Steven
Do you know what dose of copper would be used with disulfiram? Being copper seems to be involved in cancer growth if not initation, it seems that the lowest dose of copper should be used.
Also, I am of the belief that it is the copper that is beneficial, not the gluconate component (the study specified CU gluconate) Typically we see various chelated forms of minerals have different bioavailabitly, but it is the mineral with the therapeutic effect. In the disulfiram/copper combination I suspect this is the case as well. Do you know if there is something special about this particular copper preparation that gives it synergy with disulfiram?
I wouldn't necessarily say that the lowest dose of copper should be used. I'm aware that tumors use copper for angiogenesis, but in the presence of disulfiram metabolites, copper becomes highly toxic to the cancer cells. It's sort of like how iron is normally a growth factor for tumors, but when combined with radiation it improves the efficacy of the therapy.
ReplyDeleteThere's no doubt in my mind that it is the copper and not the gluconate that is the therapeutic component. I'm not sure why the gluconate form is usually recommended in this context. I suspect that the choice of copper compound should be based on bioavailability and pharmacokinetics. This is not a subject I've researched thoroughly however. I also usually defer to the copper gluconate dosing suggested in the original CUSP9 document, as we don't actually know the optimal dose. I'm not as convinced as the CUSP9 authors that copper is dispensable in combination with disulfiram, as animal studies show that additional administration of oral copper does improve the efficacy of disulfiram, at least in some models. No human study has yet been carried out on this important question, although one is currently underway at the Washington University in Missouri. They are using copper gluconate 6 mg every day in combination with disulfiram 500 mg every day. My guess is that this dose of disulfiram, esp in combination with the copper will lead to peripheral neuropathy after several months in many cases.
https://www.clinicaltrials.gov/ct2/show/NCT01907165
The synergy is between disulfiram and copper, not with any particular chelate of copper. The active molecule is copper bis(diethyldithiocarbamate), which is one molecule of copper attached to two molecules of DDC (the primary metabolite of disulfiram).
http://www.chemspider.com/Chemical-Structure.24391.html
Steven
ReplyDeleteJeremy has been taking 250 mg disulfiram in the mornings and his TMZ at night. We are going to up his dose to 500 mg disulfiram and add copper. I belevie the half life of disulfiram is failty long so it seems to me taking 500 mg in the moring will be adequate as compared to 250 mg bid. But with the addition of copper do you know if its best to take the disulfiram-CU combination shortly before ingestion of TMZ? I have not been able to see how this is being done in clinical trials and the CUSP protocol is no longer using CU so I don't know how they did it. Are you aware of how this is being experimented with? Thank you
Given that phase 1 trials are still testing whether or not taking copper makes a difference when added to disulfiram therapy, I conclude that nobody yet knows the optimal dose or scheduling. I would proceed based on knowledge of disulfiram pharmacokinetics and metabolism.
ReplyDelete1) Faiman et al, 1984 (will add to the Library) found that peak plasma levels of DDC (the metabolite that binds with copper) after single or repeated disulfiram doses occurs at 8.5, and 9.4 hours after ingestions (averages of multiple patients).
Notwithstanding the increased risk of toxicity (neuropathy etc.) when disulfiram is combined with copper, the theoretical goal would be to saturate all the disulfiram molecules with copper.
2) According to Johansson 1992 (will add to Library), "After ingestion, disulfiram (DSF) is rapidly converted, probably in the stomach, to its bis (diethyldithiocarbamato) copper complex." This is the very first sentence in the study abstract.
If this is true that DDC binds with copper in the stomach, it would make sense to take the disulfiram and copper at the same time, about 9 or 10 hrs before TMZ if you're aiming at maximum plasma levels of DDC and TMZ to co-incide.
This is all theoretical, and based on studies that are 20-30 years old. I don't know of anything else to go on though, other than mouse studies.
I added the above studies to folder 5 of the Brain Tumor Library, Pharmacokinetics folder.
ReplyDeleteOur NO has dad taking disulfiram twice daily. Reading this thread, should I give dad both pills together around noon? We do tmz at 8pm.
ReplyDeleteIn theory this would be a good idea, but in reality I'm not sure how much difference it would make. Plasma levels are not as important as levels of drug in brain extracellular fluid, which are of course a lot harder to determine experimentally without invasive procedures.
