HIF-1α inhibition by DES.

[pjoshea13]

New study below.

We are 30+ years into the Lupron era, but diethylstilbestrol [DES] was used for about 45 years before that & shouldn't be entirely ignored.

DES is a synthetic estrogen. The male response to high amounts of estrogen is reduced testosterone production (the presumed source of the estrogen, via aromatization). However, in a very small minority of men, DES does not lower T, & yet does lower PSA, indicating that it has anti-PCa properties unrelated to castration.

In fact, some men on Lupron who become "castrate-resistant", have a response to DES:

(2014 - Israel [2]) "Patients treated with DES during the castration-resistant phase following the failure of prior treatment with LH-RH analogs during the castration-sensitive phase were retrieved from a prostate cancer database of our institution. Patients were treated with a daily dose of DES of 1-4 mg (mean, 2.6 mg) and anticoagulants for thromboembolic prophylaxis until disease progression."

"Forty-three DES-treated CRPC patients were found in our database through July 2011. The median age was 66 years. Sixty-three percent of the patients achieved a ≥50% decline in their serum PSA levels during DES therapy. Median TDP {time to disease progression} was 20.4 months for LH-RH analog treatment in the castration-sensitive phase, and 7.1 months for DES treatment in the castration-resistant phase. Durable responses (>1 year) were observed in 31% of the patients. Median overall survival was 57 months from the start of the DES therapy."

Although DES production in the U.S. ended twenty years ago, it can be obtained from compounding pharmacies.

The new Spanish-Portuguese study found an interesting effect on HIF-1α.

When tumors outgrow their blood supply, the drop in oxygen (hypoxia) triggers HIF-1α (hypoxia-inducible factor 1α). This is bad news, because HIF is the ultimate survival response. Therapies stop working, new blood vessels form, etc.

"Oxygen deprivation prompted a number of changes in intracellular composition and metabolic activity, mainly reflecting upregulated glycolysis, amino acid catabolism and other compensatory mechanisms used by hypoxic cells to deal with oxidative imbalance and energy deficit."

"Cell treatment with a non-cytotoxic concentration of DES, under hypoxia, triggered significant changes in 17 metabolites. Among these, lactate, phosphocreatine and reduced glutathione, whose levels showed opposite variations in hypoxic and drug-treated cells, emerged as possible markers of DES-induced HIF-1α inhibition."

"Overall, this study has revealed a number of unanticipated metabolic changes that inform on DES ... direct cellular effects ..."

{Incidentally, my approach to HIF-1α inhibition is a daily nitroglycerine patch, which improves blood supply to tumors.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/287...

[2] ncbi.nlm.nih.gov/pubmed/242...

[Dan59]

Patrick, Thanks for your research, I too beleive DES to be a very useful and Cheap therapy in CRPC. In older groups before zytiga and xtandi, there were many men on this therapy with CRPC that did very well for long time. Studies by Mike Glode et al.showed that lower doses below the old standard of 5 mg to either 3 mg or 1 mg had nearly as good response with much better safety profile IE Blood Clots. The greater dose was always used with anticoagulation. I had never heard of HIF1alpha inhibition , Does it prevent angiogenisis to the cells to prevent new tumors. I myself was on estrogen patches whenever a treatment ie nilandron or keto or even xtandi failed I added the estrdiol patch and got more time out of the therapy being used,on the 5th rechallenge I believe I had a withdraw response. O. Sartor has said he has seen Des work when the patches failed.

Dan

[pjoshea13 in reply to Dan59]

Dan,

One of the reasons Lupron was so readily accepted, was the clotting issue with oral DES. My feeling is that everyone with cancer has a higher risk of blood clots, & that should always be addressed. & if that happens, DES is less scary. All treatments are scary, of course.

I have posted on dysfunctional coagulation. A D-dimer test can be used to assess clotting activity. A very low value = no clot. Nattokinase can be used to speed up the very slow breakdown of clots by plasmin. Useful regardless of DES use.

I know of men who have had success with low-dose (1mg) DES. Some opting to use it istead of Lupron.

HIF1alpha induces VEGF (Vascular endothelial growth factor) which is necessary for angiogenesis. One of a number of reasons that HIF1alpha is such a good target.

Siemens, in his Phase II ntroglycerine study [1] writes:

"The prolongation of the PSADT and the safety of the drug, coupled with the corresponding preclinical in vitro and in vivo data documenting the ability of nitric oxide to attenuate hypoxia-induced progression of prostate cancer, warrant further testing in a placebo-controlled study."

