July 15, 1993
D. Pearson
NEVADA
Dear Durk & Sandy:
I am sorry to be so slow in responding to your many kind letters and flood of data. I was in the hospital for 12 days, and after being at home just long enough to begin organizing the mess on my desk, I was returned to the hospital for five days more due to mysterious abdominal cramps and further kidney problems. At the moment my status seems to be more or less stable -- metastable would probably be more correct -- and I am again trying to get caught up. (A process complicated by restoring data on my computer -- hard disk died the day after I got back from my first hospital stay.) However, I am able to do very little work; most of the day I must sleep or doze.
The information on clodronate will be useful, as recent X-rays indicate bone lesions are starting to form. I will take up the question of this compound vs. other bisphosphonates with my medical team.
DHEA does look interesting, though very speculative at this stage. Protection of the heart by taurine might be of no small importance, as one treatment option under consideration involves adriamycin. I believe I sent you some months ago a summary of test data on various antioxidants for protection against cardiotoxic drugs; I think taurine was on the list but I don't remember how effective it was.
Results with retinoic acid appear to be mixed. The abstract you sent me indicates that 13-cis-RA may be useful, though rather toxic. On the other hand, a recent report from Sloan-Kettering says that all-trans-RA is definitely contraindicated for multiple myeloma; it raises IL-6 and causes hypercalcemia. Looks tricky.
As you know, in my case the cancer appears to be particularly virulent and resistant to treatment. It simply shrugged off the steroid treatment usually effective with myeloma, and we are now trying "intermediate dose" chemotherapy -- tactical nukes, so to speak -- with cyclophosphamide. Because of the kidney problems and low general system reserves -- my vitality is ebbing almost daily -- a bone-marrow transplant is not a viable option at the present time. Nutrition is a problem; my recent hospital stay was due partly to my inability to eat or drink; even a glass of water could cause nausea. (Not, apparently, due to the cyclophosphamide; the problem preceded the treatment.) At the moment I am able to eat just well enough to avoid parenteral nutrition, but the situation is being watched on a day-to-day basis. All inputs must be carefully controlled due to the kidney damage; potassium levels are critical and a couple of glasses of milk could be lethal to me in my present state.
Nothing as boring as a sick man, is there? Nothing to talk about except my medical problems. I enclose a couple of items that may interest you. Many thanks, once again, for your assistance. Live long and prosper.
July 28, 1993
D. Pearson
NEVADA
Dear Durk & Sandy:
I'm now home again after my third hospital stay. My GI system seems to be improving somewhat and I am able now to take beta-carotene and PRS; I'm trying also to get back on canthaxanthin.
The anemia associated with multiple myeloma is generally attributed to "crowding out" of the normal cells in the bone marrow by the abnormal plasmacytes. However, my hematocrit drops faster than could be accounted for by even a complete absense of hematogenesis, so something -- it's not clear what -- is destroying red blood cells. (A good case for using antioxidants, as presumably iron is being released.)
To my mind, the evidence suggests that MM is due to a subset of memory B-cells being sort of jammed in the "on" position due to a defective immune response. (The paper you sent on the anti-HIV myeloma case is very suggestive here. There are other cases where the MM protein has been shown to be antibodies to known pathogens.)
Anyway, results with cyclophosphamide are still not clear at this time. Kidney tests are not looking good, but I'm not yet on dialysis. If the kidneys do crash completely, it will seriously complicate use of nutrient supplements.
Thanks for your help. Live long & prosper --
August 9, 1993
D. Pearson
NEVADA
Dear Durk & Sandy:
Just out from another six days in the hospital. I am now on kidney dialysis. I am down from 165 lbs to 149 (in two months) and suffering almost constant low-level (sometimes not so low) nausea. This is apparently due not only to the chemotherapy (cyclophosphamide), but to the kidney problems and the cancer itself. The foremost problem is keeping enough food down to avoid hospitalization and total parenteral nutrition. This makes it difficult to apply some of the approaches I would like to, including the fish oil. However, as I investigate kidney function issues I find that vitamin toxicity is not such a problem as some of the practitioners make out. (Though flurbiprofen and all other NSAIDs are completely out of the question now--highly nephrotoxic under these conditions.) The main hazard seems to be vitamin A. C, it appears, is cleared by dialysis (presumably dehydro-C is also) and if anything I should be taking more, not less! So I'm trying to get a program reorganized.
At this point I am seven months from diagnosis--now past median survival for people with aggressive MM, so that's a milestone. The disease has shrugged off the standard steroid treatment (dexamethasone); results with the best mustard (cyclophosphamide) are not in yet. If this fails to produce a remission, I estimate I have enough vitality left for one more effort. This would have to use the remaining resource, the alkaloids--probably adriamycin with verapamil to counter drug-resistance.
On the nutritional side, I'm currently struggling to get down--and keep down--enough PRS to bring up my general vitality, and keep up at least 250,000 units of additional carotene for protection from the cyclophosphamide side-effects. The next objective is to add canthaxanthine in the hopes of getting some holding action against the plasmacytes, followed by omega-3 fatty acids and perhaps other re-normalization agents.
I'll keep you posted better when I'm stronger. Many thanks, and LL&P--
August 10, 1993
D. Pearson
NEVADA
Dear Durk & Sandy:
The enclosed paper on tocopherol and lipid peroxidation may be of interest to you.
What's all this I hear about hydrazine sulfate for cachexia? Anything in it? Sounds too weird to be true, but then who would have believed nitrous oxide a few years ago?
Latest stop-action report: paraprotein is down from 5.0 to 4.3 after the second dose of cyclophosphamide. We may be getting a remission.
--LL&P
August 17, 1993
D. Pearson
NEVADA
Dear Durk & Sandy:
This will have to be short as I'm currently at neutropenic nadir (WBC = 500) from the latest dose of cyclophosphamide and thus very weak.
"Stubborn" I am; at least, my physicians think so too! As you know, that's a survival factor for cancer patients. My situation has changed dramatically over the last few months (from what seemed to be a routine case of MM, caught very early, to what we now know is a virulent and abnormal form of the disease), and tactics have of course had to adapt to that; but the strategy has remained the same that you used: Get the best standard medical treatment and augment it with alternative therapies.
I certainly have benefited greatly from the information you've sent me. Some (eg, flurbiprofen) I couldn't use for medical reasons; some, such as the work on T-cell types and immune system "switching", is extremely interesting and relevant but hasn't yet developed into practical therapeutic methods. And a lot -- vitamin D, canthaxanthin, taurine, etc. -- has become part of my program.
Re your questions: We're holding the alkaloids (vincristine and adriamycin) in reserve because they're very toxic; also, they're known to induce resistance in MM very quickly, unlike other agents. Statistics on aggressive myeloma are poor but remissions seem generally short (less than a year). The big dietary limitation for me is potassium (<1.5 grams/day); protein and sodium are also restricted, but only modestly.
Thanks for the suggestion about using the back end for administering fish oil, etc. That hadn't occurred to me and may solve some problems. My appetite and GI stability are improving, but I still have difficulty getting enough nutrients down.
--LL&P
August 27, 1993
D. Pearson
NEVADA
Dear Durk & Sandy:
Yes, indeed, Zofran has absolutely revolutionized treatment of chemo-induced nausea. It's terrific stuff--effective and no side effects, unlike compazine or atavan. Expensive as hell--$20 per tablet--but worth it.
