I'm home, and although I tried getting back to bed this morning (at Dan's request) I can't help it but hit the ground running. My parents will be here in a few hours to spend the night, as they're flying out to get more venom tomorrow morning (man three months goes by so quickly!). My dad brought us his truck (thanks Aaron for the canopy!) so that on Friday after work, Dan and I will drive over to Wenatchee and spend the night at my parent's house. Because - for the first time - I get to pick up cherries from Stemilt and deliver a batch to Kings and Market Place in Friday Harbor. I am so excited to put faces to names, and say thank you, and give some hugs. Usually my dad, or my dad and his buddy Ron deliver cherries. The whole delivery is really quick, picking up at 7:00 am, driving to the ferry in Anacortes, taking the first ferry we can and then unloading at both grocery stores and then we're back on the next ferry off the island so that we can make it home and rest. Isn't it crazy how everything always bottlenecks? NYC, venom, cherries.
Cherry season is my favorite. They're so delicious! And really fun to eat. I mean, maybe not if you're really proper, but I'm more of a goofy tomboy who enjoys spitting the seeds. My mom has always called me G.I. Joe Barbie because I want to do what the boys do, but I like to do it with a dress, or a skirt, and now that I'm a little older, makeup. I like to be in the competition, in the mix. Now cherry season has gained even more significance. I get so excited for this fundraiser (which sneaked up on me). This year, instead of one big drop, we've divided it into three deliveries to Kings and Market Place in Friday Harbor. So to all of our Friday Harbor friends, when you're walking through the produce isle next week, and you have a hankering for cherries please know that I appreciate your support so very much!
Just yesterday I had to write the check for my shot and with the Euro so strong against the dollar it was over $5700. The treatments are stupid expensive, but surviving seems pretty smart, so whatever it takes I'm willing to do it. Also while at the doctor in NYC I discussed the sodium phenylbutyrate again. He said that it not only helps reduce glutamine/glutamate absorbtion which would slow tumor feeding, but also, the drug is a gene modifier. The problem? The market price is currently over $6000 a month. That's the actual cost of the product used in clinical trials. There is also a chemist's reproduction (you have to find a chemist pharmacy) which is not exactly the same as the drug, but very similar, essentially it's a knockoff. And it comes in at around $1200 a month. The third option is the supplement Butyrex which I own and have taken from time to time. But it's degradingly weak in comparison to the drug. So much so that it's probably a joke for what we're drying to do. There is one health insurance in the United States that will cover sodium phenylbutyrate for malignant gliomas, Aetna (technically it's an off label drug for urea cycle disorders). I do not have Aetna, but since I lost my insurance due to the Obama health care act (long story) and they bounced me down to Medicare, there could be a way when I renew in December to opt into Aetna for prescriptions. It will take until December to find out, but at least there might be a chance. As an aside, a while ago I spoke to the mother of a young woman who has taken sodium phenylbutyrate for around a year (or maybe it's two years by now) and she didn't have any real symptoms. Now, you might think I'm crazy that I'm talking about adding more
treatments, but these tumors are invasive, and they morph and outsmart
even the best cocktails. I mean, when you get a promotion, you don't just sit on your ass, it sparks you to keep the momentum going! This tumor is my career; I get paid in time. I don't want Hermie to come back. I refuse to
be complacent. And if the additional treatment has a low risk profile, I don't see why not. Especially when we already know that IDH1 tumors, like mine, love them some glutamine/glutamate.
This brings me to a another fun rabbit hole I fell into while traveling. Are you guys familiar with methionine? I wasn't until I read THIS STUDY on the airplane last night. For those who don't want to read through the article, it's about dietary changes that you can make to prevent, and mitigate gliomas. One of the points was to focus on methionine restriction, which is an amino acid that is found in the heaviest doses in animal products.
