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TNBC / testing strategies in a NED situation

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jens
 jens
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@j hi Johan. I am really uncertain when to take the buytrate when mixing with the chem. It say never together. But how long after the chem has been administered is the question.

Thanks


   
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Posted by: @jens

@j hi Johan. I am really uncertain when to take the buytrate when mixing with the chem. It say never together. But how long after the chem has been administered is the question.

Thanks

Hi @jens, the half-life for carboplatin is 2 to 6 hours and they observed synergy at low dose carboplatin (but the opposite at the high dose) so after 12 to 24 hours whatever carboplatin is still in the blood is a very low dose. So I'd say that after 12 to 24 hours it's OK to start taking the butyrate. 

 


   
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Posted by: @j

Posted by: @jens

@j hi Johan. I am really uncertain when to take the buytrate when mixing with the chem. It say never together. But how long after the chem has been administered is the question.

Thanks

Hi @jens, the half-life for carboplatin is 2 to 6 hours and they observed synergy at low dose carboplatin (but the opposite at the high dose) so after 12 to 24 hours whatever carboplatin is still in the blood is a very low dose. So I'd say that after 12 to 24 hours it's OK to start taking the butyrate. 

 

@jens I'm sorry that's the terminal half-life, it does take a little longer to clear from the body, about 50% gets cleared within the first 24 hours. So I'd wait 36 hours.

 


   
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synergies diagram updated


   
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jens
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@j thanks Johan.


   
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@jens also, that study was just on a cell line (melanoma) from in vivo studies with cisplatin and other platinum-based chemo butyrate shows enhanced inhibition when used in combination.


   
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@j sorry  Johan. Unfortunately I am still having trouble comprehending. How  can they work in synergy if I am waiting for the chemo to leave her body. Also how can we inhibit the abccs for the chemo to work. Do I give before the chemo possibly. Thanks


   
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Posted by: @jens

@j sorry  Johan. Unfortunately I am still having trouble comprehending. How  can they work in synergy if I am waiting for the chemo to leave her body. Also how can we inhibit the abccs for the chemo to work. Do I give before the chemo possibly. Thanks

@jens The study on the melanoma cell line shows synergy with carboplatin at low doses, in Vivo studies combining platinum-based chemo with butyrate showed synergy even at the regular high dose chemo when administered in parallel, other studies show butyrate sensitizes cancer to chemo. 

Hence there are different options, given prior to chemo to sensitize cancer cells, during chemo to enhance, and after or before based on the hdac inhibitory and sensitizing anticancer effect of butyrate respectively. In addition, from the study with the melanoma cell line, and once there are lower concentrations of carbo platinum in the blood this situation may mimic the synergy they observed between butyrate and low concentrations of the chemotherapeutic agent.

Sensitizing cancer cells is done prior to or in parallel with chemo. 

Hope all went well yesterday jens

 


   
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so in terms of probabilities, I'd say that at this stage it's more likely that the combination offers an additive or even synergistic effect.


   
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when looking at experimental research it's important to distinguish between the type of study, in vivo studies, meaning experiments done on animals, mice usually, are more valuable than in vitro studies which are experiments done on a cell line outside a living organism e.g. in a petri dish. There are also in silico studies these are basically simulations on a computer.


   
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@jens 

Hi, I'm not sure I've posted this combination, just in case:

methazolamide potentiates the efficacy of gemcitabine:

https://aacrjournals.org/cancerres/article/79/13_Supplement/2013/634061/Abstract-2013-A-carbonic-anhydrase-inhibitor

Acetazolamide might work as well.

Interesting synergies along that line are apigenin, rapamycin; rapamycin, acetazolamide; acetazolamide, sulforaphane.


   
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jens
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@j Hi Johan.

 

1.I don't  think you mentioned it.

2.I am now getting second thoughts about using IVC- DCA before Chem and IV Curcumin right after.  I was reading Daniels posts on Curcumin on using the same day as  they could act a  pro oxidant. What are your thoughts?

3. I am going to implement Ivermectin for nebulizer administration- Any ideas on other substances I can combine for nebulizer treatment that will reach the lung nodules.

 

Johan thanks as always for all your input..

 


   
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@jens In this study "Efficacy and safety of curcumin in combination with paclitaxel in patients with advanced, metastatic breast cancer: A comparative, randomized, double-blind, placebo-controlled clinical trial" was well tolerated and improved efficacy of the treatment:

Conclusions: Overall, treatment with curcumin in combination with paclitaxel was superior to the paclitaxel-placebo combination with respect to ORR and physical performance after 12 weeks of treatment. Intravenously administered curcumin caused no major safety issues and no reduction in quality of life, and it may be beneficial in reducing fatigue.

https://pubmed.ncbi.nlm.nih.gov/32335356/

Maybe hydrogen peroxide, I'll check on that.


   
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@jens IVM via that route will not only deliver it to the long nodules but also be taken up into the bloodstream and likely at a higher rate compared to taking it orally. What dose are you going to use and for how long? 


   
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jens
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@j very interesting,. I know I have to be careful.


   
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another update to the pathways diagram, I wanted to get coumaric acid in there, as a bcl-2 inhibitor. Green olives are a great source of this substance.