Unfortunately, Zofran and other anti-nausea agents work only on brain-induced nausea. I've also had a problem with mysterious abdominal cramps which cause vomiting, apparently by simple mechanical action on the stomach. There's also a sort of odd discomfort--not real nausea--of unknown origin. Possibly an ulcer (decadron can cause ulcers) but the CAT scan saw nothing. We've repeatedly considered taking a direct look, but running a tube down the esophagus of a guy with bleeding problems is a bit chancy, so . . .
The bone-marrow transplant doesn't look good in the present situation. Looking at long-term alternatives, I'm beginning to wonder about the Berenson machine. If it can pluck out CD34+ stem cells . . . there's a theory that the malignant cells in multiple myeloma are circulating B cells with a CD38 marker. What if we just pull 'em out the same way? Sure, we might get only 10% of them on a pass--but there's no trauma to the procedure, so we could do it as often as needed. Also, I want to find out from Biotherapeutics why they ruled out bombing the things with antibodies to CD38.
Might be nice to have a virus that attacks B cells the way AIDS attacks T cells. Or, could we get B cells to present some foreign peptides in such a way that they appear to be infected, so that the T cells would kill them?
LL&P-
October 8, 1993
D. Pearson
NEVADA
Dear Durk & Sandy:
I'm home again after two bouts in the hospital. This time a very nasty bacterial infection in the GI tract--Clostridium dificiles. This is the sort of infection that commonly finishes off multiple myeloma patients, but I survived this time.
Once again I'm trying to rebuild my strength, a problem since my digestive system is by no means stable.
Berenson at UCLA is willing to talk to me about experimental therapies using their gadget, and I plan to see him as soon as I'm strong enough to travel that far.
Many thanks for keeping me up to date on the latest stuff. LL&P--
October 22, 1993
D. Pearson
NEVADA
Dear Durk & Sandy:
Another hospital stay. Brain trouble this time; can't tell you much about it as I have amnesia for that day. I'm told I went into seizures and injured my back.
The cause is unclear. MRI shows changes in some blood vessels in the visual cortex, but the exact nature, and the cause, are unknown. Could be a side effect of the cytoxan; or a side effect of hemodialysis; or conceivably a direct effect of the myeloma. Anyway, I've had no recurrence so far after 10 days.
I indeed used acidophilus during my recent GI problems, and I think it helped restore normal functioning.
The Berenson brothers have a machine that runs blood through a column selective for cells bearing the CD34 marker. (It uses antibodies to CD34 attached to beads.) My thought is: Why not make a column selective for CD10 and/or CD19 and try to pull out the malignant myeloma cells, which are believed to bear these markers?
The paper on DHEA vs. IL-6 is very interesting indeed. I am following up on it.
I see that radioiodine-labelled monoclonal antibodies have now been used successfully against B-cell lymphoma. Unfortunately, it will probably be some years yet before the technique is applied against multiple myeloma.
Thanks again for your help. LL&P--
November 4, 1993
D. Pearson
NEVADA
Dear Durk & Sandy:
Thanks for keeping me up to date on the latest stuff. The book on cytokines looks useful. As for the aspirin, my physicians have a conniption fit every time I mention salicylate, what with my bleeding problems.
The nutritionist at the kidney dialysis center has a new book, Nutrition and the Kidney (by Mitch and somebody), and I was able to read it for a couple of hours while I was on the machine. Unfortunately I couldn't take notes, as my fistula is in my left arm! However, I retained some useful information. Kidney damage has immense effects on nutrition, it turns out. The balance of amino acids is completely upset. In particular, tyrosine, serine, and valine levels drop dramatically, while glycine goes abnormally high. Carnitine also drops; here, however, double-blind studies on supplementation give inconsistent results. There is anorexia associated with kidney failure (on top of the cachexia of cancer), which may be primarily due to failure of protein anabolism caused by amino acid imbalances. For this reason, high protein intake is often recommended. On the other hand, too much protein can cause further damage to the kidney!
The situation with vitamins is not well understood. Because anemia is generally associated with kidney failure (erythropoietin is made by the kidney) there's been a lot of work on B-12 and folate. Results are rather ambiguous, but supplementation seems indicated. Folate has been found to have mild toxic effects at 5 mg/day and above. B-6 supplementation is definitely needed. C is also required, particularly for patients on dialysis, but at over 1,000 mg/day, it is asserted, oxalate buildup becomes a problem. Vitamin A is much more toxic in kidney patients than in the normal population and should be avoided.
The situation with calcium (supplementation needed), phosphorus (needs to be reduced), potassium (very dangerous, but not usually a serious problem for people on dialysis as long as they watch their diet), and so on is well understood. For trace metals, it's a different story. I gather that just accurately measuring body content of micronutrients is state-of-the-art, cutting edge research. Indeed, apparently this is a problem even with vitamins; the serum or plasma levels don't necessarily tell you much about how much of the compound is actually in action. Anyway, once the kidney's regulation of trace metal levels is lost, some go up, some go down. Complicating the whole thing is the effect of dialysis, which generally removes most of them rather unselectively. Lots of confusion here.
Kidney failure also results in major problems with lipid metabolism, for reasons which (as far as I can tell) are not understood. Atherosclerosis is a major hazard for kidney patients.
The cause of my recent brain problems remains mysterious. CAT and MRI showed a temporary abnormality in the visual cortex, and ongoing abnormality in the white matter in general. The doctors are adamant that the edema in my face and left arm, which immediately preceded the seizures and cleared up immediately afterward, was unrelated. I remain sceptical that it was a coincidence. Anyway, I've been taking Dilantin (phenytoin) and have had no further symptoms, except that my blood pressure remains high. My personal hypothesis is that this incident was an infection of some sort that got into the brain.
It's now almost three weeks since I got out of the hospital and I'm strong enough to sit at the computer a couple of hours a day. I'm starting to work on re-evaluating the overall strategy based on the new situation.
The bone marrow (stem cell) transplant no longer looks like a viable option. Results with medium-high-dose chemo indicate my susceptibility to infection is very high, which makes a BMT very risky. Recent studies suggest that multiple myeloma may be due to a genetic defect present in the stem cells anyway. Besides, I've been denied insurance coverage.
Results with the current Cytoxan treatment have been good (abnormal protein down from 6.4 to 2.3 so far) and I expect to continue it till I'm in remission. There's always the risk, of course, that one of these infections will prove to be fatal.
Long term, I'm looking at approaches which may lead to promising experimental treatments. In particular, I want to see if I can get anyone to use me as a guinea pig for monoclonal-antibody based therapy, using radioactives or possibly photodynamic agents. I have a lot of work and study to do, as I have no idea how this sort of pre-clinical-trial research is organized.
On the nutrient side I'm also re-evaluating the approach. It will be necessary to adapt the program to take into account the kidney problems, of course. A high priority is immune-system stimulus aimed at the humoral response. My white-cell counts have been pretty good (when I'm not neutropenic, that is!); it's the humoral response that's crippled by myeloma, and that deficiency is what seems primarily responsible for all these infections I've been having. Suggestions welcome.
In short, right now I'm involved in an involuntary game of Russian Roulette. I've got very little humoral immune response left, and my cellular immune response is regularly depressed by the chemotherapy. Every few weeks I get an infection and have to go to the hospital. Eventually one of the infections is likely to prove fatal. This is how myeloma patients usually die. Once I'm in remission, the situation should improve--but I can only expect the remission to last a year or so.
