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toobs1234
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01/06/2020 1:24 am  

This paper has a summary of the expression levels of MCT1 found in studies of different types of cancer. It was at least partially expressed in all studies that looked at it except two for prostate cancer, but then they also list two papers that found that it was indeed expressed in prostate cancer. And even if it's not expressed under normal conditions, it may well be upregulated once you block MCT4.

https://www.sciencedirect.com/science/article/pii/S221287781930403X#bib93


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GgE
 GgE
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01/06/2020 1:34 am  
Posted by: @toobs

at one point in time, there were a lot of diabetics with high blood pressure who probably were prescribed both syro and metformin and yet there were no reports of spontaneously disappearing cancer.

I understand. But keep in mind that "The suggested initial dose is 1 to 2 tablets (1 to 2 mg)" and "The usual dose for long-term maintenance therapy in most cases is from ½ to 3 tablets (0.5 to 3 mg) daily." This dosage was way too low to have any impact on diabetic cancer patients back then or now.

I agree that the necessary syro level is hard to maintain for many (may be most) people due to its side effects, even if it is just the number above derived from the patent application. Syro was developed to lower blood pressure at very low doses after all. I also agree that the addition of a strong MCT1 inhibitor such as Diflunisal will likely make the triple combo much more effective and tolerable to people. I hope we can hear someone getting good results soon.

Do you plan to use it with Diflunisal? Did you check the source Daniel mentioned?:

Posted by: @daniel

(Diflunisal) Can be bought from the first compunding pharma listed on Suppliers page under News & Others.

Is anyone out there using the triple combination of syrosingopine, metformin and diflunisal or similar such as Invokana or phenformin instead of metformin?

 


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GgE
 GgE
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01/06/2020 1:59 am  
Posted by: @toobs

This paper has a summary of the expression levels of MCT1 found in studies of different types of cancer.

That's a great paper. You may like also this one where it talks about "These results pointed out the acute synthetic lethality achieved through the simultaneous block of lactic acid export and mitochondrial complex I."

https://cancerres.aacrjournals.org/content/75/1/171

 


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toobs1234
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01/06/2020 3:27 am  
Posted by: @gge
Posted by: @toobs

This paper has a summary of the expression levels of MCT1 found in studies of different types of cancer.

That's a great paper. You may like also this one where it talks about "These results pointed out the acute synthetic lethality achieved through the simultaneous block of lactic acid export and mitochondrial complex I."

https://cancerres.aacrjournals.org/content/75/1/171

 

Great find. I hadn't seen that one. It's very useful to have another in vivo experiment, this time with actual data. Although it's disappointing that the phenformin/MCT inhibition only slowed the tumor growth.


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GgE
 GgE
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01/06/2020 7:32 am  
Posted by: @toobs

it's disappointing that the phenformin/MCT inhibition only slowed the tumor growth.

I think that the article is a bit confusing. But I think all the phenformin/MCT inhibited cells died per this paragraph. Am I interpreting it wrong?:

"Although MCT1 inhibition slightly decreased the intracellular ATP of BSG/MCT-disrupted cells, combination with phenformin induced an “energetic crisis” represented by a striking decrease of ATP (up to 85%; Fig. 4A and B). This ATP drop resulted in enhanced cytotoxicity and consequently rapid cell death. Indeed, 50% of either MCT4−/− or BSG−/− cells, and 90% of BSG−/−,MCT4−/− cells died in both normoxia and hypoxia after 24 hours of combined treatment; and only 8% of BSG−/−cells survived under hypoxic conditions after 96 hours (Fig. 4C and D). These results pointed out the acute synthetic lethality achieved through the simultaneous block of lactic acid export and mitochondrial complex I."

In other words, all the cells died after 96 hrs except 8% of the BSG−/−cells, the way I understand it. The graph shows no surviving phenformin/MCT inhibited cells past 96 hours:

 

 

Figure 4.

