DISULFIRAM

Disulfiram in used in treating alcoholism byt acting on the enzyme aldehyde dehydrogenase. The same enzyme is often implicated in cancer resistance to treatment. Other possible anti-cancer actions include copper chelation. (see citrus pectin in the Supplements Library for a natural alternative).

A phase II trial in advanced stage lung cancer showed around a 40% relative risk reduction in patients that received disulfiram with chemo. In particular, the positive findings were influenced by 10% of patients (2/21) who achieved a remarkable long term remission. But this older trial requires replication, and above all an agreed targeting profile as to who may be a “responder”. A pilot trial in advanced localized liver cancers administered subsequent to chemo therapy regimes. Results provided enough evidence of effects for the researchers to recommend progression to further studies.

In contrast a recent substantial trial of disulfiram with copper in glioblastoma (brain cancer) treatment showed no improvements in relative risk but a much higher rate of adverse events during chemotherapy. Similarly a 2013 phase I study in advanced prostate cancer showed only negative adverse reactions.

So the current findings are mainly disappointing, though early phase clinical trials continue including in pancreatic and breast cancers so more evidence could emerge. Disulfiram is another example where its application may emerge in specific cancer cases, and only should be considered when proposed by your oncologist,

The addition of disulfiram to a combination regimen of cisplatin and vinorelbine was well tolerated and appeared to prolong survival in patients with newly diagnosed non-small cell lung cancer [around 40%] The unusual result is the long-term survival of two patients in the active group, an event that is extremely rare in patients with stage IV lung cancer treated by chemotherapy alone. It is important to note that the difference in survival continued after cessation of chemotherapy and maintenance with disulfiram alone. The drug is inexpensive, a...

Disulfiram dosed at 250 mg daily together with chelated Zn at doses of 50 mg three times daily is well tolerated in patients with advanced stage IV melanoma; the combination is capable of producing tumor shrinkage. The interim futility analysis endpoint of one responding patient was not met and the study will not expand to the full Phase II cohort of 29 patients. Future work with this combination may be warranted in other cancers given the favorable safety profile, and may also be considered in combination with other therapies actively in use for...

Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function

In this randomized clinical trial of 88 patients with recurrent glioblastoma, the addition of disulfiram and copper to alkylating chemotherapy did not significantly improve survival at 6 months, as compared with alkylating chemotherapy only. Significantly more patients receiving disulfiram had adverse events of grade 3 or higher (34% vs 11%) and serious adverse events (41% vs 16%). These findings suggest that the addition of disulfiram and copper to alkylating chemotherapy should not be recommended for patients with recurrent glioblastoma.

TABLE OF REFERENCES

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https://pmc.ncbi.nlm.nih.gov/articles/PMC4391770/	4	Forty patients were treated for more than two cycles, half with and half without disulfiram, which was well tolerated. An increase in survival was noted for the experimental group (10 vs. 7.1 months). Interestingly, there were only two long-term survivors, both in the disulfiram group....The addition of disulfiram to a combination regimen of cisplatin and vinorelbine was well tolerated and appeared to prolong survival in patients with newly diagnosed non-small cell lung cancer. The results from this small study seem encouraging	The unusual result is the long-term survival of two patients in the active group, an event that is extremely rare in patients with stage IV lung cancer treated by chemotherapy alone. It is important to note that the difference in survival continued after cessation of chemotherapy and maintenance with disulfiram alone. The drug is inexpensive, and its tolerability and safety have been demonstrated over years of clinical experience with a large number of patients. Our results support a larger phase III trial combining this drug with chemotherapy.
https://aacrjournals.org/cancerres/article/73/8_Supplement/LB-175/592242/	3	Disulfiram dosed at 250 mg daily together with chelated Zn at doses of 50 mg three times daily is well tolerated in patients with advanced stage IV melanoma; the combination is capable of producing tumor shrinkage. The interim futility analysis endpoint of one responding patient was not met and the study will not expand to the full Phase II cohort of 29 patients. Future work with this combination may be warranted in other cancers given the favorable safety profile, and may also be considered in combination with other therapies actively in use for stage IV melanom	Disulfiram was dosed at 250 mg orally at bedtime, while chelated Zn was given thrice daily at 50 mg elemental Zn orally with each meal. ...One patient experienced a partial response not meeting RECIST criteria with one target lesion decreasing 27% from baseline measurements. Average time on treatment for evaluable patients was 55 days (range 20-168). Progression free survival and overall survival of evaluable patients was 53 days and 203 days respectively. Overall safety data has shown this regimen to be well tolerated with only one Gr 3 or greater drug related adverse event
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-021-08242-4	2	This Phase 1 trial of disulfiram in combination with up to 8 mg of elemental copper demonstrated safety and tolerability in patients with metastatic solid tumors to the liver. While some patients had stable disease, no objective responses were observed. Given likely non-overlapping toxicities and potential for synergy, use of disulfiram-metal combinations with cytotoxic chemotherapy is an attractive avenue of investigation which enhance efficacy. ..The excellent safety profile of this combination together with the presence of multiple identified therapeutic targets, ease of use, drug availability, and low-cost warrant further study of disulfiram and metals in the treatment of cancer.	Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2802966	N/A	This randomized clinical trial found that the addition of disulfiram and copper to alkylating chemotherapy did not improve survival in patients with recurrent Glioblastoma. Instead, the treatment regimen of 400 mg disulfiram daily resulted in significantly more toxic effects. These results suggest that disulfiram and copper is not of benefit in patients with recurrent GB.	A possible reason why we failed in translating the laboratory results to the clinic may be inadequate bioavailability in the target tissue. We do not know the tissue concentrations reached in the present study, but 400 mg daily (allowing 200 mg in case of toxicity) could be considered sufficient given the signal in a study using 40 mg 3 times daily in patients with lung cancer.Nevertheless, from a toxicity point of view, a higher dose of disulfiram is not feasible.
https://onlinelibrary.wiley.com/doi/abs/10.1002/pros.24329	N/A	Oral DSF is not an effective treatment for mCRPC due to rapid metabolism into an inactive metabolite, Me-DDC. This trial has stopped enrollment and further work is needed to identify a stable DSF formulation for treatment of mCRPC.	Only five subjects were on trial for ⩾6 months, all were in cohort 1 and all had PSA progression by 6 months. No changes in PSA kinetics were observed in either cohort. Disulfiram was poorly tolerated with six patients experiencing grade 3 adverse events

DISULFIRAM

TABLE OF REFERENCES

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