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Paul Battle PA-C - Effects of LDN on Cancer (2017 Conference) (LDN, low dose naltrexone)
Good afternoon. My name is Paul Battle. I'm a Physician Assistant in the Denver, Colorado region. I've been practicing for 35 years in 11 different specialties, but I've been greatly involved with low dose naltrexone (LDN) over the last nine years, and researching different applications and trying to educate people around the country and around the world about the benefits of LDN. I'd been practicing in multiple different disciplines, and then studied immunology significantly since getting involved with naltrexone.
Today I want to present regarding some mechanisms related to naltrexone that might be helpful for cancer patients. I'd like to discuss another advantage of low dose naltrexone. We've concentrated a lot on the autoimmune benefits of LDN, and we know that's a well known mechanism, and we see many, many diseases that it's benefited throughout the world.
One of the other areas that we know naltrexone helps is with cancer, but we really haven’t known the mechanism as well. And we don't know all the applications for it. This is fairly new, and a lot more research has to be done in order to understand naltrexone and its application to cancer.
Today I want to present just different mechanisms that we do realize, and that have been studied. We certainly need more studies before we can know how to best be approved for using such thing. We can't really say naltrexone is a cure, but it can help and enhance the body's immune system, helping with cancer management. We have to understand that cancer requires a lot of cell division in order for it to reproduce. And that depends on a lot of things. It depends on a food source: they're a high glucose utilizer, and in order to do that, it incorporates the glucose, and then they have cell division.
One of the mechanisms that we know helps with cancer management of the cells is inhibiting cancer cell division. This was discovered and studied significantly so with Dr. Sagan. One of the mechanisms we'll look at is how naltrexone interferes with cancer cell division; and it might also interfere with normal cell division.
The second mechanism we're going to look at is apoptosis, cell death. What we want to look at is what we found in new research last year in London, with Dr. Wai Liu and Dr. Dalgleish, with genes that change, that help kill cancer cells. There are a lot of cancer cells that are affected by genes that are oncogenic. That is, they promote cancer development. And some genes actually help kill cancer cells. Genes are basically recipes or roadmaps that are sitting there in yourself, but they have to be activated or turned on. There was an interesting study I saw last year at a meeting I went to in San Diego where a lot of the oncogenic genes, that is the genes that promote cancer, are turned off when people go on a vegetable based diet. So what we're looking at is what genes enhance the killing of cancer cells. So we'll look at that.
The other mechanism we'll look at is angiogenesis. Angiogenesis is the creation of blood vessels, a blood supply. Cancer is a very highly metabolic cell. When you get a number of cells together, you finally form a tumor; and for the tumor to survive, you need blood vessels to supply that tumor, to keep it alive. As a matter of fact, there are some cancer therapies that are specifically designed to reduce angiogenesis, to reduce the cancer. There is an option where you actually embolize the blood vessels so that it cuts out the circulation from feeding the tumor. So that's a mechanical mechanism, and we'll look at whether naltrexone helps with that also.
Dr. Ian Zagon at Penn state in 1981, he's the one who discovered the beta endorphins and OGF that was secreted by the brain and the adrenal glands. In particular, it was met-5 enkephalin, what he calls opiate growth factor. That's a small protein or peptide that binds to a receptor, which he called opiate growth factor receptor. It has a very strong binding affinity, seven times more than the other enkephalins. It didn't really have an effect on the other receptors, mostly on the Mu receptor. This this receptor is found in the nuclear envelope, the nucleus and the perinuclear cytoplasm, so it's in several places inside the cell.
It interacts with the cyclin inhibition kinase called P21, so when the opiate growth factor combines with the growth factor receptor, it stimulates what's called the P21 pathway. What this does is it inhibits the G1-S phase of cell division. If you interrupt that the cell doesn't divide. So P21 is a common pathway that occurs in a lot of the cancers. Dr. Zagon found that in the head and neck cancers, it was inhibited more by P16, so it’s a little different pathway, but naltrexone affects both of those. There just does not seem to be as many receptors for P16 pathways as are in other parts of the body, so head and neck cancers can be a little more resistant.
The other benefit that naltrexone does is that it increases the number of NK cells. And why is that significant? Because the natural killer cells are part of your protection to kill viruses, bacteria, and also cancer cells. The other thing it does is it decreases the cytokines TH-17, TNF alpha, NF kappa B (NF-κB). Cytokines can promote cancer growth also. These are the inflammatory cytokines. These are inflammatory chemicals in the body that promote cancer cell growth, you might say.