BSG/MCTs disruption combined with phenformin induces a major drop in cellular ATP, leading to rapid cell death. Intracellular ATP levels of LS174T WT and mutant cells after treatment with MCT1i (300 nmol/L), phenformin (50 μmol/L), or both for 24 hours in normoxia (A) or hypoxia (n = 5; B). The relative luminescence units (RLU) were normalized to the quantity of protein, and the values are given as percentages. C, cell survival of LS174T WT and mutant cells after treatment with both MCT1i (300 nmol/L) and phenformin (50 μmol/L) in normoxia (C) or hypoxia (D).

 

That's what synthetic lethality is supposed to mean: take no prisoners!

 


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toobs1234
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01/06/2020 11:38 am  

@gge

Hi gge,

Take a look at figure 5C. That's the results of the in vivo experiment...only inhibition of growth. Unfortunately.


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John Pizzuto
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02/06/2020 3:17 am  

@gge

Shirley's biopsy is scheduled for Thursday.  They gave us a list of medications to avoid, including aspirin and NSAID's.  I'll try to get them to watch the video.  But, it's spread so much as it is it probably doesn't matter.


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GgE
 GgE
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02/06/2020 3:47 am  
Posted by: @jpizzuto

They gave us a list of medications to avoid, including aspirin and NSAID's.  I'll try to get them to watch the video.  But, it's spread so much as it is it probably doesn't matter.

They always want to avoid any drugs that thin the blood because they can cause bleeding and extend the healing process. But a surgeon told me they can manage these issues with a little more time and care, just the way they do when they do surgery on heart attack patients who are on very strong blood thinners and cannot stop them before or after the surgery.

I beg to differ that it doesn't matter. Does she have it in her brain? Or in her bowels? No matter how bad a situation is, it can always get worse. She doesn't need any more spread...


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John Pizzuto
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04/06/2020 12:52 am  

@gge

It’s late afternoon here.  I am waiting for our PA to return my call.  I don’t know if she has watched the video.

I need to talk to the oncologist, as it would be up to her to prescribe ketorolac.

In the event they say no, or we fail to connect, what would happen if she were to take Melloxicam before the biopsy?

I think it will be from the lung.  


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John Pizzuto
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04/06/2020 12:57 am  

If we take it, we should tell them before hand.  But, they may cancel the procedure.


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John Pizzuto
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04/06/2020 1:53 am  

I just spoke to the PA.  She said the surgeon will cancel if we take the Melloxicam, due to the risk of bleeding.

I asked her if the risk of bleeding was greater than the risk of further mets.  She said we know there are mets already, it's a small needle, reseeding only occurs with ovarian cancer which she doesn't have, and we'll get some good information about the PIK3 gene.

I read her the link to the video and asked her to promise to watch the first ten minutes when she got home tonight.  She said she had another patient to get to.  I pressed her about watching it tonight, but she replied "We'll discuss the video at your next visit."

Due to the virus thing, I will not be allowed in with my wife, so I probably won't get a chance to make a case with the surgeon, but I'll try.  At one point, the PA said it would be up to him.


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Yudaitheska
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04/06/2020 1:55 am  

Dear Jhon... You can use sublingual ketorolac. Such dose wouldn't risk bleeding from the biopsy 


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John Pizzuto
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04/06/2020 2:02 am  

@yudaitheska

Thank you, but I believe the surgeon will cancel if we try anything.


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GgE
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04/06/2020 3:39 am  
Posted by: @jpizzuto

reseeding only occurs with ovarian cancer

This may be the official story. But they won't even do biopsies in testicular cancer because they have been proven to cause mets. And there is evidence that other cancer types also spread from biopsies. However, this is not officially acknowledged yet and will not be until liquid biopsies get perfected because it would leave the doctors without a very important tool.

When you are enrolled in most cancer clinical trials in the USA they make you sign a consent that you acknowledge that the biopsies they will take may spread your cancer but that you waive all your rights to sue them on this basis. This is not put there for no reason.

Posted by: @jpizzuto

I believe the surgeon will cancel if we try anything.