Well, enough about my life-extension program; let's boogie! When I'm not busy with medical matters I try to do some writing, including a little science-fiction. There's also a fairly interesting computer conference on objectivism I recently joined. (I can't believe you guys aren't on the Internet, by the way.) My chemical database venture was a complete failure in test-marketing, but what the hell, I haven't got enough strength right now to implement it anyway.
It's not likely I'll be strong enough to travel as far as Tonopah in the near future. But if you ever venture into L.A., come and see us. I'll even make you some pumpkin pies.
LL&P-
November 18, 1993
D. Pearson
NEVADA
Dear Durk & Sandy:
Thanks for your latest--the NEJM article on immunoglobulin deposition was very sobering. As for ethoxyquin, does this affect protein deposition in general, or only the specific type of amyloid produced in Alzheimer's disease?
As you may recall, I had a 2.5-month holiday from chemotherapy because I was in too bad shape to take it. Unfortunately, this resulted in a reversal of the progress we'd been making; paraprotein rose from its low of 2.3 back to 3.1. So I had another dose of Cytoxan on 11/9. I'm now in the neutropenic period (WBC = 200 !) and very weak.
Though I can only work an hour or two a day in my present condition, I'm slowly making progress on identifying experimental treatments and getting together a new strategy. There are rumors that the Hutchinson (Seattle) is running a clinical trial with its monoclonal antibodies method (which was successful against B-cell lymphoma) on multiple myeloma now. Also I hear that UCLA is trying retinoic acid. Probably this wouldn't be effective in my case, however. RA works by hitting IL-6 production, and probably would be ineffective against myeloma cells that are capable of autocrine IL-6 production. Still, it's worth investigating.
I also talked to a woman with B-cell lymphoma who says Fludarabine is effective and has low toxicity. I want to see if there's any data on its use against myeloma.
Thought the enclosed articles from Forbes might interest you. LL&P--
January 12, 1994
D. Pearson
NEVADA
Dear Durk & Sandy:
Happy New Year! I've now lived one year from diagnosis, which is a milestone of sorts.
There is not much new to report at the moment. The December blood tests indicated that the renewed Cytoxan treatment is again beating down the disease, though still slowly. At this point it's not clear how long I'll continue on this therapy; however, within a few months, either Cytoxan should produce a remission or the disease become resistant and take off again.
My major effort is in finding novel experimental approaches to treatment. I have a couple of leads but am running up against secrecy problems and difficulties getting hold of the informed people. Major nutrient consideration is fighting the side-effects of Cytoxan. Each cycle produces a lower neutropenic nadir (WBC last time was only 200 at the bottom), which suggests my bone marrow is showing permanent damage from the cumulative dose (24 grams so far, which is a lot of Cytoxan).
I've had no signs of additional brain damage; the symptoms remaining are a slight memory problems and some difficulties with balance. I'm still pretty weak and now have almost continual digestive problems.
The enclosed articles may be of interest to you. All the best, and give us a ring if you're in the area.
LL&P--
January 28, 1994
D. Pearson
NEVADA
Dear Durk & Sandy:
Here are a couple of items that may interest you. In the article on Shalala, note the role played by WARF. You may recall that this is the outfit that laundered the sugar-industry money for the infamous cyclamate experiments.
Not much news on this front. We continue to make progress toward remission with Cytoxan, but it's slow. I had another brief hospital stay this month--GI infection. Not too bad, but GI troubles never seem to completely go away. The lead in Seattle didn't pan out, but I'm still trying to get info on the rumored UCLA research.
LL&P--
March 17, 1994
D. Pearson
NEVADA
Dear Durk & Sandy:
Just a quick update: I am now recovering from the seventh and, I hope, last dose of Cytoxan (cumulative dose 28 grams). Based on the trend line, this should get me into technical remission (75% decrease of paraprotein from level at diagnosis). The question is whether it will be a true remission; will it stay down for a while, or will the disease jump right back? Cytoxan has controlled the disease; without chemo I would almost certainly have died last year. But the cost has been heavy. My weight dropped to 130, about 35 lbs below normal and less than I've ever weighed as an adult. Remission or not, I doubt I can go back on chemo again soon; system reserves are just too low.
This cycle put me in the hospital again--another bout with clostridium, nasty stuff. I was on total parenteral nutrition for a while. Now that I can eat again I can start getting in some nutrients.
Thanks for the info you sent me. Anti-IL6 is certainly a logical approach; unfortunately, since continuous treatment is needed, the practical and economical factors don't look good. (Even G-CSF or GM-CSF runs about $2,000/week--this recombinant stuff ain't cheap!) Pentoxyfylline sounds better; I have to review my files and see where TNF fits in with multiple myeloma. I don't know how much of my weight loss is due to cachexia and how much to simply not being able to eat half the time.
It's getting complicated using drugs. It now appears that my convulsive seizure last year may have been iatrogenic. Several antibiotics can cause seizures, notably metronidazole but also amikacin, imipenem, and ciprofloxazole. Many others can aggravate kidney damage. But, like the chemo, we have no other options. I've had a dozen serious infections in the last nine months, and without massive doses of antibiotics any one of them could have killed me.
Anyway, thanks for the help. How's your Hg mine doing?
May 11, 1994
D. Pearson
NEVADA
Dear Durk & Sandy:
I though the enclosed article on designer oils might interest you.
News here is not particularly good. Since I seemed to be approaching remission, we reduced the Cytoxan dose from 4 grams (which was murdering me) to 2 grams. The disease immediately jumped back. We're now trying 3 grams; the next (and nearly last) resort is VAD (vincristine/adriamycin/dexamethasone).
I've been concentrating lately on boning up on the kidney problem and assembling lab data on it, as this is a very serious complication both to my life and to the treatment of the myeloma. The nutritional issues are intricate.
I'm trying to assemble data for a report summarizing the progress of my case and the role of nutritional therapy in it. I haven't forgotten my status as an experimental subject. Probably be the first paper ever written by one of the white mice . . . (Incidentally, there's a hilarious science fiction story about a behavioral psychologist who's captured by an alien species and run through mazes by one of their behavioral psychologists. When he finally realizes what's happening and starts to change his behavior to show that he's intelligent, he gets "sacrificed"--obviously he must be sick, since he's showing the wrong responses!)
Later I want to talk to you about DHEA, and particularly any effects on sex hormones, but I need to review the literature you sent me so I can ask intelligent questions.
LL&P--
July 5, 1994
D. Pearson
NEVADA
Dear Durk & Sandy:
Just a short note to thank you for the data. I've been on vacation in Oregon (and boy, does kidney dialysis make travel a scheduling nightmare!) and am digging through a pile of accumulated mail and e-mail. (Which reminds me, it's time for me to bug you again about not being on the Internet. When are you guys going to move out of the neolithic?)
I've been looking into bromocryptine for other reasons--viz, sexual disfunction. My prolactin level is 22 (3-30 is "normal") so it's not likely bromocryptine would help from that point of view. Zinc, I find, is way low--around the bottom of the 50-150 "normal" range. I've been getting around 25 mg/day from PRS, and for the last few weeks I've added 30 mg/day of Zn picolinate, but this has had no discernable effect on serum zinc, so I'm going to up that. Testosterone is on the high end of the normal range in a preliminary test (can't remember the exact number offhand). Blood's been drawn for more detailed hormone tests but I haven't got results yet. If bromocryptine has (as the paper you sent implies) some immunosuppressive character, it would certainly be contraindicated.
