"NEVER MIND DRUG RESISTANCE" IN CLINICAL ONCOLOGY.

As we are advancing toward the cure, one of the thing that should change is our general attitude in Oncology clinical practice and clinic trial build up, is to stop dismissing drug resistance as an important component or criteria to include in our drug selection.  With that dismissal comes however a significant effect on outcome.
It is known that addressing mechanisms of resistance to drug improves outcome.  This is entering now clinical practice when it comes down to use of Tamoxifen and related pathway modulators, and the P450 Isoforms CYP2.

In each individual cancer patient there Resistance mechanism due to the host, and those due strictly to the cancer cells.  The complexity of this resistance lead to its dismissal. We kind of walk away from this hoping it is not coming to haunt us!    Unfortunately it does.

Variable Host factors include rate of absorption of the intended drug, rapid metabolism, excretion, poor tolerance and ability to deliver at the site of the intended action.

Variable Cancer cellular Factors include blood vessel variations, loss of surface receptors or transporters, presence of MDR (multiple drug resistance factor), gene heterogeneity/heterozygosity , and ability to compartmentalize the drug once absorbed by simple diffusion, active transport or Endocytosis.

There are Variable factors inherent to the drug itself, its molecular size (immunotoxin requires Endocytosis), liposolubility and hydrosolubility.

The worse of the resistance mechanism  is of course the MDR that we try very much to forget.  Yet we know something about it.  We know it works with ATP interaction, we know it is a Technetium Sestamibi  substrate and can be visualized radiologically, we know there are various kinds.  Some kinds can only handle neutral electrically charged molecules, some more effective in neutralizing cationic or anionic molecules.  And of course we know what drug behave electrically opposite to the MDR tendency.  Suffice is to say that knowing more about the mechanism of resistance we face in individual cancer provide an opportunity to increase outcome.  The future will require this level of discernment.