ETHICAL ISSUES IN CANCER THERAPY USED IN CLINICAL TRIALS.
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In desperate times and in situations where there is no known standard therapy left or existing, patients are involved in various phases of clinical trials and off label use of medications occurs.  One difference between off label use with On label use is that early on, people had been willing to put their life at risk, and consented to participate in a clinical trial aimed at proving a point or concept.. These trials often are with a limited scope of objectives to reduce specific biases. But once proof of concept is established, can we extrapolate  these findings to other parallel situations?  Or do we need to do clinical trials even though similar situations, concepts, mechanisms and possible responses apply?  Several scenarios can be asked:

1. If A leads to B and B leads to C, can we conclude without a trial that A leads to C?
2. If A=B and B=C, can we conclude that A=C ?
3. If A-B=C can we conclude the A-C=B?
4. If A using B gets C, therefore A using C gets B?

While some of the scenarios are clearly true, some are not fully true and some conclusions are completely wrong. And resulting consequences could be devastating. The variables are what happens between the letters. And the intensity of the quality of the conclusion depends very much on these various variables.  Ethicists around the world struggle with these Issues all the time.

When it comes to Humans, the variables become endless: Gene differences, gender, age, previous exposures, set of circumstances, state of main organs, and susceptibilities are just a few known and unknown variables.   Reaction to something known will depend on the mentioned variable.  And even though the drug and side effects are known, these variables still question or challenge us because they can change the outcome.  The safety or acceptability of the outcome determines or influences the ethical nature of the outcome.  The moral nature of the outcome is another dimension that is part of the Ethical decision and is a tall order that also nees do be met.
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Case in point:

3 decades ago a young researcher was working with a drug that was banned because pregnant women who took the drug had babies with short limbs. The drug was Thalidomide of course.  He was trying to know why this drug led to this calamity.  History taught us that restricted growth of blood vessels in the embryo was one of the main reasons; of course we know now.  But as he worked with Thalidomide, he fell ill.  He was diagnosed with Myeloma.  He wanted to learn more about his disease and soon learned about the pathways in Myeloma and quickly concluded that based on what he knew about Thalidomide, it could help in Myeloma.  He also knew that it would take time for the drug manufacturer to allow the use of the drug for his condition.  Off label use was authorized by someone in this desperate situation and the rest is history!
Now that we know the drug used is effective, was it ethical to try or allow the use of thalidomide without having the results of a clinical trial?  This situation judged today brings out the notion that what is not ethical today may not be unethical tomorrow. The ethical nature of a practice is relative to time, place and culture and? you think it, it's good!

Case in point 2:

Dr Maurie Markman commented on a case about the possible use of Bexarotene, a medication approved for treatment of Cutaneous T-cell lymphoma, in Alzheimer dementia.  Based on what target and mechanisms, one may conclude it can work in this disease.  But a physician says "NO" to recommending it off label.
Who should decide, the desperate, but informed patient, or the Doctor?
And what are the possible reasons this Doctor makes that decision?
At what threshold is a trial needed to allow us to conclude that the OFF-LABEL USE IS WORTH WHILE? IS OUR IGNORANCE ENOUGH OF A REASON TO NOT TRY SOMETHING CONSENTED? IS AN ETHIC PANEL ENOUGH PROOF TO ALLOW SUCH A USE?
Or both patient consent and an ethical panel decision need to reach the threshold together?
YOU TELL ME!
SHOULD WE LEARN SOMETHING FROM THE FIRST CASE? 

NOMENCLATURE OF GENES AND PATHWAYS INVOLVED IN BUTEIN INHIBITIONS: IKK and Sirtuin

IKK:
The subunit to be inhibited for the activation of the Nuclear factor and pathway NF-kB which has versatile transforming capacity to combat, escape and resist various attackers including infection and chemotherapy.  Inhibition here reduces the cell capacity to adapt.  It appears that the Transcription factor NFkB is sitting there in the Cytosol totally inactive, touch the IKK through phosphorylation, wakes the NFkB which spring into motion and unleashes its power.  One of the best described pathway flow is TNF posphorylation of IKK which detaches and goes on to  being ubiquitinated and degraded through the Proteasome.  detachment of the IKK lead to a free NFkB kinase which enter the nucleus to unleash all kinds of genes of defense.  DO REMEMBER that upstream NFkB go through MEK (also involved in Angiogenesis) to reach MAP3K and you can see how through networking of these pathways the phenomena gets global.

Sirtuin:
This compound is SIRT1, it is  activated by BUTEIN
Butein actually activate SIRT1 and may induce aging in the cell.  Remember Butein by activating Sirtuin will have a role in Diabetes, Gout, Alzheimer dementia, and Amyloid related disease.  Butein, a versatile anti-inflammatory drug with effect on NAD (Nicotinamid), and may be a Histone De-acetylase inhibitor. This stuff has potential!