I don't think he would see such results unless HIF1alpha was inhibited.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/194...

[Dan59 in reply to pjoshea13]

Thanks for your response Patrick.

[rococo in reply to Dan59]

Interesting, seen this many times with older drugs wiich I always reconsider and rechallenge in my future treatments. Good news for some who haven't the resources for the new stuff.

[E2-Guy in reply to rococo]

rococo, Patrick believes that you and Dan59 were never privy to this post so I am reposting.

"Looking at the sequence of posts in this thread, only "Appraiser" & myself would have received notification of your post. i.e. 'Dan59', & 'rococo' aren't ignoring you. You need to send them individual replies to get their attention. It's a weakness of the system. Ideally, everyone who has participated in a thread should be notified of new posts."

Best, -Patrick

HI 'Appraiser', 'pjoshea13', 'Dan59', 'rococo', I find your posts extremely interesting since I am approaching the point at which I should start thinking about ADT. I live in Thailand and my US Medicare insurance doesn't cover any medical expenses out of the country; therefore, I am looking into alternative therapies to help slow down the progression my stage 4 PCa. I think you can find my profile information that I posted a few months back when I joined this forum...if not, I can post my info again. Just briefly, I have recurrence after a robotic radical 12 years ago. I feel very fortunate to have gone this long without any adjuvant therapy especially since my Gleason was 4+4 and my staging was T3a. My PSA has been rising slowly over the years (1.3 in May of 2017) and I have recently had a 68Ga/PSMA/PET/CT/scan performed in Melbourne, AU which identified sacral lymph node involvement. I just had robotic LN surgery and my PSA has decreased to 0.54; however, the pathology report showed that I also have 'soft tissue' involvement. I am quite happy with the results since I was pessimistic prior to getting the PSA results...I thought that the LN surgery would have been a waste since there is additional tissue involvement. Back to DES and other affordable ADT drugs. My father was on DES (radical at about 60 years of age) for many years before he was castrated at around 80 (I believe he chose castration as an alternative to Lupron since doctors stopped using DES (I think) in the early 80's. My dad died at 89 of heart failure; however, never complained about side effects. I have discussed DES with my urologist/oncologist and he told me that recent research is of the belief that DES may not have been as responsible for cardiovascular failure as previously thought...reduced 'T' effects are of consideration. As I have mentioned, I live in Thailand where 'transgenderism' is quite common and many young boys are put on hormones by their poor parents in hopes that they may as adults find men that will support them and the family. Our pharmacies have numerous oral and transdermal forms of estradiol at very reasonable prices. I haven't done my homework yet regarding these drugs/hormones with the exception of 'Estrogel' which many transgenders are using and don't seem to be experiencing the side effects that modern, expensive ADT drugs produce. Dr. Meyers talks about the 'patch', a form of transdermal estradiol. Richard Wassersug (gentleman on this forum) is also very knowledgeable regarding this subject. Hoping to hear everyone's comments.

Ron ([e-mail])

[E2-Guy in reply to Dan59]

Dan, Patrick believes that you and 'rococo' were never privy to this post so I am reposting. "Looking at the sequence of posts in this thread, only "Appraiser" & myself would have received notification of your post. i.e. 'Dan59', & 'rococo' aren't ignoring you. You need to send them individual replies to get their attention. It's a weakness of the system. Ideally, everyone who has participated in a thread should be notified of new posts."