I understand your anguish. It is awful that patients have to choose between doing what they think is right for them and appeasing doctors who won't consider alternative ways of doing things...What you are going through happens to thousands of people every day. Some people go with the doctors' decisions; others change doctors; and others do what they think is the right thing and don't tell the doctors that they have done it. There are risks in every option.

Unfortunately, neither I or anyone else can tell you what is the best way forward here. It all comes to an educated decision where you do some soul searching and balance your options for the above 3 paths. Then you decide which one is best for her.

Like, how much you like this surgeon and what is the risk that he'd become less interested in her case if you don't follow his advise? Will you actually need that surgeon (or any surgeon, really) in the future? How long and how hard would it be to find a doctor who would allow some NSAID before the biopsy? It doesn't need to be a surgeon. Many oncos and radiologists do it. What protection from further progression would she have during that time? What other health factors does Shirley have which could impact her bleeding and healing time? And so on with other relevant factors.

You started a bit this decision-making analysis when you said "What is there to lose? She already has many mets anyway." But you seem to have stopped there. You will feel more at peace with yourself if more mets pop up after this (God forbid) if you do your soul searching a little more in depth now. Sorry for my preaching...

Can you find out where will the biopsy be taken from? The risk of bleeding from a fine needle biopsy taken from a common solid tumor while under a low dose of NSAID would be very small in my humble opinion. You could get a rough idea of this by poking one of her finger tips with a pin as diabetics do all the time to measure their blood glucose and take the time to stop bleeding, then giving her the pill, then poking her finger again elsewhere and see how much longer it bleeds. Of course, disinfect the finger tips before you do the pricks.

According to this article ketorolac increased the bleeding time in healthy volunteers from 5.3 min to 8.5 minutes after intramuscular kerotolac administration of 30 mg, while not significantly affecting the standard platelet aggregation.

https://core.ac.uk/display/16734499

However, if the biopsy is to taken from a lung nodule, I have no idea how the NSAID would affect the healing process. The needle will probably go through very delicate tissues that are full of veins and arteries to get to the tumor. This makes it more tricky and only an experienced doctor can tell you if this issue is trivial or not.

I wish I could help you with this one...But I can't. However, if I were in your shoes and had decided to go with the surgeon's advise, at the very least,  I would ask him how soon after the procedure I could take an NSAID and I would take it for several days. There is a chance that the cancer cells loosened up and awakened by the procedure might not have settled yet anywhere in her body and the NSAID might be able to avoid that they do.

You may also consider giving her something to strengthen her immune system that does not cause blood thinning. This might be a good strategy even if she were to take an NSAID. According to the current thought part of the problem of spread from with surgical procedures may be the confluence of the immune cells to the cut site which leaves the rest of the body with reduced immune cells to watch over the cancer cells. If she can increase her immune cell population before the procedure she might have enough immune surveillance all over her body even with the procedure. I think there is good info in this site about stimulants.

 

 

 

 


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asafsh
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04/06/2020 4:15 am  

imho, before raising consent, the second opinion from another surgeon, stating necessity of nsaid administration and operation risk assessment must be obtained. That is because of no MD will accept patient's opinion which is not backed by another professionals. They won't watch youtube or read papers as MD are guided by approved treatment protocols where NSAID administration isn't mentioned. Insurance companies may cover second opinion cost.

Once second opinion is obtained, consent can be raised, patient advocacy in hospital, and medical ombudsmen could be contacted. 

May be contacting medical ombudsmen, and/or patient advocacy in advance to get an information about patient's rights, consent, second opinion, and possible ways to proceed will be better.


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MajorTom
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04/06/2020 12:29 pm  

All the best to your wife John, let's hope everything goes well.

To go back to a speculation further up in the thread, the Basel group showed in their 2018 paper that adding a powerful MCT1 inhibitor (RAC155858) to syrosingopine-metformin greatly increases cell killing. This is in Fig S5E in the supplementary data of their paper. Titrating in metformin in a sub-lethal background of syrosingopine (1uM) and ARC155858 (20nM) showed a synthetic lethality for all 3 components of the cocktail at significantly lower concentrations when used as a double combination.