Incidentally, I've noticed my susceptibility to colds and the flu is definitely greatly reduced since I was diagnosed with multiple myeloma. Makes me wonder if boosting antiviral immune defenses (as opposed to antibacterial) is a property of the disease--perhaps due to changes in T-cell subset populations?
The case study with beta carotene vs. CLL was interesting. 400 mg is 667,000 units, right? I'm taking 250,000 normally, 400,000 during cytoxan pulses.
Anyway--I'm feeling better, gaining weight, and my paraprotein is down to 1.4 on the latest test. Now that I'm back I'm resuming my search for experimental therapies.
LL&P--
September 1, 1994
D. Pearson
NEVADA
Dear Durk & Sandy:
The enclosed abstract on apoptosis and carcinogenesis may interest you.
My paraprotein level was still 1.4 at the last test and it now seems clear that I am in the "plateau" phase of the disease. Median duration of the plateau is about 18 months; normally chemotherapy is not administered during this phase, as studies have shown it does not extend survival. However, there is some evidence that alpha-interferon can prolong remission, and we are considering this.
I've started taking canthaxanthin. Incidentally, I cannot find, either in my files or via MEDLARS, any paper on canthaxanthin and connexin. If you run across that reference, please send me a copy, would you?
There are signs that zinc supplementation is starting to have beneficial results, even though serum zinc in August was still only 59. It's known that serum concentrations of metals often don't correlate well with total body stores, so I suspect body zinc is increasing even though it's not showing up in the blood. I'm taking about 125 mg/day now, using Twinlabs' mixture of picolinate and gluconate. (I can't get straight gluconate except in tablets, and I strongly prefer capsules.)
LL&P--
September 16, 1994
D. Pearson
NEVADA
Dear Durk & Sandy:
Thanks for the recent data. I was particularly interested in the note on prophylactic immunoglobulin. We had this under consideration, but it doesn't look like it brings significant benefit during the plateau phase.
My last visit to the library turned up a couple of interesting papers. In one, it is shown that "receptor for hyaluronon-mediated motility" (RHAMM) is present on malignant B-cells, including those in multiple myeloma; but not on normal B-cells except during response to infection. I don't suppose, however, that this has any therapeutic potential. Surely hyaluronic acid is so ubiquitous and necessary that one could not fiddle with it safely?
Another paper describes experiments with anti-CD3 to activate T-cells to attack plasma cells. This is mostly in vitro, but they've started some Phase I clinical stuff which shows that T-cell activation does occur in vivo. Still no evidence for actual clinical benefit, however.
Let me know when you're on the Internet. (My email address is ronmerrill@bix.com.) Also, let me know when you're in the area; hope you'll have time for us to get together.
LL&P--
September 29, 1994
D. Pearson
NEVADA
Dear Durk & Sandy:
I've been trying to figure out the arithmetic with zinc. The time series looks like this:
9/93 48 (~12) 6/94 56 (~25)
12/93 44 (~25) 8/94 59 (~55)
3/94 61 (~25) 9/94 65 (~125)
That's serum zinc in mcg/dL; the numbers in parentheses are supplementation of zinc, in mg/day. Now, what I'm wondering is: where the hell is all that zinc going? Total body stores are about 1-2.5 grams; and only a few mg of that is in the blood.
It's known that zinc is low in dialysis patients, and before I actually looked at the numbers I assumed the zinc was being pulled out by the machine. But no way! If it took out all the zinc I'd lose only about 1 mg/day--assuming no exchange of zinc between the blood and the rest of the body during dialysis. Even if we assumed extremely rapid exchange--let's see, total body blood volume goes through every 12 minutes . . . I would lose about 15 mg/day if dialysis removed zinc with 100% efficiency. But in fact almost all serum zinc is bound to proteins and practically none of it should be removed by dialysis. And this is confirmed by experiments in which dialysate was loaded with zinc--patients' zinc levels did not benefit.
So how am I losing zinc? Peeing it out? But most dialysis patients don't pee at all, and it takes weeks to raise their zinc levels with a 30 mg/day supplement. So (unless zinc is concentrated in sweat!) it must be in the feces. But then why should kidney trouble affect absorption or excretion? Am I stupid or is something strange going on here?
Will you have a chance to get together with us in October? Please let me know. If it's inconvenient for you to come up to Torrance, I can drive down and have dinner with you in Irvine.
March 24, 1995
D. Pearson
NEVADA
Dear Durk & Sandy:
Here's a paper on vitamin C and toxic amine derivatives that may interest you, and some abstracts from the Anaheim ACS meeting.
My paraprotein was steady last month at least. I'm feeling fairly good, though interferon (3 X 5 million units weekly) seems to be causing a fair amount of nausea.
I've cut back zinc to 76 mg/day, partly because of stomach trouble and partly because I read that it interferes with selenium.
I'm still trying to line up possible treatment with hexamethylene bisacetamide (HMBA), which is reputed to cause the abnormal plasmacytes to differentiate properly and go through apoptosis. I was reading of a trial of IL-2 for myeloma; some patients benefitted, others got worse. More and more I am impressed by the importance of individual differences in response to treatment. I find that a trial of IL-4 is running.
Many thanks for your assistance.
LL&P--
May 22, 1995
D. Pearson
NEVADA
Dear Durk & Sandy:
Thanks for calling me with Sandy's latest idea. It sounds very promising and I'll be interested to see what kind of DNA fragments would be effective for it.
I've been attending the meeting of the American Society of Clinical Oncology here in L.A. There are all sorts of intriguing possibilities coming out--especially telomerase inhibition, of course--but still most of the stuff is hardly beyond the petri dish stage.
I stopped taking methionine in view of reports that cancer cells in general are more dependent on methionine than normal cells. See the enclosed brochure from Anticancer Inc. I talked to the company's president. He says methioninase both deaminates and demethylthiolates methionine(!!!) I personally have never heard of an enzyme with two independent active sites with distinct catalytic activities. But he swears the material is homogeneous. Weird.
Many thanks for your continued assistance. Come see us next time you're in the area.
LL&P--
June 6, 1995
D. Pearson
NEVADA
Dear Durk & Sandy:
Thanks for the papers. The manganese SOD results remain very interesting, though their clinical significance is still very iffy. Particularly notable is the point that an oncogene--or, rather, a tumor-suppressor gene--can occur in the mitochondrial DNA. Makes one wonder: Since it's believed that mitochondria were once independent organisms, now living in symbiosis with eukaryotes, could we somehow create an infectious strain of mitochondria?
The use of DNA fragments for tanning is very ingenious. However, I'm skeptical about an anti-cancer application. Since cancer cells are, if anything, less able to undergo apoptosis than regular cells, I should think the treatment would be pretty toxic.
As always, the problem is to target therapy to the cancer cells. I wonder again whether there's no way to exploit the metabolic abnormalities of cancer cells in amino acid processing (eg, met and asn) to cause them to make abnormal peptides, which upon presentation on the surface would induce the T-cells to kill them. The high levels of lactate and corresponding pH difference might also form a point of attack. Might even get good results with something very crude--eg, low dosages of fluoroacetate. Since cancer cells run their Krebs Cycles faster, they should be poisoned more rapidly, right?
My paraprotein levels continue to creep up. I've had some bad back pain recently; X-rays showed a broken rib. I'm headed to Switzerland soon for a consulting job. In September, I plan to visit France to attend a major workshop on myeloma. Hope all is well with you.