Best, -Patrick

HI 'Appraiser', 'pjoshea13', 'Dan59', 'rococo', I find your posts extremely interesting since I am approaching the point at which I should start thinking about ADT. I live in Thailand and my US Medicare insurance doesn't cover any medical expenses out of the country; therefore, I am looking into alternative therapies to help slow down the progression my stage 4 PCa. I think you can find my profile information that I posted a few months back when I joined this forum...if not, I can post my info again. Just briefly, I have recurrence after a robotic radical 12 years ago. I feel very fortunate to have gone this long without any adjuvant therapy especially since my Gleason was 4+4 and my staging was T3a. My PSA has been rising slowly over the years (1.3 in May of 2017) and I have recently had a 68Ga/PSMA/PET/CT/scan performed in Melbourne, AU which identified sacral lymph node involvement. I just had robotic LN surgery and my PSA has decreased to 0.54; however, the pathology report showed that I also have 'soft tissue' involvement. I am quite happy with the results since I was pessimistic prior to getting the PSA results...I thought that the LN surgery would have been a waste since there is additional tissue involvement. Back to DES and other affordable ADT drugs. My father was on DES (radical at about 60 years of age) for many years before he was castrated at around 80 (I believe he chose castration as an alternative to Lupron since doctors stopped using DES (I think) in the early 80's. My dad died at 89 of heart failure; however, never complained about side effects. I have discussed DES with my urologist/oncologist and he told me that recent research is of the belief that DES may not have been as responsible for cardiovascular failure as previously thought...reduced 'T' effects are of consideration. As I have mentioned, I live in Thailand where 'transgenderism' is quite common and many young boys are put on hormones by their poor parents in hopes that they may as adults find men that will support them and the family. Our pharmacies have numerous oral and transdermal forms of estradiol at very reasonable prices. I haven't done my homework yet regarding these drugs/hormones with the exception of 'Estrogel' which many transgenders are using and don't seem to be experiencing the side effects that modern, expensive ADT drugs produce. Dr. Meyers talks about the 'patch', a form of transdermal estradiol. Richard Wassersug (gentleman on this forum) is also very knowledgeable regarding this subject. Hoping to hear everyone's comments.

Ron ([e-mail])

[Dan59 in reply to E2-Guy]

If the modern treatment are not available or affordable, DES is certainly an option. I used transdermal estradiol, 6 times .1 mg patches per week, The transdermal route has been shown to bypass the liver and not have such a blood clot problem, I wish you the best.

Dan

[E2-Guy in reply to Dan59]

Thank you Dan!

[Appraiser]

Hi Patrick

I've been on .5 of DES for over 3 years now and it's been a miracle drug for me. My testosterone remains close to 500.I did add Metformin about a year and half ago. (Gleason 9 diagnosed in 2004) my latest psa came back at .7 where it's been for the last couple of years. My last visit my oncologist was interesting and let to a pretty good argument when I mentioned he doing his patients especially the younger ones an injustice by not telling them what's going on with me and how DES could work for some people. I told him you give patients those crappy drugs that cost a fortune, they go home and don't even want to look at there wife's because they take away all their testosterone. You should be trying this first.......To make a long story short, and he admitted it, in his words " there's no money in your drug". Drug Companies would never open up Studies on a drug that cost $90 a month. I will say one thing. 3 years ago he thought I was nuts doing DES and tried to get me to do Lupron or whatever. Today he tells me although he can't prescribe DES, if someone comes in his office and says they'd like to try it. He'd tell them. GO FOR IT

[pjoshea13 in reply to Appraiser]

I now have 3 accounts of low-dose DES not affecting T levels while controling PSA. Unfortunately, it does result in castrate T for most men. Would be good to have a DES analog that did not castrate.

0.5 mg is a low dose, but everyone with PCa has increased risk for clots. I have posted on the issue, but it all comes down to this:

i) monitor D-dimer - it should be near zero.

ii) use Nattokinase to work on suspected clots if D-dimer is high. It will go higher while clots dissolve, but D-dimer will eventually fall to near zero. A maintenance dose of nattokinase will be needed.

The above is opinion, rather than medical advice, of course.

-Patrick

[E2-Guy in reply to Appraiser]

HI 'Appraiser', 'pjoshea13', 'Dan59', 'rococo', I find your posts extremely interesting since I am approaching the point at which I should start thinking about ADT. I live in Thailand and my US Medicare insurance doesn't cover any medical expenses out of the country; therefore, I am looking into alternative therapies to help slow down the progression my stage 4 PCa. I think you can find my profile information that I posted a few months back when I joined this forum...if not, I can post my info again. Just briefly, I have recurrence after a robotic radical 12 years ago. I feel very fortunate to have gone this long without any adjuvant therapy especially since my Gleason was 4+4 and my staging was T3a. My PSA has been rising slowly over the years (1.3 in May of 2017) and I have recently had a 68Ga/PSMA/PET/CT/scan performed in Melbourne, AU which identified sacral lymph node involvement. I just had robotic LN surgery and my PSA has decreased to 0.54; however, the pathology report showed that I also have 'soft tissue' involvement. I am quite happy with the results since I was pessimistic prior to getting the PSA results...I thought that the LN surgery would have been a waste since there is additional tissue involvement. Back to DES and other affordable ADT drugs. My father was on DES (radical at about 60 years of age) for many years before he was castrated at around 80 (I believe he chose castration as an alternative to Lupron since doctors stopped using DES (I think) in the early 80's. My dad died at 89 of heart failure; however, never complained about side effects. I have discussed DES with my urologist/oncologist and he told me that recent research is of the belief that DES may not have been as responsible for cardiovascular failure as previously thought...reduced 'T' effects are of consideration. As I have mentioned, I live in Thailand where 'transgenderism' is quite common and many young boys are put on hormones by their poor parents in hopes that they may as adults find men that will support them and the family. Our pharmacies have numerous oral and transdermal forms of estradiol at very reasonable prices. I haven't done my homework yet regarding these drugs/hormones with the exception of 'Estrogel' which many transgenders are using and don't seem to be experiencing the side effects that modern, expensive ADT drugs produce. Dr. Meyers talks about the 'patch', a form of transdermal estradiol. Richard Wassersug (gentleman on this forum) is also very knowledgeable regarding this subject. Hoping to hear everyone's comments.