Of course, then this morning, I had to know more. I started searching "methionine glioma", "methionine seizures", "low methionine foods", "methionine longevity". Each search result gave me more information, and more avenues to explore. Again I see that a vegan diet is best, but if you can't go strictly vegan, it would behoove all of us - especially cancer fighters - to cut back on animal products. Even the research with the ketogenic diet shows that it's not healthy unless it's restricted. A purely ketogenic diet is horrible for you. It irks me when I see articles and news reports touting the benefits of the ketogenic diet because they're missing the key point which is the restriction. The diet is actually mostly fat. Like 80% fat. So, of course you're eliminating a lot of glutamate/glutamine, glucose, methionine, etc. Heck, the restricted ketogenic diet is actually more like an elimination diet. You remove a lot of allergens. Anyway, not my point. The reading from last night and this morning reaffirms my choice to go heavy veggies, with an emphasis on superfoods (it really should be a one word term).
See - I can't help it, I start doing tumor research even when I'm supposed to be focusing on my seizure issues. The seizure issues are incredibly complex, almost too complicated to figure out. And the research about seizures is either very inconclusive or correlative but not necessarily causal. There's just so little we know about what causes seizures, or how to prevent them. Another horribly complicated riddle. I actually enjoyed researching methionine since there was clear information I could absorb and use. But for now, I'd better give my brain a break before it short circuits again. Also, thanks for all of the recent comments lately, I'll go through them soon!
Showing posts with label sodium phenylbutyrate. Show all posts
Showing posts with label sodium phenylbutyrate. Show all posts
6.26.2014
5.22.2014
Flubbed The Obvious
I had an obnoxiously long blog post full of crazy information and charts, and things about glutamine - I had been working on it all day - then my mind was blown with a shattering epiphany, things started piecing together. If low grade tumors feed mostly off of glutamine/glutamate, then what's the story with glucose? So I talked it out with Dan and as we both started searching online (boy do we have some sexy phone dates) we finally started asking the right questions. What is in my special F-DOPA PET scan that I fly down to UCLA for? I felt like a moron, how had I never wondered that? If they weren't measuring glucose, which they clearly stated, what were they measuring? We typed it in and bam, if I'm understanding this correctly, the F-DOPA PET is essentially measuring an amino acid on the glutamine-glutamate pathway (click for a study).
How did I not ask that? How did I not figure it out? I remember being completely distracted by the fact that they were using radioactive particles. I guess that's where my mind went. It never occurred to me to wonder what was being mixed with those particles. I remember talking to my doctors after the surgery, in the neruosurgery ICU, about the idea of me going on the restricted keto to slow tumor growth. They thought it was great. How did it not come up that glutamine is the food source for my type of tumor, not glucose? Had they not pieced that together either? It seems as if they would have, yet, clearly they didn't or I think they would have said something. It's the whole point of this latest fancy scan, this exclusive machine that's only available at a few centers across the country, to measure the glutamine-ish stuff going on in my low grade tumor. How are the fragments of knowledge scattered so far apart throughout the tumor world that it's this hard for tumor patients to piece it together? What's going on? Oh, I feel sick. We really do have to figure stuff out on our own. Thank God I give a fart. At least now I can adjust. If I would have stayed on the Paleo diet it would have sped up tumor growth. The way that I have been eating has been full speed down the pro-amino acid freeway. No stoplights. And according to what I'm reading, the more glutamine in your system, the faster your tumor shifts into using glucose as fuel. It's a catalyst. Hello faster growing tumor. Hello death. I am literally glaring at an imagined Grim Reaper right now. I just told him I'm not ready, and if he comes near me he's going to regret it. Scythe or no scythe, this girl is scrappy.
Here's a scary, but necessary read about glutamine (for the record, I have shifted from Coldplay to straight up Enya's greatist hits - in dire need of some uplifting):
Deregulated energetics. One hallmark of cancer cells is aberrant bioenergetics (26). Glutamine’s involvement in the pathways outlined above contributes to a phenotype conducive to energy formation, survival, and growth. In addition to its role in mitochondrial metabolism, glutamine also suppresses expression of thioredoxin-interacting protein, a negative regulator of glucose uptake (27). Thus, glutamine contributes to both of the energy-forming pathways in cancer cells: oxidative phosphorylation and glycolysis. Glutamine also modulates hallmarks not traditionally thought to be metabolic, as outlined below. These interactions highlight the complex interplay between glutamine metabolism and many aspects of cell biology.