   
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@jens

Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice

https://www.anticancerfund.org/sites/default/files/attachments/selvanesan_2020_nicotinamide_combined_with_gemcitabine_is_an_immunomodulatory_therapy_that_restrains_pancreatic_cancer_in_mice_0.pdf


   
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pathways diagram updated


   
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Synergies diagram updated


   
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@j Thanks Johan!


   
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@rosed you're welcome, Rosaleen!


   
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Synergistic effect in SK-BR-3 breast cancer cell line (ER- PR- Her2+) @rosed

https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-11-149 (in vitro)

"It can be seen that the combination of CCM+DHA (2:3 ratio) when used below 50 μM exerted a synergistic effect only in the SK-BR-3 breast cancer cell line. CCM+DHA also affected the MDA-MB-231, MDA-MB-361, MCF7, and MCF10AT cell lines, but subadditive to additive results were observed at all combinations tested
We observed that genes involved in tumor progression/growth, cell cycle progression, metastasis, and anti-apoptosis/survival were synergistically downregulated by the combination, while genes involved in apoptosis, tumor suppression, and inhibition of metastasis were synergistically upregulated."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848456/ (in vivo)

4 groups and fed ad libitum diets containing corn oil (control diet), corn oil with CCM (CCM-diet), DHASCO (DHA-diet), or DHASCO with CCM (DHA + CCM-diet) (Taklad, Harlan laboratories, Madison, WI, USA) for 3 weeks prior to tumor induction. Mice continued feeding on the corresponding diets and were weighed every week throughout the study. The diets contained similar quantities of protein (20% of calories), carbohydrates (42% of calories), lipids (38% of calories), vitamins, and minerals as described in Table 1. They only differed in the types of lipids (i.e., corn and DHASCO) and their fatty acids composition as described in Table 2. At six weeks of age, the mice were gavaged with 200 μl of DMBA (1 mg/ml in sesame oil) one time per week for six weeks [42,43]. Mice were examined daily for the appearance of tumor by palpation, and the first day of tumor detection was recorded. Mice were anesthetized using Isoflurane 15 days after the first appearance of tumor. A blood specimen was collected by cardiac puncture, and the tumor was dissected out, measured, and weighed.

"there were significantly fewer breast tumors per animal when treatment with DHA and CCM was combined. In addition, the average tumor mass (Table 4 & Figure 3) in the DHA + CCM group was also significantly less (0.3 g) compared to other groups (1.2 - 1.4 g) (P = 0.026). Furthermore, the length of time for the initial tumor to appear in animals fed DHA + CCM was significantly longer (P = 0.018) than that of animals fed control, DHA, or CCM diets."

"One possible mechanism for the synergistic effects of DHA + CCM on ER-/Her-2+ breast tumors involves the re-expression of maspin and the suppression of survivin."


   
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updated


   
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@j       Oh wow........ need to add DHA ..... wow.  How much do you think a human would need to consume?  I use the MCS liposomal curcumin..... how much should I be taking of that, in your opinion?  This is very impressive.... easy to add DHA... I was only focusing on good olive oil for food.  Thank you so much for this find!!!!!!!!!!!!!!!  🌺 👍 🌺 👍 🌺


   
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@rosed 🙂 it really is a great study, and shows how the right combinations can make quite a big difference. Through their in vitro studies they found that a combination of DHA + CCM in a 3:2 ratio was the most synergistic and in the in vivo study they fed the mice in the curcumin groups 2 grams per kilo, which would be 8,9 grams of curcumin for a 55kg human. That's a lot but this was just plain curcumin, no special formula to enhance bioactivity. And this is where it gets tough to calculate how much of each substance to use when using liposomol or other curcumin formulations that enhance bioactivity of curcumin such as curcumin c3 which has bioperine which could enhance bioactivity 20-fold, or products such as curcuwin 46 fold etc.

With plain curcumin, if you'd take 2 grams of it, you'd then take 3000mg of DHA in order to reproduce the ratio used in the study. In this article, they say 3000-4000 mg EPA+DHA per day is healthy. I don't know if going above that amount could produce even greater benefits.  So you could use 2 grams of plain curcumin in combination with 3000mg of DHA. 

The liposomal C3 formulations may boost bioactivity 20 fold vs plain curcumin, so one 250 mg capsule would be like taking 5 grams of plain curcumin. 2 capsules would then be similar to taking approx 10 grams of plain curcumin. 

Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers

https://pubmed.ncbi.nlm.nih.gov/9619120/

"On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects."

So if one 250mg C3 capsule equals about 5 grams of plain curcumin, in order to maintain the 2:3 CURC/DHA ratio, you'd have to take 6000mg of DHA, which seems a bit too much. And there's really no way of knowing if the actual increase of bioactivity will always be 20-fold, it could be far less. The most reliable way of maintaining the 2:3 ratio would be to use plain curcumin with DHA e.g. 2000mg of curcumin with 3000mg of DHA and when using liposomal curcumin use one or two capsules with 3000mg of DHA. In any case, not hitting the 2:3 ratio perfectly may reduce some of the synergy but you still get an additive effect.

 

 


   
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I like this DHA supplement because it has 1000mg in one capsule and they mixed tocopherols to keep the oil fresh instead of just a-tocopherol, as most DHA supplements use. 

https://www.vitaminshoppe.com/p/dha-1000mg/vs-3911


   
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they *use* mixed tocopherols


   
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An omega-3 that's poison for tumors (DHA)
https://www.sciencedaily.com/releases/2021/06/210611110802.htm

 


   
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