This is just a diagram of what LDN does. It increases OGF, opiate growth factor, [Met5]enkephalin, and then that combines to the OGF receptor, which then stimulates - oops, I have a little X there, which is an incorrect - but it stimulates the P16 and P21 pathways, which then reduces the cell division and the nucleus. So what Dr. Zagon did is, he experimented with cancer cells and found that this mechanism is present in 31 different cancer lines, which represents 90% of human malignancies. That's very significant when you're talking about cancer management around the world. The hematologic cancers, I don't think he studied; there is much more about solid tumors, so we still have yet to see how they respond to the blood cancers like leukemia. There are some cases I know where it actually did also help with leukemia or blood cancers, but not as many cases as the other solid tumors. Like I said before, the head and neck cancers have less OGF and OGF receptors, so they're a little bit less responsive to therapy.
So what Dr. Zagon and McLaughlin did in this one study is, they gave mice OGF, which is opiate growth factor; it's an extraction that increases with the naltrexone. And they found that the tumor volume was 55% of what it was in the control mice that did not have OGF, almost just half the size. They also had a slower tumor growth rate. At 42 days, they were only 70% of the size of the control mice without the OGF.
This has been applied now to patients clinically with Dr. Burton Berkson. He has published these cases in the literature where he's had several patients that had pancreatic cancer with liver metastases, and had been told really basically, pack your bags, this is terminal. What Dr. Berkson did, courageously, is started them on IV alpha lipoic acid and he added low dose naltrexone and he had a very positive response with several patients, some of which you cannot see the primary pancreatic cancer on the scans, even eight years later. He presented this at a meeting. I saw myself. It was quite remarkable. It has been so remarkable that some people, even the patients question, maybe they didn't have pancreatic cancer. We went back to their doctors and said, Oh, maybe the slide wasn't pancreatic cancer, but it was well documented.
Then there was another experiment Dr. Zagon did to see what happens when you give chemotherapy agents with the opioid growth factor and gemcitabine, which is a chemotherapy given to pancreatic cancer patients. Combined with OGF it reduced pancreatic cell growth rate by 46% compared to those that did not have the OGF. So it obviously had a synergistic effect on the use of gemcitabine. It reduced the tumor volume in 36 to 85% of the control mice, and also reduced the incidence, that is, the number of times the mice would develop tumors; and then reduced the whole tumor size by 75%.
There was another study with ovarian cancer. Ovarian cancer cells were given to mice that developed ovarian cancers and they studied the cancer cell growth with LDN, low dose naltrexone. It showed that it did up regulate the OGF in OGF receptors. It increases the number of those. Then it showed that combined with cisplatin, which is another chemotherapy agent, it suppressed the ovarian cancer cell growth significantly compared to the control mice, without LDN. It reduced DNA synthesis and angiogenesis, and it did not have as much toxicity.
Going on to another mechanism that we were mentioning earlier is what happens with genes that help kill cancer cells when they are exposed to low dose naltrexone? Doctors Liu, Scott, Dennis, Kaminsky, Levett, and Dalgleish in England published this study last year in the International Journal of Oncology. And what they did is they studied these colon cancer cells, HCT116, and they combined them with oxaliplatin, and the kill rate of the cells increased from 14% to 49%, which is quite dramatic, to triple the kill rate of chemotherapy by pre-treating the cancers. This is not in patients, this is in the laboratory: pre-treating cancer cells with LDN, and then exposing them to the chemotherapy tripled the rate. They looked at gene patterns that changed with this experiment, and they found that there were two genes that changed. One was the BAD gene and one was the BIK1 gene. So what do these genes do? Well, they have to be genes that increase apoptosis, again, the death of cancer cells. They were up regulated with the LDN, which is very exciting for clinical applications after more clinical trials are done to see if this occurs with patients also.
Now I'll give you an example of some of the cases that I've had clinically. I have a 67 year old who six years ago had recurrent ovarian cancer. She had cancer of the ovaries two years prior, was treated, thought she was in remission; but then, unfortunately ended up with metastasis throughout the liver, spleen, and colon. She had a debulking procedure, basically going in, cutting out gross tumor that can be seen. She's been on maintenance chemotherapy. Most women who have recurrent ovarian cancers don't survive very long, especially when they have extensive metastases that she had. So she came to me through a nursing friend of mine at the hospital, six years ago, and I started her on naltrexone for a couple of years at 3 mg, then I upped it to 4.5 and she's still doing very well. Just this year she had two local liver mets that were treated with precise radiation therapy to take care of those, but her tumors that are present basically are growing very slowly or are just not growing much at all. Some of them may not even be active cancers. There's a mass there, but it may be just dying in and of itself, and may be necrotic tissue that's left. So that's quite surprising for a woman with ovarian cancer to still be around and doing well six years later.
The second case on the slide is a 44 year old who had been treated at MD Anderson for squamous cell carcinoma of the tonsil. And that was again, six years ago. He's done well; his oncologist said there's no signs of recurrent cancer, and actually he said he doesn't even really have to follow him anymore. His PET scans have been clean. And the interesting thing is this patient met two men with the exact same diagnosis, same stage 4 diagnosis at MD Anderson, and both of those men died two years prior. And this patient is still doing well, traveling around the world, doing quite remarkably well.