Sustaining proliferative signaling. Pathological cancer cell growth relies on maintenance of proliferative signaling pathways with increased autonomy relative to non-malignant cells. Several lines of evidence argue that glutamine reinforces activity of these pathways. In some cancer cells, excess glutamine is exported in exchange for leucine and other essential amino acids. This exchange facilitates activation of the serine/threonine kinase mTOR, a major positive regulator of cell growth (28). In addition, glutamine-derived nitrogen is a component of amino sugars, known as hexosamines, that are used to glycosylate growth factor receptors and promote their localization to the cell surface. Disruption of hexosamine synthesis reduces the ability to initiate signaling pathways downstream of growth factors (29).
Enabling replicative immortality. Some aspects of glutamine metabolism oppose senescence and promote replicative immortality in cultured cells. In IMR90 lung fibroblasts, silencing either of two NADPH-generating isoforms of malic enzyme (ME1, ME2) rapidly induced senescence, while malic enzyme overexpression suppressed senescence (30). Both malic enzyme isoforms are repressed at the transcriptional level by p53 and contribute to enhanced levels of glutamine consumption and NADPH production in p53-deficient cells. The ability of p53-replete cells to resist senescence required the expression of ME1 and ME2, and silencing either enzyme reduced the growth of TP53+/+ and, to a lesser degree, TP53–/– tumors (30). These observations position malic enzymes as potential therapeutic targets.
Resisting cell death. Although many cancer cells require glutamine for survival, cells with enhanced expression of Myc oncoproteins are particularly sensitive to glutamine deprivation (8, 12, 16). In these cells, glutamine deprivation induces depletion of TCA cycle intermediates, depression of ATP levels, delayed growth, diminished glutathione pools, and apoptosis. Myc drives glutamine uptake and catabolism by activating the expression of genes involved in glutamine metabolism, including GLS and SLC1A5, which encodes the Na+-dependent amino acid transporter ASCT2 (12, 16). Silencing GLS mimicked some of the effects of glutamine deprivation, including growth suppression in Myc-expressing cells and tumors (10, 12). MYCN amplification occurs in 20%–25% of neuroblastomas and is correlated with poor outcome (31). In cells with high N-Myc levels, glutamine deprivation triggered an ATF4-dependent induction of apoptosis that could be prevented by restoring downstream metabolites oxaloacetate and α-ketoglutarate (15). In this model, pharmacological activation of ATF4, inhibition of glutamine metabolic enzymes, or combinations of these treatments mimicked the effects of glutamine deprivation in cells and suppressed growth of MYCN-amplified subcutaneous and transgenic tumors in mice.
The PKC isoform PKC-ζ also regulates glutamine metabolism. Loss of PKC-ζ enhances glutamine utilization and enables cells to survive glucose deprivation (32). This effect requires flux of carbon and nitrogen from glutamine into serine. PKC-ζ reduces the expression of phosphoglycerate dehydrogenase, an enzyme required for glutamine-dependent serine biosynthesis, and also phosphorylates and inactivates this enzyme. Thus, PKC-ζ loss, which promotes intestinal
tumorigenesis in mice, enables cells to alter glutamine metabolism in response to nutrient stress.
Invasion and metastasis. Loss of the epithelial cell-cell adhesion molecule E-cadherin is a component of the epithelial-mesenchymal transition, and is sufficient to induce migration, invasion, and tumor progression (33, 34). Addiction to glutamine may oppose this process because glutamine favors stabilization of tight junctions in some cells (35). Furthermore, the selection of breast cancer cells with the ability to grow without glutamine yielded highly adaptable subpopulations with enhanced mesenchymal marker expression and improved capacity for anchorage-independent growth, therapeutic resistance, and metastasis in vivo (36). It is unknown whether this result reflects a primary role for glutamine in suppressing these markers of aggressiveness in breast cancer, or whether prolonged glutamine deprivation selects for cells with enhanced fitness across a number of phenotypes.