LL&P--
June 20, 1995
D. Pearson
NEVADA
Dear Durk & Sandy:
Thanks for the paper on clotrimazole. Sounds interesting, though (I assume) it would have the same side-effects as most chemo due to its general effect on cell proliferation.
What do you think of the recent theory that AIDS is due to synergistic infection by HIV and mycoplasma? I wonder if a modified mycoplasma might be a good agent for gene therapy? As I pointed out in my last letter, if we could develop some sort of "infectious mitochondria," we could use them to correct the deficiency in Mn-SOD, and maybe other things.
I think I told you that I attended the meeting of the American Society for Clinical Oncology. There's a little bit of innovative work happening on the biotech side, but most research in cancer seems to be clinical studies of YACD (Yet Another Cytotoxic Drug). In September I'm going over to France for the Fifth Myeloma Workshop, which I hope will provide some more practical guidance.
There's a running debate on the BIX computer net regarding the value of taking S-adenosylmethionine. I enclose some questions from the publisher Jim Baen. Any comments?
LL&P--
==========================
tojerry/baen #2157, from jim_baen, 1469 chars, Sat Jun 17 02:16:48 1995 This is a comment to message 1954.
There are additional comments to message 1954.
--------------------------
I'm uneasy about only one element in this posting: it assumes that the rate of flow through the methionine salvage pathway (SAM to SAH to HC to Methionine) (((er, SAM = S-adenosylmethionine; SAH = S-adenosylhomocysteine; HC = homocysteine; Methionine = (hereafter :) Met.)))
Hm... the last sentence would seem to be a fragment; let me rephrase...
What is the rate of flow through this cyclic pathway under optimum conditions, and is it fast enough to allow the synthesis of SAM beyond "normal" levels for normal metabolisms on the one hand, and for most non-normal metabolisms on the other.
I'm personally acting on the assumption that the posting is essentially correct on this, especially if the system is enhanced with folINic acid (the rich man's folic acid :) and B12 in five mg doses together with three grams of methionine, plus other things intended to facilitate the conversion of tetrahydrofolate (THf) back to N5-methyltetrahydrofolate (required in reactoin quantities to convert HC to Met; the 5 CH3 ions are contributed to the synthesis, leaving a naked THF. B12 is an absolutely required catalyst: without it all the folate in the body is trapped in the N5-methylTHF form, which is useless except in this reaction, which is the source of the confusion of the roles of folate and B12, btw. But I parenthetically digress.)
With either SAM or methionine, one question that arises is how fast the folate cycles between THF and N5methylTHF. From hints in methionine loading experiments, I suspect it's on the order of an hour or two. Anybody know? It's important because since N5mTHF is needed in reaction quantities, that constant together with throughput rate are most of the answer as to how much SAM one can inveigle the system to generate by jamming with methionine.
Anyway, if you can get it, take SAM to be sure. Of course we Americans can't get it, unlike the various free peoples of the world.
July 23, 1995
D. Pearson
NEVADA
Dear Durk & Sandy:
I ran across the enclosed review on Alzheimer's on the Net and thought it might interest you.
I can't believe you guys are not on the Internet yet. When are you going to move into the Twentieth Century? Are you waiting for the Twenty-First?
Was thinking of coming up to Tacoma in September, but my schedule is too busy these days. I was over in Switzerland last month on a major consulting assignment, which continues to tie up most of my time, and which will require me to go over there again in August. Also, I'm going to a myeloma workshop in France in September--for which I have high hopes. All the top people in the field, worldwide, will be there.
These days I'm feeling pretty good, but test results are ominous. I'm back on cytoxan, but the oral form instead of the big bolus IV doses I was getting before. Much easier to take, but I wonder if this wimpy little dose will have any effect on the disease.
LL&P
August 16, 1995
D. Pearson
NEVADA
Dear Durk & Sandy:
The enclosed Forbes article on medical statistics might interest you. I assume, by the way, that you saw the article on Twinlabs in the Wall Street Journal.
Paraprotein stopped rising this month, which suggests the cytoxan is working and I may get a second remission. I'm still feeling pretty good, anyway. I upped my vitamin E to about 2 grams a day based on a paper that found it can prevent hair loss (due to adriamycin, but presumably it could be effective with cytoxan also). I wonder if it might have an additional beneficial effect by down-regulating IL-6.
I'm still scheduled to go to France next month for the myeloma workshop. I had been worried that I would be too sick to travel. Friday I leave for Basel on a consulting assignment.
Can't believe you guys aren't on the Net yet . . .
LL&P--
November 17, 1995
D. Pearson
NEVADA
Dear Durk & Sandy:
It was great to see you again and I really enjoyed talking to you last night.
I enclose some notes on historical parallels that might interest you.
Many thanks for your advice, which I always appreciate and learn from--even when I don't take it! At the moment I'm pretty heavily involved in trying to do something with HMBA. However, I do plan to re-examine and revise my nutrient program shortly.
By the way, I read your article on green tea this morning. Regarding Japanese lung cancer, I just read an article--in The Economist, I think--pointing out that recent statistical studies show that Japanese are essentially exactly as susceptible to lung cancer as Americans or Europeans. They simply took up heavy smoking at a later period. If you track the incidence curve vs. time, it correlates beautifully with the post-WWII smoking trend in Japan, with of course the appropriate induction delay.
Hope to see you again soon.
LL&P--
December 13, 1995
D. Pearson
NEVADA
Dear Durk & Sandy:
Here's the paper you asked for. Interesting. You know that anemia is a major symptom of multiple myeloma--usually this is attributed to "crowding out" of the bone marrow by the abnormal plasmacytes, but based on this paper I wonder if elevated IL-6 levels might be making at least some contribution.
Best wishes for the holidays.
LL&P--
December 28, 1995
S. Shaw
NEVADA
Dear Sandy:
Just got back from a short holiday vacation in Oregon. Thanks for your letter and for the book on IL-6, which I look forward to getting and reading.
It is indeed true, as you say, that multiple myeloma is driven by IL-6. Statistically, serum IL-6 is elevated in myeloma patients. However, the level varies wildly over several orders of magnitude from patient to patient. (Assay is complicated by the fact that much IL-6 may be bound to soluble IL-6 receptor.) Anti-IL-6 has been tried for treatment in Japan (by Kawano, if I remember correctly); at the recent Myeloma Workshop he reported that this is effective, at least temporarily, in patients with low serum IL-6 levels, but not in others.
It's likely that serum IL-6 does not directly measure the important values. It's known that the myeloma cells must be in actual contact with the stromal cells that produce IL-6 in order to divide. The local concentration of IL-6 is probably far more important than serum levels in most cases.
Drugs such as dexamethasone are known to work (when they do work) by suppressing IL-6 expression. I suspect that the other effective agents work, not by killing the myeloma cells directly, but by killing the stromal cells. The most effective cytotoxic agent against myeloma, melphalan, is notorious for its destructive effects on bone marrow.
So it's interesting that IL-6 may be directly responsible for the anemia symptom--but if we could do anything about it, we'd have a treatment for the disease itself!
I enclose a paper on ruthenium and nitric oxide that may interest you. Many thanks for your continued assistance.
LL&P--
January 7, 1996
S. Shaw
NEVADA
Dear Sandy:
Thank you for your letters and papers. Let me begin by clarifying my objectives and philosophy.