I'll present another case from another physician out of Toronto, Canada. He had an excellent case that he published in the oral health journals, where he had a patient with cancer of the tongue. Cancer of the tongue is a very tough cancer. Most of the time you have to remove a good portion of the tongue, a lot of the lymph nodes of the neck, and other structures, to try and preserve a person's life. Well, this patient told the doctor that he was not interested in any of this kind of therapy. He did not want to go on in time without being able to speak and eat right. So he just said, I'm not doing anything for a year. And he said, you know, is there anything else available? So this doctor came up with the idea of using low dose naltrexone on this patient. He found a 3.2 centimeter mass in the left side of the tongue, which was well documented with MRIs. He started him on 3 mg of naltrexone, and increased to 4 mg, similar to what I do with my patients; and also added a 10,000 units of vitamin D3, and then reduced it to 5,000 later on. And why D3? D3 has been associated with reduced cancer rates, and it also controls about 15% of the total genes that you have, which is significant with the 30,000 genes we have, to have 15% of them controlled by vitamin D3. D3 also is involved with apoptosis, like we mentioned in the gene study. So that is one of the reasons why the D3 was added to the LDN. The followup on that patient: he said two years later, even four years later, there's no evidence of any active disease with only treatment with LDN and vitamin D3, and no chemotherapy. This is quite, quite remarkable, especially when, as I mentioned, the P16 pathway does not have as many receptors in the head and neck cancers compared to other solid tumors.
Going onto the third mechanism that LDN works on is through the inhibition of angiogenesis. Again, angiogenesis is the development of the blood supply and the blood vessels to the tumor. This is one of the reasons I like recommending thermograms to my women for monitoring breast cancer, because the thermogram can pick up heat that is generated by these new blood vessels compared to most mammograms. The tumors have been there for several years, and they can miss about 20% of cancers on normal breast tissue. So I like to monitor the development of angiogenesis with thermography or with breast scans. So angiogenesis is important. Like I mentioned before, it’s what feeds the tumor. Any tumor that's greater than 2 - 3 mm requires a blood supply, so if we can reduce that, then we can reduce the chance of the tumor surviving.
There are certain characteristics that occur with angiogenesis in feeding the tumor. What the people at University of Chicago found in this patent application in 2004, was that opiates actually help stimulate tumor size. And we know even in the early stages of cancer there's pain, so more than 50% of people are treated with opiates for pain related to cancer conditions. Those dosages can end up being anywhere from 10 to 350 ng/cc in the blood for patients. But what's been found is that the opiates can increase the tumor size with dosages of 100 ng/cc, which is well within the dosing range of people who are on opiates for cancer pain. In other words, the opiates help stimulate cancer growth when given to patients. So what the study found was when they gave methylnaltrexone - it’s an opioid receptor antagonist like low dose naltrexone - it inhibited cell proliferation from 55% to 30%. That is reproduction of cells, which then lead to tumors. It also reduces the cell migration from 60% to 28%. That is the collection of cells getting together to form tumors.
Then, like other studies we mentioned today, they wanted to see what happened with adding chemotherapy with the naltrexone. They added 5 FU, for example, and it reduced the vascular endothelial growth factor (VEGF) induced cell proliferation from 85% to 55% with colon cancer cells. The VEGF is important to stimulate, in order to provide the blood supply to the tumor. So that showed again, there was a synergistic effect with 5 FU and using naltrexone in reducing the cell proliferation in colon cancer cells.
In conclusion, we've talked about three different mechanisms, how naltrexone may be beneficial in enhancing the patient's immune system and helping manage their cancers. It may not cure them, but it certainly can help them in several ways that we described today, to reduce cancer cell growth. What we need is more research to determine which cancers this works in. Is it 90% that Dr. Zagon found? Is that mechanism, or OGF and OGF receptor present? Or do we have to do more studies to find out which cancers are sensitive to these other mechanisms. We've got to find out what are the correct dosages, because we have found that when people use greater than 6 mg of naltrexone compared to 2 - 3 or 4.5 mg, it actually can block the OGF-OGF receptor binding and actually have negative effects on cancer cell growth. We also want to find out which chemotherapy agents will be synergistic. In this patent study I just mentioned, some of the chemotherapy agents weren’t synergistic; they didn’t have any benefit with naltrexone. We have to do further studies to find out what chemotherapy agents and what cancer cells will actually be synergistic rather than antagonistic. And the next stage would be to actually bring it to patients. After we do the laboratory studies on the cells, does that also correlate with patients having better outcomes and less toxicity from chemotherapy agents?
So hopefully this lecture today gives you some thoughts to ponder about how naltrexone can benefit patients with cancer. Thank you very much.
To watch past conference presentations click https://ldnresearchtrust.org/ldn-conferences