I am mortified and kicking myself that this fell through my fingers. There is en masse of information out there about what to do, what to eat, how to survive cancer, and the hard part is that much of it contradicts. You never know which boat to jump on, but one thing is for certain you'll never survive long if you are stuck treading water. But how did I not follow the tracks? The obviousness of the F-DOPA; the uptake of an unknown substance that was allowing my tumor to glow on this special scan. How did I not think to ask what caused the illumination? I feel like a fool. It saddens me that I've spent a year and a half headed in the wrong direction, eating almost exactly what I shouldn't have. The nauseating irony. All this falls right before my MRI. I have spent the last four months eating glutamine rich foods, just nurturing old Hermie, pampering him. I've already called my doctor to get the ball rolling on adding sodium phenylbytrate (a plasma glutamine lowering drug) at my June 25th appointment - gotta sign some legal documents since it's off label. The crazy thing is that my team of nutritionists who specialize specifically in brain cancer patients were emphatic about me having protein with every meal, and snack, to keep blood glucose stable. The peanut butter was pushed to join in with the apple. But now I know, from checking the levels, peanut butter has a crazy high volume of glutamine. It looks like I would have been better off with just my original apple. How crazy is that!? It's so confusing.
I gotta go decompress. Time restart Enya's greatest hits or something. And maybe munch on one of those juicily tart apples.
Cool thing of the day: Earlier I got an email from Julene, a very sweet blog reader. We had never met, but she offered to drop off a care package to help me survive until Dan arrives (saving me from resorting to my mom's granola bars - definitely not on the new diet).
It was just what I needed. I met a new friend, I stole a few much needed hugs from her, and little did I know that vegetables were going to be paramount in my new diet. And apples have one of the lowest concentrations of glutamine in foods. Why wasn't I listening to my gut!?!? You guys know I love apples. Ugh. FOOL.
How did I not ask that? How did I not figure it out? I remember being completely distracted by the fact that they were using radioactive particles. I guess that's where my mind went. It never occurred to me to wonder what was being mixed with those particles. I remember talking to my doctors after the surgery, in the neruosurgery ICU, about the idea of me going on the restricted keto to slow tumor growth. They thought it was great. How did it not come up that glutamine is the food source for my type of tumor, not glucose? Had they not pieced that together either? It seems as if they would have, yet, clearly they didn't or I think they would have said something. It's the whole point of this latest fancy scan, this exclusive machine that's only available at a few centers across the country, to measure the glutamine-ish stuff going on in my low grade tumor. How are the fragments of knowledge scattered so far apart throughout the tumor world that it's this hard for tumor patients to piece it together? What's going on? Oh, I feel sick. We really do have to figure stuff out on our own. Thank God I give a fart. At least now I can adjust. If I would have stayed on the Paleo diet it would have sped up tumor growth. The way that I have been eating has been full speed down the pro-amino acid freeway. No stoplights. And according to what I'm reading, the more glutamine in your system, the faster your tumor shifts into using glucose as fuel. It's a catalyst. Hello faster growing tumor. Hello death. I am literally glaring at an imagined Grim Reaper right now. I just told him I'm not ready, and if he comes near me he's going to regret it. Scythe or no scythe, this girl is scrappy.
Here's a scary, but necessary read about glutamine (for the record, I have shifted from Coldplay to straight up Enya's greatist hits - in dire need of some uplifting):
Glutamine promotes hallmarks of malignancy (click for full article)
Deregulated energetics. One hallmark of cancer cells is aberrant bioenergetics (26). Glutamine’s involvement in the pathways outlined above contributes to a phenotype conducive to energy formation, survival, and growth. In addition to its role in mitochondrial metabolism, glutamine also suppresses expression of thioredoxin-interacting protein, a negative regulator of glucose uptake (27). Thus, glutamine contributes to both of the energy-forming pathways in cancer cells: oxidative phosphorylation and glycolysis. Glutamine also modulates hallmarks not traditionally thought to be metabolic, as outlined below. These interactions highlight the complex interplay between glutamine metabolism and many aspects of cell biology.