I absolutely agree that even slowing down the progression of the disease is a valid goal, and I am in no way rejecting options that offer less than a "cure". My approach is indeed based on the methods you set out in Life Extension--with, however, a rather higher level of conservatism, which has been increased by experience.
Specifically: You will recall that, pursuant to our discussions shortly after my diagnosis, in early 1993 I began raising my vitamin C intake. Had I known at that time about Kimler & Park's paper showing that ascorbate can stimulate myeloma, I certainly would not have done this. (In hindsight, it's perhaps significant that even Cameron & Pauling would not recommend C for myeloma patients.) Moreover, I did not know at the time that, though vitamin C is easily tolerated by healthy kidneys, high doses can be lethal to kidneys under stress. There can be little doubt that this supplement was, if not the sole source, at least a powerful contributing cause, of my kidney failure in May 1993. And that was a major setback--I nearly died at the time, and the kidney failure probably will eventually prove deadly in itself even if I were cured of myeloma.
Let me stress that I do not assign any responsibility for this catastrophe to you and Durk. My physician was aware of my vitamin C intake, and failed to recognize the danger. (It was only later, talking to a myeloma expert from Mayo Clinic, that I found out what had happened.) As always, I am accountable for my own choices. But this experience taught me a lesson. If even vitamin C, which has been so thoroughly studied and is normally one of the safest nutrients one can consume, could prove so treacherous, I had better be very careful with less well-understood agents.
I appreciate the trouble you've gone to in finding possible treatment options for me, and your frustration that I am not willing to adopt all of them. In some cases, as you know, I have found that certain agents would be too dangerous for one in my condition. NSAIDs, for instance, are clearly contraindicated due to their high toxicity to the kidneys. In other cases, there were questions that, to me, argued for caution. I stopped taking methionine, for instance, when I learned that cancer cells in general have an elevated requirement for this amino acid. Again, I stopped canthaxanthin when it began to crystallize into my eyes.
I simply do not feel I can safely undertake an unselective, "shotgun" approach. My policy is to add agents for which: there is reason to believe that they will be specifically helpful against multiple myeloma or its complications; and positive evidence that they are not harmful--not just to normal people, but to me.
Based on these considerations, the program at present looks like this:
* antioxidant and vitamin mixture (PRS)--general health and nutrition and reduction of oxidative stress
* beta-carotene 250,000-400,000 units/day--protection against mucositis, and possibly bladder cancer, from cytoxan
* vitamin E 1,600 units/day--down-regulation of IL-6 and protection from cardiotoxicity and alopecia from cytoxan
* coenzyme Q10 20 mg/day (rising to 50 mg/day)--stimulation of NK cell response (known to be part of the body's effort to deal with myeloma)
* calcitriol 3 mcg/week--possible anti-cancer effect, and also counters hypocalcemia, a complication of myeloma
I'm looking seriously at other options that may be added to this. Specifically:
* omega-3 fatty acids: After carefully reviewing the literature on these agents, I am unimpressed by the anti-cancer potential in my case. They seem to be effective only as chemopreventives, and perhaps as inhibitors of metastasis--neither of which seems relevant to my case. Reduction of serum IL-1 may be good (possible indirect reduction of IL-6) or bad (increased susceptibility to infection, a very serious danger in myeloma patients). However--omega-3 fatty acids may have a positive effect on the kidneys (based on the results with a lupus-like condition), and I am searching this issue.
* DHEA: Upregulation of IL-2 may be useful; high serum IL-2 is a good prognostic sign in myeloma patients. On the other hand, a study of treatment with low-dose IL-2 found some patients benefit, others are harmed; it appears to depend on the plasma cell labelling index of the specific patient. In any case, downregulation of IL-4 is a negative of this agent. Still worth further investigation. Chiapelli's paper leaves me a bit confused on dosages; in one place I see 30-90 mg/day, in another 1-5 mg/week--and you've recommended 200 mg/day. I am warned that commercial material is often of doubtful purity or even identity. Some sources are provided on the enclosed sheet--are you familiar with any of them?
I see on the Internet that there is now an outfit in San Diego specifically devoted to running blood tests for various antioxidants. Do you know anything about this? Any recommendations?
I hope I have convinced you that I am not "holding out for a better conventional approach" in opposition to nutritional or alternative methods; nor refusing to try new agents out of timidity or laziness; nor suffering from some sort of death wish. I have a policy that makes sense to me as a scientist. Obviously there is room for disagreement on how opportunities and dangers ought to be balanced. I'm sorry your judgment on this issue is not the same as mine; but I hope you'll continue to offer your suggestions even so.
Enclosed is a copy of a Scientific American article on caloric restriction and aging that may interest you even though it probably contains little you don't already know. LL&P--
February 19, 1996
D. Pearson
NEVADA
Dear Durk & Sandy:
I enclose an article from Forbes on the collector value of old computers. I thought it might interest you, as I recall that you own several classic models.
My medical situation at the moment is stable. I'm continuing on oral Cytoxan, and test results indicate that we're holding the disease and maybe gaining a little bit. I'm quite functional, except that I tire easily, and already my schedule is stacking up for the new year. I'll be at the ACS meeting in New Orleans next month.
HMBA continues to interest me. However, I now have a copy of the protocol, and find that it excludes kidney patients; so I would not be eligible even if we could get the trial running. There is another agent, suberic acid bishydroxylamide, that is at least 100 times as potent in vitro, but has not been tested in humans. I am looking into having some synthesized, and taking it myself when conventional agents have failed.
Thanks for your continued support, and best wishes. LL&P--
February 19, 1996
S. Shaw
NEVADA
Dear Sandy:
I was able to find five of the papers you requested in my visit to the Caltech library yesterday. The other journals are not carried there, except Am. Zool., but they don't have issues of that one back to 1970.
I have a guy I've used before when I was overloaded with library work. If you have enough stuff to justify it, I could put him on it and send him up to USC or UCLA, which have more extensive biomedical collections.
Hope this has been helpful to you. Thanks and best wishes.
LL&P--
April 5, 1996
S. Shaw
NEVADA
Dear Sandy:
I just want to drop you a note to thank you for the book on IL-6, which arrived yesterday.
I found it interesting that a number of other cytokines, such as IL-11, have similar effects. There are some multiple myeloma cell lines that seem to be independent of IL-6; this has been ascribed to autocrine IL-6 expression, but I wonder if there might be varieties that are dependent on other growth factors instead of IL-6. It's also notable that some patients--myself for example--do not respond to dexamethasone. Is this because the myeloma cell response to IL-6 is not turned off by dexamethasone in these patients--or because they are not IL-6 dependent?
Also of interest is the point that measurement of IL-6 in the blood is extremely tricky, and that it is commonly bound to other proteins. I think this throws the whole issue of IL-6 dependence in myeloma into question, because as far as I can see the only reliable evidence relies on in vitro studies in which non-bound IL-6 was added. Another odd anomaly is that BHA at 2-3 microM reduces serum IL-6, but BHT does not, even at 50-100 microM. But what are they really measuring?
In any case, I am increasingly convinced that anti-IL-6 will be a dead end for myeloma treatment. It would have to be administered continuously for life, and surely this would result in serious immunosuppresion and disturbance of hematopoesis.