Ron ([e-mail])

[pjoshea13 in reply to E2-Guy]

Ron,

I hesitate to offer suggestions regarding such a serious step.

But if you were to opt for DES, I would try the 1mg dose, rather than the much larger doses that were commonly used for decades. Some would say start with 0.5mg.

DES is a synthetic estrogen & appears to have anti-PCa properties beyond lowering testosterone [T]. Interestingly, a very small minority of men obtain benefit without any effect on T.

Oral estrogens are associated with an increased risk of clotting. I would suggest that you use nattokinase to dissolve any clots that may be forming. You should check D-dimer periodically. If it is elevated, you need to up the dose of nattokinase to bring D-dimer close to zero.

Looking at the sequence of posts in this thread, only "Appraiser" & myself would have received notification of your post. i.e. 'Dan59', & 'rococo' aren't ignoring you. You need to send them individual replies to get their attention. It's a weakness of the system. Ideally, everone who has participated in a thread should be notified of new posts.

Best, -Patrick

[E2-Guy in reply to pjoshea13]

Thank you Patrick for your most helpful input!

[Stuart291 in reply to Appraiser]

Hi appraiser

my name is Stuart I'm in New York, I became aware of low does Des after reading about pc -spes, the clinical results are amazing, it seems like it was spiked with Des

Do you know how I can acquire Some Des? I would very much appreciate your help thank you

[Appraiser in reply to Stuart291]

Hi Stuart

I’m pretty sure you would need to find a doctor who would prescribe it. I was quite lucky in that respect as I found one who practices natural medicine and was willing to go above and beyond. He is located in Massachusetts. I’m pretty sure you would have to make an appointment

[Stuart291 in reply to Appraiser]

Thanks for getting back to me! In NY naturopaths aren't licensed and therefore cannot prescribe , could you give me his contact info?

Again thanks some much for your help

[Appraiser in reply to Stuart291]

He’s not a naturopath, he’s an actual MD practicing natural healing. His business is Dr Dansnatural healing center. His website is drdansnaturalhealing.com

[Stuart291 in reply to Appraiser]

Thanks so much appraiser

I really appreciate your help, from what I am understand dES is no longer manufactured in the US, can you tell me where your fill your prescription? Also perhaps I could use your name when I'm speaking to dr. Dan? first name? If not that's okay, I understand

again thank you for your help

[Appraiser in reply to Stuart291]

Hi Stuart

Dr Dan just writes the Scrip......I get it filled at a compounding pharmacy in the same town. Tell him Joe Dagati referenced you. He'll know when you mention DES. Let me know how it goes.

[Stuart291 in reply to Appraiser]

Thanks so much again Joe I owe you

Forever in your debt Stuart

[Dan59]

Ron, Dr Glode has done studies that you could find on google scholar on the use of low dose DES, Glode et al. low dose DES. I am currently traveling but soon I will be home and could post these if you can not find them. There was also a guy with advanced disease that used low dose DES for many years with good results, he claimed the cost to be 100 dollars a year. I myself got a lot of time out of climera estradiol patches .1 mg daily six out of seven days prepped with 90% alcohol to skin. as Patrick said oral estrogens are associated with blood clots and may require antocoagulation. Transdermal on the other hand is notcleared by the liver and not associated so much with clots.

wishing you the best

Dan

[E2-Guy in reply to Dan59]

Thank you Dan for the valuable suggestions. Your, Patrick's, and Richard Wassersug's info has convinced me to start transdermal estradiol gel...available here in Thailand for about $10/tube.