It suggests that syrosingopine is a good MCT4 inhibitor but that it's MCT1 inhibitory effect is weak and hence can be aided with addition of potent MCT1 specific inhibitors. ARC155858 has been developed as a trial drug AZD3965 by AstraZeneca and is in clinical trials, but only in a sub-set of cancers that do not express MCT4 (in which case it would be useless). It is not available yet as a drug which is a pity.

 


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John Pizzuto
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04/06/2020 4:06 pm  

@asafsh

Yes, resistance is futile at this point, as she needs the biopsy.

We have decided to not make any waves, then take an aspirin and a Melloxicam as soon as we leave the facility.

Would it help to crush them first or is that necessary?


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asafsh
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04/06/2020 5:12 pm  

@jpizzuto

It is hard for me to answer that (i am not MD).

As i can't assess risk of bleeding and other complications, it would be good if surgeon will be informed about that before operation, so necessary measures could be taken during and after surgical operation in case if needed.

All the best and Good luck!


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GgE
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04/06/2020 5:42 pm  
Posted by: @jpizzuto

Yes, resistance is futile at this point, as she needs the biopsy.

We have decided to not make any waves, then take an aspirin and a Melloxicam as soon as we leave the facility.

Would it help to crush them first or is that necessary?

In favor of your decision we can argue that the risk of spread from one single fine needle biopsy is probably small. It'd be better not to have to take it but given the circumstances nobody can say you are taking the wrong decision.

Did you ask if the biopsy is from the lung or from elsewhere? I'd try to find out how soon the wound will take to heal enough to prevent bleeding if she takes NSAIDs afterwards. If from the lung, it might be riskier.

Crushing them speeds up the absorption process and they start being effective a little sooner. It also reduces stomach aches. If I were to take them I would add food to further reduce stomach ache risks.


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GgE
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04/06/2020 5:49 pm  
Posted by: @majortom

the Basel group showed in their 2018 paper that adding a powerful MCT1 inhibitor (RAC155858) to syrosingopine-metformin greatly increases cell killing. 

Posted by: @majortom

Titrating in metformin in a sub-lethal background of syrosingopine (1uM) and ARC155858 (20nM) showed a synthetic lethality for all 3 components of the cocktail at significantly lower concentrations when used as a double combination.

syrosingopine is a good MCT4 inhibitor but that it's MCT1 inhibitory effect is weak and hence can be aided with addition of potent MCT1 specific inhibitors.

Then the logical choice would be to add Diflunisal to the syrosingopine and metformin combo. I believe that Diflunisal is such a strong MCT1 inhibitor that it reduces the activity of MCT1 even when MCT1 is already bound to lactate.

I understand that (100) 500mg capsules can be special ordered from the German supplier cited by Daniel for under $200 and that they can ship to most places in Europe. They may have a problem shipping to the US though.


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Daniel
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04/06/2020 8:25 pm  

@gge

Hi GgE, 

The source I mentioned is a pharmacy providing Diflunisal in solution form for intravenous administration. Capsules should be easier to find. It was around 150 euro for a 5g bag. Capsules will be cheaper.

Kind regards,

Daniel


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MajorTom
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04/06/2020 9:34 pm  

Diflunisal has an in vitro IC50 against MCT1 of 50uM. Syrosingopine is synthetic lethal in K562 cells (that rely solely on MCT1) at the 3-5uM range. As synthetic lethality is presumably elicited only when MCT1 is effectively inhibited, it suggests that syrosingopine is about 10x better than diflunisal as an MCT1 inhibitor and there is nothing to be gained from adding diflunisal.

On the other hand, the AR and AZD class of drugs have an in vitro IC50 against MCT1 from 1.6 to 85nM (depending on cell type) and are thus around 1000x more potent than syrosingopine for MCT1 inhibition. The clinical trials are testing it as a single agent in patients with MCT1+/MCT4- tumors. Sadly this might not show the full potential of the drug and it might never make it to market as a consequence.