LL&P--
April 18, 1996
S. Shaw
NEVADA
Dear Sandy:
I enclose a meeting abstract with some Russian results that look rather interesting. However, this strikes me as a very high dose of thiamine. A man has, what, a hundred times the surface area of a rat? That would come out to 2.5-5.0 grams for a human. Of course, that's a single bolus. What about 300 mg/day of thiamine for 14 days while I'm taking a cycle of cytoxan? My current dose of thiamine is 42 mg/day.
Latest test results are a little better. Seems to be some slow progress.
I'm still interested in HMBA (hexamethylene bisacetamide) and suberic bishydroxamide. I need to find a source for the latter. Regarding HMBA, I talked to Michaeli recently and he told me he has now definitely established that it induces apoptosis in myeloma cells by down-regulating bcl-2. (He had previously shown that it down-regulates bcl-2, and that it induces apoptosis; now he's proved that the apoptosis is caused by the bcl-2 reduction.)
Best regards, and LL&P--
May 7, 1996
S. Shaw
NEVADA
Dear Durk & Sandy:
Here is a communication from JACS that may interest you, concerning possible formation of ozone (!) from nitrite and O2 in biological systems.
Thanks for the ref you sent me. I'll try to find the papers you're looking for next time I'm up at Caltech.
I'm feeling OK and test results indicate we're holding it, maybe gaining a little. Anemia's taken a sudden turn for the worse, however--had to have a transfusion when my hemoglobin dropped to 8.1. Also, surprisingly, I seem to be getting quite a bit of hair loss from this last cycle of cytoxan; on six or eight previous cycles, the D and E had protected me quite effectively.
LL&P--
May 13, 1996
S. Shaw
NEVADA
Dear Durk & Sandy:
Thanks for your advice on my recent problems. I forgot to ask when we were talking about iron as a factor in oxidative stress. You'll recall that, after my most recent chemo, my hemoglobin dropped sharply, to the point that I had to have a transfusion. I assume one cannot lose so many red blood cells so quickly without an increase in iron levels, which might perhaps account for some oxidative stress.
The enclosed article from Forbes on privacy of medical records may interest you. I hadn't realized that the situation was already so bad.
Thanks for the paper on the abl inhibitor. My mother had sent me, the same day, a newspaper article on the subject, so it was very timely! Now, if we could just find an inhibitor for the bcl-2 protein, we'd have something. Wonder how much of its chemistry is known; have to run a search.
LL&P--
July 20, 1996
S. Shaw
NEVADA
Dear Durk & Sandy:
Thanks for the information you sent me on BMTs and other stuff. The French paper has already created quite a stir on the Net as rumors floated around. (Apropos, when are you guys going to get on the Net?) That was the crucial question for BMTs--would a prospective study show superiority over conventional treatment?
It still leaves open the question of why chemo works at all on myeloma, since the myeloma cells themselves divide very slowly if at all. My own theory is that chemo kills the bone marrow stromal cells, and the myeloma cells die from lack of supporting IL-6, which the stromal cells produce. It's interesting that the most effective cytotoxic agent for myeloma is melphalan, which is notorious for its destructive effect on the bone marrow. On the other side, vincristine, which is very marrow-sparing, is ineffectual for myeloma.
Following up our earlier discussion, I've upped my vitamin E to 2250+ units/day and added extra B-1 (300 mg/day while on chemo, 100 mg/day while off). I've been feeling much better, but let's see what happens on the current cycle. Also, I'm taking (during chemo) 600 mg of N-acetylcysteine twice a day; that seems to be effective in preventing bladder irritation from the Cytoxan.
LL&P--
July 30, 1996
S. Shaw
NEVADA
Dear Durk & Sandy:
Thanks again for the additional literature. We now have two completely contradictory prospective studies on the effectiveness of BMT for myeloma. One last year found that if BMT-eligible patients were treated with conventional therapy, they did exceptionally well, with median survival over 5 years. Now we have the NEJM study showing just the opposite. Anyway, a BMT isn't likely for me for a number of reasons.
I'm just finishing up another cycle of cytoxan, and again I'm coming through much better. The increased nutrient intake--E, acetylcysteine, and thiamine--definitely seems to help.
Speaking of B-1, I see in the latest C&EN that a simple thiazolium salt is being promoted to reverse collagen cross-linking. From the chemistry, it sure looks to me like thiamine should work for this. Why isn't it mentioned?
Although I can't find any mention of it in Life Extension, I get the impression also that the increased B-1 is doing something helpful for my sex life.
What's the scoop on beta-carotene? I read the letter by Lachance you sent me, but I can't make out his point.
LL&P--
September 13, 1996
S. Shaw
NEVADA
Dear Durk & Sandy:
Finally got a copy of one of the papers you requested. My lit search guy will probably be going up to UCLA soon, so I may be able to get the others.
Not much change here. I'm still on cytoxan, still holding OK as of the August test. Results aren't in yet for September.
I was wondering about vitamin C and IL-6. Since it plays an important role in wound-healing and infection-fighting, might ascorbate upregulate IL-6 or IL-6R?
A paper recently came out from UCLA showing that adriamycin may create resistance in myeloma cells by upregulating bcl-2. As you may recall, Michaeli at Sloan-Kettering thinks bcl-2 prevention of apoptosis is the basic problem in myeloma. Now this most recent paper finds that sub-lethal doses of adriamycin (and etoposide, another topoisomerase inhibitor) raise bcl-2. The other thing they found that upregulated bcl-2 was hydrogen peroxide. Does bcl-2 play a normal role in fighting oxidative stress? Another paper I just found indicates that erythropoietin, which myeloma patients (including myself) are given to treat anemia, works by upregulating bcl-2 in the hematopoietic process! Aaaaargh!
LL&P--
September 16, 1996
S. Shaw
NEVADA
Dear Durk & Sandy:
Managed to find a copy of another of the papers you requested.
October 9, 1996
S. Shaw
NEVADA
Dear Durk & Sandy:
Here's a copy of the paper you requested.
Things about the same here. The extra E and B-1 seem to be working well. I think I told you also that the acetylcysteine seems effective in preventing bladder irritation by cytoxan.
Saw an interesting paper recently that suggested (to me) a new line of attack for myeloma. Harvest some of the patient's B-cells, culture a clone, and insert a gene for expression of something toxic. Return to the patient's blood and stimulate with the appropriate antigen. The B-cells migrate to the bone marrow and proliferate into plasmacytes which poison the MM cells. As for the killer cells, if they don't poison themselves they'll undergo apoptosis anyway in a couple of days. Nice way to deliver the toxin where it's needed. In the paper (Blood 88, 2192) they used a herpes simplex thymidine kinase as the suicide gene and later treated the mouse with ganciclovir. Be years yet before the technology is practical, but it's an interesting concept.
LL&P__
November 5, 1996
S. Shaw
NEVADA
Dear Durk & Sandy:
Thanks for the literature you sent me. I was particularly interested in the abstract about oxidative stress in renal failure (Ceballos-Picot et al, Free Rad. Biol. & Med. 21(6), 845). Do you have the full paper?
If I understand correctly what they're saying, in renal failure both GSH and glutathione peroxidase drop. Presumably the former can be helped by taking cysteine and antioxidants. But what about the other? Without the peroxidase, the glutathione must surely lose a lot of its effectiveness, but how to upregulate the enzyme?
In general, one of my concerns at the moment is how to increase antioxidant levels on the water-soluble side without increasing vitamin C, which, as you know, is contraindicated by both the myeloma and the kidney problem. On the lipophilic side it's no problem, as I'm taking plenty of E and beta carotene. So the issue is, what supplements will most help keep ascorbate in the reduced form and increase GSH?