DeleteSteven or anyone with thoughts on this....
ReplyDeleteDisulfiram question relative to demethylation. As we prepare to shift away from monthly TMZ for Jeremy, I am considering using disulfiram on a more regular basis with the hope of taking out GSC’s. Because he was IDH1 mutant, and therefore likely MGMT methylated (interestingly this was never checked), Jeremy has been using disulfiram only for the 5 days he was using TMZ.
What I am wondering is if disulfiram is used consistently, with a break periodically to reduce the chance of PN, and if disulfiram acts as a demethylating agent, will he increase the likelihood that in the case of recurrence, the recurrent tumor would lose its MGMT methylation status, or would that return once the disulfiram was discontinued?
If it is likely that the recurrence would not be MGMT methylated as a result of more continuous use, what would be a reasonable number of days to take disulfiram before rotating off? This approach makes me wonder about developing disulfiram resistant GSC’s. Any thoughts? I have settled on 500 mg daily with 5 mg CU. Just need to determine the schedule.
Johns Hopkins actually did a small human pharmacodynamic study in prostate cancer to test disulfiram as a DNA demethylating agent.
Deletehttp://www.ncbi.nlm.nih.gov/pubmed/23958896
It was found to be a not very effective demethylating agent, so I wouldn't worry about any permanent disulfiram-induced demethylation of the MGMT promoter.
However, MGMT could become unmethylated anyway in the course of tumor evolution, especially post-temozolomide, as the MGMT-unmethylated subclones in the tumor would be most resistant to TMZ and most likely to have survived the TMZ treatment.
Since disulfiram works, at least partially, through copper-dependent cytotoxicity, it may be thought of as a continuation of chemotherapy. The best schedule is anyone's guess.
Drugs.com describes a schedule of 500 mg daily for two weeks, followed by 6-12 months of 250 mg daily maintenance. This is of course for alcohol deterrence, but could be used as a starting point. As you point out, there is the question of how long to continue cytotoxic therapy in a tumor that is stable or dormant. It will be interesting to see if the more continuous disulfiram treatment makes any difference on the next MRI.
Steven
ReplyDeleteThere is a completed phase 1 study using disulfiram and copper for liver cancer. This was completed in 2013. I have been unable to locate the results. Would you happen to know anything about this? Interesting that in this trial copper was to be taken at a different time than disulfiram. I wonder why. Here is the link to the trial. https://clinicaltrials.gov/ct2/show/NCT00742911
I'm aware of this trial, but have not seen any results for it. I'm not sure why they would separate the copper and disulfiram dose in time, as the disulfiram (or its metabolite DDC) likely chelates copper in the stomach, improving its absorption in the process:
Delete"However, DDC is a strong metal chelating sub-
stance, especially in a complex with heavy metal ions,
e.g. cupric ions (3, with which some of the liberated
DDC forms a bis(diethy1dithiocarbamato) copper
complex (Cu(DDC),). Cu(DDC), is more acid-stable
than is DDC, and unlike DDC is also neutral and ex-
tremely hydrophobic, which permits absorption along
the entire length of the upper gastrointestinal tract."
"DDC is a highly
polar and hydrophilic compound even in the non-
ionized form. Therefore, to be absorbed into the blood
stream a hydrophobic complex with cupric ions must
be formed. Accordingly, formation of Cu(DDC)*
might be the explanation for the enhanced uptake of
DDC "
quotes from this review, which I'll upload to the Library (if I haven't already)
http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0447.1992.tb03310.x/abstract
Reports of a phase 1 trial of disulfiram + TMZ were in the 2015 SNO abstracts.
http://neuro-oncology.oxfordjournals.org/content/17/suppl_5/v12.3
The conclusion was that 500 mg per day was the maximum tolerated dose, but only two doses were tested (500 and 1000 mg).
I suspect giving disulfiram with copper could increase the therapeutic potential, while also increasing the possibility for adverse side-effects.
Yes, the pharmacokinetic/pharmacodynamic study of disulfiram (Johansson 1992) is already in the library, folder 5.
DeleteHmm. I hoped that the results would be better . Only 1 patient did not progress. :( I hoped that disulfiram would be a magic bullet :(
Delete