GrouseMan wrote:So - There might still be life in this old drug yet, especially if they manage to fine more ways to tune its activity by using these findings. Perhaps they will be able to test precisely when this will become no longer effective. Maybe add another drug that makes it so again by inhibiting another pathway?
5FU is a most impressive molecule for CRC that remains seriously underutilized, more than 60 years after its discovery.
Much has been previously found by empirical experience but not really understood in detail, and fully used.
One hopes that the improved understanding will fuel new candidates and protocols.
I was very wary of 5FU compounds at the start and thought surely some of the newer molecules must be "better" and deserve priority. After extended reading I found that many 5FU opportunities had been missed for a variety of reasons, many of them competitive bias or inertial in nature rather than merit based objections. This included the "nicest" form of 5FU, UFT, not available in US and Canada, now roughly covered by Xeloda as an oral 5FU prodrug.
One important area for us was 5FU (re)-sensitization via a variety of tactics, including adding beneficial (e.g. specific vitamers) or small footprint adjuncts (celebrex) to 5FU off-label, instead of oxi or iri-, and trialing ingredients for specific effects and improvements where possible.
One other important 5FU re-sentization tactic is surgery - removal of big ugly, drug resistant mets/clusters may allow a previously inadequate 5FU regime to work again.
We found opportunities to improve the 5FU-LV therapeutic index, and increase the 5FU quantity used, by better optimizing dietary contents of folic acid (ruthess elimination), optimum leucovorin (folinic acid, often overdosed), and increased natural folate (L-5MHTF).
5FU chronomodulation is something long used in Asia, albeit not optimized, but little used in the West at all. It can be used to improve tolerance, dose intensity, and continuity where other patients burn up or fail by resistance.