjoying your blog — you and I are looking at the research of many of the same things, but you have been at it far longer! Wonderful work!

    I wonder if this is related to melatonin’s effects? My research shows it seems to help people tolerate chemo better, as well as fighting cancer directly.

    Just a little thought before I head to bed! I will enjoy reading more of you research later.

    Take care!

    Reply

Leave a Reply

Your email address will not be published. Required fields are marked *