I'm off to Brussels next week for a chemical conference. Hope all is well in Tonopah.
LL&P---
February 6, 1997
S. Shaw
NEVADA
Dear Durk & Sandy:
The enclosed JACS paper on carotenoids and vitamins E and C may interest you.
I have been off chemo, in plateau phase, since October. However, test results are starting to look pretty ominous and I expect to be back on chemo in a few weeks. Too bad, as I have felt so much better lately.
My vitamin D intake is being increased. I now get 3 micrograms twice a week at dialysis, in addition to the dose from the PRS. As I mentioned to you on the phone, there's some evidence that D may inhibit myeloma growth.
Hope all is well in Tonopah.
LL&P--
April 14, 1997
S. Shaw
NEVADA
Dear Durk & Sandy:
The enclosed JACS paper on oxidative damage to lipids may interest you.
My condition remains pretty stable in spite of being off chemo since October. However, my hemoglobin fell off a cliff a few weeks ago, which suggests the disease may be getting active again.
I've been looking at an interesting compound called vitaletheine. This is the N-carboxy derivative of beta-alanylcysteamine (the free amine is beta-aletheine). It's related to 4'-phosphopantetheine, from which it may be formed in the body. It seems to have a very powerful effect on hematopoiesis, apparently by modulating bcl-2. And in a mouse model, N-carbobenzoxy-beta-aletheine proved extremely potent against myeloma. All this may tie in to anti-oxidant effects, which are thought to explain why several thiols have key regulatory roles. The leading ref is G. D. Knight et al, Cancer Research 54, 5623 (1994), if you want to look it up.
Hope you continue to prosper in Tonopah.
LL&P--
May 19, 1997
S. Shaw
NEVADA
Dear Durk & Sandy:
The enclosed JACS paper on vitamin E analogs may interest you.
Thanks for the information you sent. Vitamin K3 looks worth adding to my program. My dose of vitamin D has been cut at the dialysis center because my PTH fell off a cliff. I'm going to try adding curcumin, in the form of turmeric.
My latest test results were very bad and I am back on cytoxan. Meanwhile, though, I just heard from James Berenson at UCLA that they isolated a brand-new oncogene from my bone marrow (the sample they took four years ago) and want another sample. He also says they are finding a herpes virus in the bone marrow of myeloma patients. Sounds like BHT may be indicated.
How are things in Tonopah?
LL&P--
June 19, 1997
S. Shaw
NEVADA
Dear Durk & Sandy:
I'm back from Boston with some more information. The UCLA work was reported; there are two new discoveries.
From my bone marrow they isolated a new myeloma oncogene; it's a member of the FGF family, which they call FGF-X. Other genes of this type stimulated cell proliferation, as well as angiogenesis.
The virus implicated is Kaposi Sarcoma-associated Herpes Virus, KSHV or HHV-8. They find it in all myeloma patients, and about 25% of people with the pre-myeloma MGUS. They do not find it in healthy people or people with other leukemias. And they find the virus only in the dendritic cells of the bone marrow stroma, definitely not in the myeloma cells themselves. (Another group rushed a lab confirmation that the virus is present, but they think it's also in the myeloma cells. I suspect they just failed to separate the types properly; myeloma cells are practically glued to the stromal cells. Easy mistake to make, especially when you're in a hurry.) Theory: The virus makes the stromal environment much more favorable to MM cells. And, since dendritic cells also occur in the germinal centers, KSHV may even play a role in the oncogenic event.
Interestingly, KSHV has a gene for "viral-IL-6", and vIL-6 is active in humans. KSHV also has a gene for a viral version of bcl-2 (very logical, after all, that it would).
My mission, of course, is to stop the KSHV, using BHT to hit it as a viral particles and probably gancyclovir to attack it inside the cells. Any suggestions? You guys, I know, have a lot of experience with treating herpes, but have you dealt with KSHV before?
LL&P--
Ron
July 1, 1997
S. Shaw
NEVADA
Dear Durk & Sandy:
Thanks for the paper on monoglycerides vs. herpes, which I just received. I'm trying to get together an integrated program of BHT and similar agents, along with some antiviral drug that can attack the KSHV in the cell. Incidentally, there was an anecdotal report in Boston that suggests a possible connection with hepatitis C (for which, however, I'm negative).
I enclose some abstracts on antioxidant chemistry and related subjects from the San Francisco ACS meeting. I didn't attend, but did order the abstracts.
At the moment I'm sweating the latest test results. It's rare for a patient to get a third remission in myeloma, but we'll see if cytoxan can do it. If not, probably adriamycin. Of course, I've been taking BHT since late May, so we may begin to see an effect from it soon.
We'll be on vacation in Oregon and various parts of the West during the first two weeks of August. Tonopah, alas, is a bit too far out of the way for this trip.
LL&P--
August 13, 1997
S. Shaw
NEVADA
Dear Durk & Sandy:
Here is the Lancet paper on KSHV you requested. Also, I found an interesting paper in Chem. Pharm. Bull. on a conjugate of vitamins E and C.
Latest test results are OK; we're holding it, maybe gaining a little. No way to tell, of course, whether it's the cytoxan or the BHT or maybe both. I'm still trying to arrange treatment with gancyclovir or some other anti-viral.
Had to cancel our vacation, as Yoon just got promoted at work. (And about bloody time, too! -- the promotion, that is.)
Hope all is well in Tonopah. It's been hot as hell here.
LL&P--
September 15, 1997
S. Shaw
NEVADA
Dear Durk & Sandy:
Thanks for the material you've been sending me. The enclosed JACS article on vitamin E and beta-carotene may interest you.
I'm now taking 900 mg per day of BHT. Still waiting for the latest test results. Overall, however, I feel pretty good except when I'm on chemo.
Yoon is very busy, and very happy, with her promotion. However, we will be able to get away for a short vacation in October. I have been doing mostly writing; just finished up a paper on biological fallacies and their influence on the Objectivist ethics, which will be published in Objectivity. Consulting work should pick up in a few weeks, however.
I trust things are going well with your work.
LL&P--
December 12, 1997
S. Shaw
NEVADA
Dear Durk & Sandy:
Thanks for the material you've been sending me, and for your kind inquiries.
I had some heavy consulting work for several months that required more travel than I was really fit for. I came back from Philadelphia last month and pretty much collapsed. My energy levels are the lowest they've been since 1993 (when I was spending half my time in the hospital), and I am spending a lot of time dozing on the couch. I also developed a compression fracture in my spine and have had a lot of back pain.
My paraprotein, though, is not too bad. We're holding it and maybe gaining a little. Unfortunately, my tolerance for cytoxan is giving out. I have decided to insist on having a rest from this drug; it is weakening me too much.
Gancyclovir is a possibility; we would have tried it already except that it is rough on the bone marrow. Not wise to take it at the same time as cytoxan.
The latest excitement is a clinical trial of the antibiotic Biaxin (clarithromycin) as front-line therapy for myeloma. They got about 40-45% response, which is comparable to, eg, high-dose decadron. Not clear why the stuff should work at all, but I believe it can inhibit RNA synthesis. Anyway, I am trying to find out more about it--so far all I have is an Am. Soc. Hematology meeting abstract--and, if it continues to look good, press for giving it a try.
Hope all is well in your neck of the woods. Best wishes for the holidays.
LL&P--