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GgE
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04/06/2020 10:44 pm  
Posted by: @daniel

Capsules should be easier to find. It was around 150 euro for a 5g bag. Capsules will be cheaper.

Can you post a source, please?

Also for Phenformin, if you know of any


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GgE
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05/06/2020 1:02 am  
Posted by: @toobs

We don't know much about the pharmacodynamics of Syrosingopine, but it seems unlikely to me that we can actually achieve 10uM safely at home. In their 2016 in vivo experiment, they injected the mice with 7.5mg/kg. The equivalent injected dose would be around 50mg. Who knows what the equivalent oral dose would be, but it's for sure much higher than the levels used for treatment of high blood pressure.

However, the same level of intracellular lactate accumulation as for the wild type cells HAP1 was achieved with only 50nM in MCT1 knockout cells. This led me to look for MCT1 inhibitors that are easily available, with a good safety profile, and that can achieve meaningful inhibition of MCT1 with known-to-be-safe oral doses. There are lots of MCT1 inhibitors, but after days and days of research, the only candidate I found that meets the above criteria is Diflunisal.

- Diflunisal is a non-competitive MCT1 inhibitor

- At 0.8mM, Diflusinal is highly synergistic In Vitro with Diclofenac (0.1mM), an MCT4 inhibitor, and Metformin (1mM). As an aside, although Diclofenac is readily available and cheap, you're never going to achieve 1mM with Diclofenac.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224440/

- After 7 days of dosing at 500mg twice daily, the mean trough plasma level of Diflunisal was 0.34mM

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.1977.tb04511.x

- The official max daily dose is 1500mg per day

This find has me enthusiastic about syro again. Although some tumors have low levels of MCT1 activation, many don't. Prostate cancer for instance often has activated MCT1 and MCT4.

Posted by: @majortom

the AR and AZD class of drugs have an in vitro IC50 against MCT1 from 1.6 to 85nM (depending on cell type) and are thus around 1000x more potent than syrosingopine for MCT1 inhibition. The clinical trials are testing it as a single agent in patients with MCT1+/MCT4- tumors. Sadly this might not show the full potential of the drug and it might never make it to market as a consequence.

Tom, you say that because Diflunisal has an in vitro IC50 against MCT1 of 50uM while syro's is at the 3-5uM range then syrosingopine is about 10x better than diflunisal as an MCT1 inhibitor and there is nothing to be gained from adding diflunisal. You may be right. Unfortunately nobody can wait for the AR or AZD drugs to be made available, as you imply.

We all know that people need to find what could work for them now. It appears as though the syrosingopine + metformin combination has worked for some cancer patients but not for others. We need to find a way to improve it and make it work for more people.

I am reading the above quote from Toobs. Apparently it is easy to get diflunisal levels 7 times higher than its IC50, may be even higher with a 1500 mg a day dose. Do you have data about its effectiveness at this higher concentration? Do you know if diflunisal synergizes with syrosingopine to inhibit MCT1 better than the sum of both substances by themselves?

In the meantime, please help us find something that inhibits MCT1 better than diflunisal and is available .

We might consider adding old Loratadine (old anti-allergy Claritin) to the combo: "Loratadine was determined to be the most potent l-lactic acid efflux inhibitor in this study, with an average IC50 of 15 µM at pH 7.4" from 

https://www.mdpi.com/1999-4923/9/4/42/htm

(Loratadine might have different effectiveness at the more acidic tumor pH levels.)

See also "The efflux transport was next examined: loratadine (IC50: 10 and 61 µM) and atorvastatin (IC50: 78 and 41 µM) demonstrated the greatest potency for inhibition of L-lactic acid efflux by MCT1 and MCT4, respectively." posted by Daniel on this forum on Nov. 27, 2019 from

http://www.eurekaselect.com/160298/article

Do you think that diclofenac could help inhibit the last MCT1s in the tumor cells?


