Thursday 24 March 2016

Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of Glioblastoma.

View study here

This study is exciting as it is the first study of disulfiram + copper in orthotopic GBM patient-derived xenograft mouse models.  Disulfiram and copper were given orally, not by injection, at clinically relevant doses.  The disulfiram + copper had little effect on its own in the mice, but sensitized the tumors to TMZ.  The testing was done on both newly diagnosed and recurrent samples.

8 comments:

  1. Great article Stephen. The dose of 2 mg/kg copper was used. what is the human equivalent? Looks like they gave the disulfiram copper TMZ combination at the same time. I wonder if this is best or if taking the disulfiram /copper combination at a different time would allow for accumulation in the glioma cells making the addition of TMZ even more of a potent combination. Jeremy has been using 500 mg DSF and 4 mg copper gluconate. The questions that are always on my mind is should we dose DSF/CU once or twice daily, how much copper and how long before TMZ or concurrent with TMZ. I recall from a previous discussion here that taking DSF about 9 hours prior to TMZ might be a good idea. Any thoughts on these burning questions?

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  2. Mike, the conversion of mouse dose to human dose is only a rough approximation, but using a standard allometric scaling conversion it would be approximately 10 mg. The original version of CUSP9 recommended 2 mg twice daily of copper gluconate.

    One pharmacokinetic study I have shows the maximum level of disulfiram metabolites in the blood is reached in 6-9 hours after ingestion (this study is in the Brain Tumor Library, folder 5-Pharmacokinetics, Faiman et al 1984), whereas TMZ reaches maximum much quicker (one or two hours). So one strategy could be to take 500 mg disulfiram + copper 5-8 hours before TMZ, with the idea that they would both be reaching maximal concentrations around the same time. However concentrations in the central nervous system usually lag behind concentrations in the blood.

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  3. This copper , dose it have to be a certain type of copper or can it be just a copper supplyment you buy from the store

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  4. Copper gluconate is the form most commonly used.

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  5. Stephen

    I have been thinking about the following comment from this article:

    Our observations suggest that as a single agent
    DSF-Cu has limited in vivo efficacy, however, when given in the context of a DNA alkylating
    agent (TMZ or BCNU) and/or DNA damaging agent (IR), DSF-Cu has the potential to be
    repurposed for the treatment of patients with highly infiltrative glioma.

    Specifically the comment about limited in vivo efficacy in the absence of TMZ. Are there other studies showing efficacy of DSF-CU or even DSF as a single agent in the absence of TMZ or other chemotherapeutic agent? If not, then it would seem the prudent approach would be to use DSF-CU only during TMZ. This reduces the potential for side effects, and the issue around DSF acting a a demethylating agent. Thoughts?

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  6. There are a number of animal studies showing disulfiram or disulfiram+copper having tumor-limiting effects in the absence of chemotherapy. However these are mostly in subcutaneous tumor models (no blood-brain barrier). There have been a couple prior studies in orthotopic brain tumor models, but the disulfiram has been injected intravenously or intraperitoneally in these studies.
    I would venture to guess that the limited effect of disulfiram + copper without chemo in the new study is at least partially due to limited brain penetration.

    As part of a cocktail, there may be other agents that disulfiram would co-operate with (apart from chemotherapy). For example disulfiram + auranofin synergy has been published in several studies.

    As you suggest though, only taking disulfiram on chemotherapy days might maximize benefit, and taking a rest would allow the greater use of other agents with overlapping toxicities such as DCA.





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  7. Clinical trial with DSF in different doses and Copper gluconate 2mg TID concurrent with chemo and radioteraphy https://clinicaltrials.gov/ct2/show/NCT02715609

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  8. And another one after chemo and radioteraphy DSF 500 od 1000 mg QD and Copper gluconate 6mg QD on data 1-28 https://clinicaltrials.gov/ct2/show/NCT01907165?term=Glioblastoma+AND+Temozolomide&rank=63

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