Sustaining proliferative signaling. Pathological cancer cell growth relies on maintenance of proliferative signaling pathways with increased autonomy relative to non-malignant cells. Several lines of evidence argue that glutamine reinforces activity of these pathways. In some cancer cells, excess glutamine is exported in exchange for leucine and other essential amino acids. This exchange facilitates activation of the serine/threonine kinase mTOR, a major positive regulator of cell growth (28). In addition, glutamine-derived nitrogen is a component of amino sugars, known as hexosamines, that are used to glycosylate growth factor receptors and promote their localization to the cell surface. Disruption of hexosamine synthesis reduces the ability to initiate signaling pathways downstream of growth factors (29).
Enabling replicative immortality. Some aspects of glutamine metabolism oppose senescence and promote replicative immortality in cultured cells. In IMR90 lung fibroblasts, silencing either of two NADPH-generating isoforms of malic enzyme (ME1, ME2) rapidly induced senescence, while malic enzyme overexpression suppressed senescence (30). Both malic enzyme isoforms are repressed at the transcriptional level by p53 and contribute to enhanced levels of glutamine consumption and NADPH production in p53-deficient cells. The ability of p53-replete cells to resist senescence required the expression of ME1 and ME2, and silencing either enzyme reduced the growth of TP53+/+ and, to a lesser degree, TP53–/– tumors (30). These observations position malic enzymes as potential therapeutic targets.
Resisting cell death. Although many cancer cells require glutamine for survival, cells with enhanced expression of Myc oncoproteins are particularly sensitive to glutamine deprivation (8, 12, 16). In these cells, glutamine deprivation induces depletion of TCA cycle intermediates, depression of ATP levels, delayed growth, diminished glutathione pools, and apoptosis. Myc drives glutamine uptake and catabolism by activating the expression of genes involved in glutamine metabolism, including GLS and SLC1A5, which encodes the Na+-dependent amino acid transporter ASCT2 (12, 16). Silencing GLS mimicked some of the effects of glutamine deprivation, including growth suppression in Myc-expressing cells and tumors (10, 12). MYCN amplification occurs in 20%–25% of neuroblastomas and is correlated with poor outcome (31). In cells with high N-Myc levels, glutamine deprivation triggered an ATF4-dependent induction of apoptosis that could be prevented by restoring downstream metabolites oxaloacetate and α-ketoglutarate (15). In this model, pharmacological activation of ATF4, inhibition of glutamine metabolic enzymes, or combinations of these treatments mimicked the effects of glutamine deprivation in cells and suppressed growth of MYCN-amplified subcutaneous and transgenic tumors in mice.
The PKC isoform PKC-ζ also regulates glutamine metabolism. Loss of PKC-ζ enhances glutamine utilization and enables cells to survive glucose deprivation (32). This effect requires flux of carbon and nitrogen from glutamine into serine. PKC-ζ reduces the expression of phosphoglycerate dehydrogenase, an enzyme required for glutamine-dependent serine biosynthesis, and also phosphorylates and inactivates this enzyme. Thus, PKC-ζ loss, which promotes intestinal
tumorigenesis in mice, enables cells to alter glutamine metabolism in response to nutrient stress.
Invasion and metastasis. Loss of the epithelial cell-cell adhesion molecule E-cadherin is a component of the epithelial-mesenchymal transition, and is sufficient to induce migration, invasion, and tumor progression (33, 34). Addiction to glutamine may oppose this process because glutamine favors stabilization of tight junctions in some cells (35). Furthermore, the selection of breast cancer cells with the ability to grow without glutamine yielded highly adaptable subpopulations with enhanced mesenchymal marker expression and improved capacity for anchorage-independent growth, therapeutic resistance, and metastasis in vivo (36). It is unknown whether this result reflects a primary role for glutamine in suppressing these markers of aggressiveness in breast cancer, or whether prolonged glutamine deprivation selects for cells with enhanced fitness across a number of phenotypes.
