Dangerous Vehicle

Dangerous Vehicle

Like many of the science hype articles in the media, the picture below is misleading. In Buddhini Samarasinghe’s post about cutting through the hype about “exploding” cancer cells: “Exploding Cancer Cells” Explained (http://goo.gl/kZMpVM), we talked about the vehicle control, dimethyl sulfoxide or DMSO. The vehicles below are dangerous but we aren’t talking about that kind of vehicle.

∇ What is a vehicle?

So in biomedical research, what is a vehicle? The American Heritage Medical Dictionary defines vehicle as a substance of no therapeutic value that is used to convey an active medicine for administration. So a drug in a liquid form may use saline (salt water) or a liquid buffer as a vehicle, i.e., the drug is dissolved or mixed with the vehicle. This maybe necessary to get the dose right, i.e., dilute the drug/compound. It maybe necessary to use a vehicle because the compound needs assistance to be transported depending on the route of administration. So for skin creams (transdermal drug delivery) a lotion-like vehicle might be used.

∇ Vehicle Control

No I’m not talking about Automatic Brake Systems or sway-bars. Vehicle controls in biomedical research means a group of test subjects that are given the vehicle alone. It’s like a placebo group but is more specific than that. You’ve probably heard of sugar pills being used for the placebo effect. A vehicle control tests to confirm that the vehicle has no effect on its own. Imagine if you are testing a new drug without a vehicle control group and all of the subjects get sick. You don’t know if it is due to the drug or the vehicle. Similarly, what if all of the subjects show improvement but there is no vehicle group to test to demonstrate that it was the drug alone. In the study that Buddhini Samarasinghe discusses, DMSO was the vehicle.

∇ Dimethyl Sulfoxide (DMSO)

DMSO is often used as a vehicle because a lot of drugs are not water soluble and but are soluble in DMSO. If you want to get a drug into the blood stream, it’s best if it is water soluble. However, some drugs are hydrophobic (they don’t like water but they like oil). If a drug is promising enough, you don’t let hydrophobicity stop you. The LD50 of DMSO is 13.4–15.5 g/kg (12.2–14.1 ml/kg). What does that mean? The LD50 is the dose at which half of the subjects die. LD stands for Lethal Dose. Unfortunately the authors don’t say what dose they used for the vehicle. We don’t know if the vehicle could have had an effect alone.  We do know that DMSO can have effects even at low doses.

For example Julien et al found that DMSO had an effect on some enzymes they were interested in for Alzheimer’s disease. They state: These data should caution researchers working with DMSO as it can induce artifactual results both in vivo and in vitro. Galvao et al reported that even low doses of DMSO had toxicity. Finally, Hanslick et al discuss DMSO producing apoptosis in the central nervous system. If you have been paying attention to Buddhini’s Hallmark of Cancer series, you’ll know that apoptosis is programmed cell death.

A couple more comments about the “exploding” cancer cell paper. In one part they show that tumor volume is reduced with treatment and not with DMSO. Tumor volume alone, can be misleading. There are drugs that kill the tumor but the tumor does not shrink, at least not right away. So if the tumor stays the same size, the drug did not necessarily fail. You need functional imaging to show that the tumor is still viable (regardless of size) or the tumor is dying. Also some drugs can make the tumor swell with fluid but the tumor is nevertheless dying. That is another example where tumor volume alone, is misleading. The second comment about the paper is that the live cell imaging experiments were done with an Operetta system. I recommend you check out the video Watch Operetta Product Overview Video (http://goo.gl/FUyKLu) It’s on the right side.

A couple of my favorite quotes are applicable here:

Alle Ding’ sind Gift, und nichts ohn’ Gift; allein die Dosis macht, daß ein Ding kein Gift ist.

“All things are poison, and nothing is without poison; only the dose permits something not to be poisonous.” Paracelsus

The only real difference between medicine and poison is the dose….and intent. Oscar G. Hernandez, MD

∇ References:

LD50 of 13.4–15.5 g/kg (12.2–14.1 ml/kg) 

Caujolle F, Caujolle D, H B, Calvet MM (1964) [Toxicity and pharmacological aptitudes of dimethylsulfoxide]. C R Hebd Seances Acad Sci 258: 2224–2226.

Farrant J (1964) Pharmacological actions and toxicity of dimethyl sulphoxide and other compounds which protect smooth muscle during freezing and thawing. J Pharm Pharmacol 16: 472–483.

http://cancerres.aacrjournals.org/content/53/24/5877.short

Dimethyl Sulfoxide Induces Both Direct and Indirect Tau Hyperphosphorylation

Carl Julien, François Marcouiller, Alexis Bretteville, Noura B. El Khoury, Joanie Baillargeon, Sébastien S. Hébert, Emmanuel Planel

PLoS One. 2012;7(6):e40020. doi: 10.1371/journal.pone.0040020. Epub 2012 Jun 29.

http://goo.gl/8IyqcW

Unexpected low-dose toxicity of the universal solvent DMSO.

Galvao J1, Davis B, Tilley M, Normando E, Duchen MR, Cordeiro MF.

FASEB J. 2014 Mar;28(3):1317-30. doi: 10.1096/fj.13-235440. Epub 2013 Dec 10.

http://www.ncbi.nlm.nih.gov/pubmed/24327606

Dimethyl sulfoxide (DMSO) produces widespread apoptosis in the developing central nervous system

Hanslick JL, Lau K, Noguchi KK, Olney JW, Zorumski CF, Mennerick S, Farber NB

Neurobiol Dis. 2009 Apr;34(1):1-10. doi: 10.1016/j.nbd.2008.11.006. Epub 2008 Dec 3.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682536/

If you like the cars, I recommend you watch the video in the link for the image source.

Image source:

http://goo.gl/SOTSpH

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