New research into the effects of 5-FU

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GrouseMan
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Joined: Mon Aug 12, 2013 12:30 pm
Location: SE Michigan USA

New research into the effects of 5-FU

Postby GrouseMan » Thu Jul 15, 2021 12:53 pm

Well 5-FU has been around for over 50 Years. Almost if not everyone on this forum has most likely experienced its use. Seems its not too old a drug to determine more about its function and maybe learn more about ways it might be able to be applied or enhanced through the use of these other recently discovered mechanisms of action. Here is a commentary from one of my favorite blogs about drug discovery. Finally after over a year the Blog owner is back to talking drug research instead of Covid!!! Here is a link. Its pretty technical.

https://blogs.sciencemag.org/pipeline/a ... -you-think

This article as usual links back to the original paper, but its behind a pay wall. Generally speaking the article indicates that unlike was primarily thought to be the mechanism via inhibition of thymidylate synthase. See: https://en.wikipedia.org/wiki/Thymidylate_synthase that actually many of its actions seem to be on RNA signaling, rather than just its messing with DNA repair.

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?

Good luck

GrouseMan
DW 53 dx Jun 2013
CT mets Liver Spleen lung. IVb CEA~110
Jul 2013 Sig Resct
8/13 FolFox,Avastin 12Tx mild sfx, Ongoing 5-FU Avastin every 3 wks.
CEA: good marker
7/7/14 CT Can't see the spleen Mets.
8/16/15 CEA Up, CT new abdominal mets. Iri, 5-FU, Avastin every 2 wks.
1/16 Iri, Erbitux and likely Avastin (Trial) CEA going >.
1/17 CEA up again dropped from Trial, Mets growth 4-6 mm in abdomen
5/2/17 Failed second trial, Hospitalized 15 days 5/11. Home Hospice 5/26, at peace 6/4/2017

catstaff
Posts: 101
Joined: Wed Mar 03, 2021 11:37 am

Re: New research into the effects of 5-FU

Postby catstaff » Thu Jul 15, 2021 3:35 pm

I saw a recent comment at In the Pipeline that I thought must have been from you. I think the mechanism of action of oxaliplatin is also not what they thought initially. Maybe this will lead to "designer" versions, and to better understanding of mechanisms of resistance.
D/H Dx 10/2019 RC age 61
Clinical T4bN2M1a (common iliac and para-aortic lymph nodes)
MSS KRAS G12D
CRT 11/19-1/20 FOLFOX 3/20-7/20
Pelvic exenteration w/LAR 8/20
ypT4bN0Mx G3 0/14 nodes LVI not seen PNI-
CEA 10/19:20, 1/20-11/20:1.6, 4.3, 3.4, 2.7, 2/21:9.0 3/21:18,40 4/21:28,19, 5/21:13.3,8.6
PET 3/21 recurrence in distal nodes, L5 vertebra, pelvis
FOLFIRI+bev 3/21-

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GrouseMan
Posts: 865
Joined: Mon Aug 12, 2013 12:30 pm
Location: SE Michigan USA

Re: New research into the effects of 5-FU

Postby GrouseMan » Fri Jul 16, 2021 11:07 am

catstaff wrote:I saw a recent comment at In the Pipeline that I thought must have been from you. I think the mechanism of action of oxaliplatin is also not what they thought initially. Maybe this will lead to "designer" versions, and to better understanding of mechanisms of resistance.


Nope wasn't me. I have not commented on In the Pipeline posts in quite sometime. I read it all the time but rarely post, especially in the past year where its been nothing but discussion of Covid. I am just glad it is finally getting back to Med Chem and chemistry in general. I am sure just about every drug has some effects off target like this including Oxaliplatin. These early drugs come from a time when much more discovery was centered around whole body effects not as much on mechanism based studies. Back then we didn't have the molecular biology and Biochemical tools to study these interactions in depth as we do now. The 5-FU study was likely instituted because 1) its a drug long off patent so anyone can study it and publish about it. 2) Quite a lot is know about its active metabolites already and is the basis of some prodrugs already. 3) There are still outstanding questions about why it works better in some people than in others.

Maybe someone will do the same study on Oxaliplatin, and Irinotecan. It would be nice if some of the bigger Pharma companies did this sort of detailed study on many of their drugs before Phase II clinical studies. Could provide a lot of insight as to if a Phase II trials really working or some other mechanism is at play in a small subgroup. Might indicate some other direction to take. Might even prevent a lot of wasted effort on Phase III trials where most drugs fail, saving a lot of research dollars in the end.

Having been in the drug discovery business front lines I can tell you it can be a very discouraging career to be in. I have seen projects that look very promising crash and burn, because the target of the drug was not what we thought it was (this was a Cardiovascular indication). This is what is currently happening with Alzheimer's drug development in my opinion. Even when you get a drug out the door, poorly run clinical trial can relegate the drug to the back burner, supplanted by others very similar in structure that came later and had better run and targeted trial, so better patient selection criteria etc, making this drug supposedly better and a market leader. Its a crap shoot. As a business model Pharma R&D is a bad investment compared to say selling Pizza.

Oh well... Good luck

GrouseMan
DW 53 dx Jun 2013
CT mets Liver Spleen lung. IVb CEA~110
Jul 2013 Sig Resct
8/13 FolFox,Avastin 12Tx mild sfx, Ongoing 5-FU Avastin every 3 wks.
CEA: good marker
7/7/14 CT Can't see the spleen Mets.
8/16/15 CEA Up, CT new abdominal mets. Iri, 5-FU, Avastin every 2 wks.
1/16 Iri, Erbitux and likely Avastin (Trial) CEA going >.
1/17 CEA up again dropped from Trial, Mets growth 4-6 mm in abdomen
5/2/17 Failed second trial, Hospitalized 15 days 5/11. Home Hospice 5/26, at peace 6/4/2017

stu
Posts: 1503
Joined: Sat Aug 17, 2013 5:46 pm

Re: New research into the effects of 5-FU

Postby stu » Fri Jul 16, 2021 11:58 am

Not even going to pretend to understand most of it but kind of getting a feel for some of it !
Interesting point about the subgroup of patients maybe responding differently. My mum is in the process of signing up to take part in some form of research . They are looking into long term survival. Roughly , very roughly to see if her body identified it as some form of infection . There was also a mention of some protein being identified.
They want current stool samples , bloods and access to her tumour sample . Not sure if it will lead anywhere, as I have read your post for a while and realistic , but even if it’s to rule out rather than rule in it may have some value for others in the future .
It seems a slow and frustrating process all round ! However my mum’s friend lived through the cure of his leukaemia and that keeps me hopeful!

Take care ,
Stu
supporter to my mum who lives a great life despite a difficult diagnosis
stage4 2009 significant spread to liver
2010 colon /liver resection
chemo following recurrence
73% of liver removed
enjoying life treatment free
2016 lung resection
Oct 2017 nice clear scan . Two lung nodules disappeared
Oct 2018. Another clear scan .

rp1954
Posts: 1561
Joined: Mon Jun 13, 2011 1:13 am

Re: New research into the effects of 5-FU

Postby rp1954 » Fri Jul 16, 2021 4:09 pm

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.
watchful, active researcher and caregiver for stage IVb/c CC. surgeries 4/10 sigmoid etc & 5/11 para-aortic LN cluster; 8 yrs immuno-Chemo for mCRC; now no chemo
most of 2010 Life Extension recommendations and possibilities + more, some (much) higher, peaking ~2011-12, taper to almost nothing mid 2018, mostly IV C


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