I've discussed this issue before. It comes up regularly because people often want to base treatment decisions on studies in which some drug or supplement seemed to have potent effects on cancer cells in a dish. The problem is that the scientists carrying out these studies often seem to pay no attention to the achievable levels of the drug or supplement in human plasma or other tissues in the body with reasonable dosing schedules. It's fairly common to see studies showing marvelous effects, without mention that the drug is being tested at 100 or 1000 times the achievable level in the body.
As a case study, here is one example:
Genistein Suppression of Matrix Metalloproteinase 2 (MMP-2)and Vascular Endothelial Growth Factor (VEGF) Expressionin Mesenchymal Stem Cell Like Cells Isolated from High andLow Grade Gliomas
"Results: Expression of MMP-2 demonstrated 580-fold reduction in expression
in low grade glioma cells post treatment with genistein compared to untreated cells (P value= 0.05). In cells derived
from high grade lesions, expression of MMP-2 was 2-fold lower than in controls (P value> 0.05). Genistein caused a
4.7-fold reduction in VEGF transcript in high grade glioma cells (P value> 0.05) but no effects were evident in low
grade glioma cells. Conclusion. Based on the data of the present study, low grade glioma cells appear much more
sensitive to genistein and this isoflavone might offer an appropriate therapeutic intervention in these patients. Further
investigation of this possibility is clearly warranted."
Oh, and by the way, the study states that genistein was tested at a variety of concentrations: "variety concentrations of genestein (Sigma,
UK) (0, 0.01, 0.004, 0.002 and 0.001M)"
This is actually not much of a variety of concentrations because all these concentrations are absurdly high. M stands for molar (moles/liter). 0.001 M is therefore 1 millimolar. The only drugs I'm aware of that even come close to 1 millimolar in the plasma are lithium and phenylacetate and maybe DCA with high doses. Most drugs are achievable in the nanomolar or low micromolar range at best. For genistein we'll be generous and include glucuronidated genistein (the form predominantly found in the plasma which may or may not have pharmacological activity compared to free genistein). Even still, concentrations of around 2 micromolar is about what is achievable in the blood with a single 300 mg dose. Let's be generous again and assume that 10 micromolar total genistein would be achievable with a high dose. The 1 millimolar tested in this study is 100 times higher the 10 micromolar achievable at best, including glucuronidated and free genistein. In many cases the only way to match concentrations used in vitro would be high dose intravenous injection, but the safety of that would be unknown without phase 1 clinical trials. It's possible that 1 millimolar free genistein in the bloodstream would be very toxic, and that normally non-toxic substances would become toxic at these high concentrations.
I've also seen studies testing melatonin up to 1 millimolar, whereas the maximum concentration achievable with an 80 mg dose (4 times more than most GBM patients are using) is only 500 nanomolar. 1 millimolar used in vitro is then at least 2000 times higher then what we could expect in the plasma.
These studies are very misleading, especially when read without a scientific background that can make sense of the concentrations being used (what is 1 mM?). I do my best to bring awareness to this issue, that in vitro work can usually not be taken at face value (thinking the conclusions reached and the concentration-dependent mechanisms described necessarily have any clinical relevance).