I am mortified and kicking myself that this fell through my fingers. There is en masse of information out there about what to do, what to eat, how to survive cancer, and the hard part is that much of it contradicts. You never know which boat to jump on, but one thing is for certain you'll never survive long if you are stuck treading water. But how did I not follow the tracks? The obviousness of the F-DOPA; the uptake of an unknown substance that was allowing my tumor to glow on this special scan. How did I not think to ask what caused the illumination? I feel like a fool. It saddens me that I've spent a year and a half headed in the wrong direction, eating almost exactly what I shouldn't have. The nauseating irony. All this falls right before my MRI. I have spent the last four months eating glutamine rich foods, just nurturing old Hermie, pampering him. I've already called my doctor to get the ball rolling on adding sodium phenylbytrate (a plasma glutamine lowering drug) at my June 25th appointment - gotta sign some legal documents since it's off label. The crazy thing is that my team of nutritionists who specialize specifically in brain cancer patients were emphatic about me having protein with every meal, and snack, to keep blood glucose stable. The peanut butter was pushed to join in with the apple. But now I know, from checking the levels, peanut butter has a crazy high volume of glutamine. It looks like I would have been better off with just my original apple. How crazy is that!? It's so confusing.
I gotta go decompress. Time restart Enya's greatest hits or something. And maybe munch on one of those juicily tart apples.
Cool thing of the day: Earlier I got an email from Julene, a very sweet blog reader. We had never met, but she offered to drop off a care package to help me survive until Dan arrives (saving me from resorting to my mom's granola bars - definitely not on the new diet).
It was just what I needed. I met a new friend, I stole a few much needed hugs from her, and little did I know that vegetables were going to be paramount in my new diet. And apples have one of the lowest concentrations of glutamine in foods. Why wasn't I listening to my gut!?!? You guys know I love apples. Ugh. FOOL.
5.30.2013
Buphenyl (Sodium Phenylbutyrate)
I'm embarrassed. Remember back a few months ago when I was ranting about that very expensive drug that treats gliomas? (As an aside, it's the same drug that Dr Burzynski uses to create his antineoplastons.) Well, apparently, I'm one of the lucky ones that can get it. I kind of assumed I couldn't because my doctor said it was a long shot. So, like a defeatist, I didn't bother to even check with my insurance. Yesterday, as I was reviewing my lists of recommended supplements and recommended medications, I decided to bite the bullet and not be afraid of hearing, "No".
After several phone calls, lots of hanging out on hold, it looks like Buphenyl (sodium phenylbutyrate) is mostly covered. If you recall, that is the prescription medication that is for people with urea cycle disorders (UCD); it is also used for off label use to fight various cancers.
After a little bit of web surfing I read that Aetna health insurance (not my health insurance - I'll be getting it though Blue Cross Blue Shield) goes as far as covering Buphenyl for UCD and also acute promyelocytic leukemia and malignant gliomas. Wow! The problem? As I try to find more proof that Buphenyl is effective to treat malignant gliomas, I can't seem to find it. There has been one complete response that I've found, but that's just one person. Shoot - that result could be as simple as tumor genetics.
I feel dumb because I wanted this drug, and now I wonder if it's actually worth the side effects and effort. I'm posting the study here for my other brain tumor fighters so that you guys have the info if you're interested...
There's more out on the web, but not much. Please feel free to email me (jessoldwyn@hotmail.com) or post links in the comments section with any information you find - or opinions. I'm not a fast responder to emails, but I read all of them and appreciate the help.
After several phone calls, lots of hanging out on hold, it looks like Buphenyl (sodium phenylbutyrate) is mostly covered. If you recall, that is the prescription medication that is for people with urea cycle disorders (UCD); it is also used for off label use to fight various cancers.
After a little bit of web surfing I read that Aetna health insurance (not my health insurance - I'll be getting it though Blue Cross Blue Shield) goes as far as covering Buphenyl for UCD and also acute promyelocytic leukemia and malignant gliomas. Wow! The problem? As I try to find more proof that Buphenyl is effective to treat malignant gliomas, I can't seem to find it. There has been one complete response that I've found, but that's just one person. Shoot - that result could be as simple as tumor genetics.
I feel dumb because I wanted this drug, and now I wonder if it's actually worth the side effects and effort. I'm posting the study here for my other brain tumor fighters so that you guys have the info if you're interested...
There's more out on the web, but not much. Please feel free to email me (jessoldwyn@hotmail.com) or post links in the comments section with any information you find - or opinions. I'm not a fast responder to emails, but I read all of them and appreciate the help.
Subscribe to:
Posts (Atom)