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Daniel
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05/06/2020 1:33 am  
Posted by: @gge
Posted by: @daniel

Capsules should be easier to find. It was around 150 euro for a 5g bag. Capsules will be cheaper.

Can you post a source, please?

Also for Phenformin, if you know of any

Solution for IV: first pharmacy listed on this website, under NEWS & OTHERS/SUPPLIERS

Oral: here is an example http://www.unohealthcare.com/products/item/124-diflunisal but you can search for more options using "Diflunisal and Rising" or "Dolobid" as keywords.

Kind regards,
Daniel


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toobs1234
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05/06/2020 1:43 am  
Posted by: @majortom
it suggests that syrosingopine is about 10x better than diflunisal as an MCT1 inhibitor and there is nothing to be gained from adding diflunisal.

I think you may have missed the point of diflunisal+syro...you can't dose syro high enough orally to get effective MCT1 inhibition. You can, however, dose diflunisal high enough to get effective MCT1 inhibition and hopefully dose syro high enough to get MCT4 inhibition.


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GgE
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05/06/2020 3:05 am  
Posted by: @toobs

You can, however, dose diflunisal high enough to get effective MCT1 inhibition

Can you please explain why you think the above? Tom seems to doubt that the diflunisal level can ever get high enough to inhibit MCT1 sufficiently as to cause synthetic lethality.

Also, do you have info about the levels diflunisal can reach in tissues, esp. cancer tissues, and whether it accumulates in them so that its concentration level can be much higher than in plasma?


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MajorTom
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05/06/2020 9:32 am  

I'm just quoting the in vitro data. In vivo bioavailability and pharmacokinetics is a different beast altogether. I'm not discouraging trying them out, provided there is some sort of medical oversight (hopefully one has a sympathetic doctor). It just important to lay all the cards out. As you said, we cannot wait for drugs to be available, which in certain cases, may be never. 


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GgE
 GgE
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05/06/2020 7:20 pm  
Posted by: @majortom

It just important to lay all the cards out. As you said, we cannot wait for drugs to be available, which in certain cases, may be never. 

I agree that it is important to be objective and to put forward all the info we can gather so that everyone can make their own decisions. We all appreciate your efforts, as well as Toobs, Daniel, Johhny, and many others.

I think we all see there is a great potential in this metabolic strategy. There are others that could work also. But I have personally seen hard to treat hormone positive breast cancer skin metastases shrivel and die within weeks while on a plain syrosingopine + metformin + loratadine + low carb diet as the only treatment. Unfortunately the low blood pressure and undernourishment side effects became too bad for the patient to take.

So, the issue is how to select the best available drugs that can reach tissue levels to the point where they're effective in killing more cancer cells than the cells can create while controlling the nutrition and side effects within tolerable levels.

For millions of people the AR and AZD MCT1 inhibitors will come out too late, if ever. If we could all make a concerted effort here to brain storm and come up with what we think might be the combo with the highest chances of success (not guarantees) we might help many of those people, even if not all, to expand their lives and their life quality to some degree.

Can we count you and everyone in, please?


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toobs1234
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07/06/2020 1:47 pm  
Posted by: @gge
Posted by: @toobs

You can, however, dose diflunisal high enough to get effective MCT1 inhibition

Can you please explain why you think the above? Tom seems to doubt that the diflunisal level can ever get high enough to inhibit MCT1 sufficiently as to cause synthetic lethality.

Also, do you have info about the levels diflunisal can reach in tissues, esp. cancer tissues, and whether it accumulates in them so that its concentration level can be much higher than in plasma?

Hi gge,

I'm separated from my computer right now, but when I get back I'll post some references that support the MCT1  inhibition effectiveness of diflunisal at achievable doses...in addition to the difunisal/diclofenac/metformin study that I mentioned earlier.

I don't have any reason to believe that the diflunisal will accumulate, but I'm not a specialist. The attraction of metformin to the mitochondria is due to the mitochondrial membrane potential and as far as I know is somewhat unique.


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