Long‐term Antabuse treatment: tolerance and reasons for withdrawal

Børup, C.; Kaiser, Antonia; Jensen, Egil

doi:10.1111/j.1600-0447.1992.tb03315.x

Cited by 24 publications

(17 citation statements)

References 2 publications

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“…Disulfiram not only enhanced the antitumor efficacy of g-radiation delivered from an external source but also potentiated the efficacy of 131 I-MIBG targeted radionuclide therapy, in both spheroid and xenograft models. Significantly, the synergistic activity in vivo was achieved at a disulfiram dosage that had negligible effect on xenograft tumor growth and has previously been demonstrated to be associated with insignificant side effects (9). Such features are highly desirable in a radiosensitizing agent.…”

Section: Resultsmentioning

confidence: 83%

“…These include the induction of oxidative stress (2,3), the generation of copper-dependent toxicity (2,4), proteasome inhibition (4-6), and nuclear factor-kB inhibition (7,8). Despite its diverse range of pharmacologic activities, prolonged treatment with disulfiram has negligible, reversible, adverse effects and is considered a safe drug (9). Disulfiram is currently undergoing clinical trials for the treatment of various cancers including melanoma and liver, lung, and prostate.…”

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confidence: 99%

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The Role of Copper in Disulfiram-Induced Toxicity and Radiosensitization of Cancer Cells

Rae

Tesson

Babich³

et al. 2013

J Nucl Med

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Disulfiram has been used for several decades in the treatment of alcoholism. It now shows promise as an anticancer drug and radiosensitizer. Proposed mechanisms of action include the induction of oxidative stress and inhibition of proteasome activity. Our purpose was to determine the potential of disulfiram to enhance the antitumor efficacy of external-beam g-irradiation and 131 I-metaiodobenzylguanidine ( 131 I-MIBG), a radiopharmaceutical used for the therapy of neuroendocrine tumors. Methods: The role of copper in disulfiram-induced toxicity was investigated by clonogenic assay after treatment of human SK-N-BE (2c) neuroblastoma and UVW/noradrenaline transporter (NAT) glioma cells. The synergistic interaction between disulfiram and radiotherapy was evaluated by combination-index analysis. Tumor growth delay was determined in vitro using multicellular tumor spheroids and in vivo using human tumor xenografts in athymic mice. Results: Escalating the disulfiram dosage caused a biphasic reduction in the surviving fraction of clonogens. Clonogenic cell kill after treatment with disulfiram concentrations less than 4 mM was copper-dependent, whereas cytotoxicity at concentrations greater than 10 mM was caused by oxidative stress. The cytotoxic effect of disulfiram was maximal when administered with equimolar copper. Likewise, disulfiram radiosensitization of tumor cells was copper-dependent. Furthermore, disulfiram treatment enhanced the toxicity of 131 I-MIBG to spheroids and xenografts expressing the noradrenaline transporter. Conclusion: The results demonstrate that the cytotoxicity of disulfiram was copper-dependent, the molar excess of disulfiram relative to copper resulted in attenuation of disulfiram-mediated cytotoxicity, copper was required for the radiosensitizing activity of disulfiram, and copper-complexed disulfiram enhanced the efficacy not only of external-beam radiation but also of targeted radionuclide therapy in the form of 131 I-MIBG. Therefore, disulfiram may have anticancer potential in combination with radiotherapy.

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Section: Resultsmentioning

confidence: 83%

mentioning

confidence: 99%

The Role of Copper in Disulfiram-Induced Toxicity and Radiosensitization of Cancer Cells

Rae

Tesson

Babich³

et al. 2013

J Nucl Med

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“…S1A, S2B, and S3). From these candidate compounds, we chose montelukast, a leukotriene receptor antagonist used for the treatment of acute asthma (36,37), clioquinol, a hydroxyquinoline that has been used as an antifungal and antiprotozoal drug (38), and disulfiram, an off-patent drug previously used to treat alcoholism (21,39) for further assessment. While in vitro studies were validated for clioquinol ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…As DSF has been used clinically for over 60 years to treat alcoholism, its pharmacokinetics has been extensively studied and shown to have an excellent safety record at FDArecommended doses (20,21). DSF is available, inexpensive, safe, and overall well-tolerated making it an attractive candidate for "repurposing" in the context of glioblastoma.…”

Section: Introductionmentioning

confidence: 99%

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Lun

Wells

Grinshtein

et al. 2016

Clinical Cancer Research

161

119

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Purpose: Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, and the presence of a stem-like population of cells, termed brain tumor-initiating cells (BTIC) that confer resistance to conventional therapies.Experimental Design: To develop therapeutic strategies that target BTICs, we focused on a repurposing approach that explored already-marketed (clinically approved) drugs for therapeutic potential against patient-derived BTICs that encompass the genetic and phenotypic heterogeneity of glioblastoma observed clinically.Results: Using a high-throughput in vitro drug screen, we found that montelukast, clioquinol, and disulfiram (DSF) were cytotoxic against a large panel of patient-derived BTICs. Of these compounds, disulfiram, an off-patent drug previously used to treat alcoholism, in the presence of a copper supplement, showed low nanomolar efficacy in BTICs including those resistant to temozolomide and the highly infiltrative quiescent stem-like population. Low dose DSF-Cu significantly augmented temozolomide activity in vitro, and importantly, prolonged in vivo survival in patient-derived BTIC models established from both newly diagnosed and recurrent tumors. Moreover, we found that in addition to acting as a potent proteasome inhibitor, DSF-Cu functionally impairs DNA repair pathways and enhances the effects of DNA alkylating agents and radiation. These observations suggest that DSF-Cu inhibits proteasome activity and augments the therapeutic effects of DNA-damaging agents (temozolomide and radiation).Conclusions: DSF-Cu should be considered as an adjuvant therapy for the treatment of patients with glioblastoma in both newly diagnosed and recurrent settings.

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“…However, there are other studies that add weight to the evidence that disulfiram is not a drug with high incidence of adverse effects [6]. Larson FW et al (1992) reported that in treatment of alcohol dependence, disulfiram is most useful in conjuction with a structured, supervised, aftercare program [7].…”

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confidence: 99%

Current Status of Disulfiram Therapy

Singh

Divinakumar

2001

Medical Journal Armed Forces India

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The effectiven""s of disulfiram is linked to the disnlflram-ethanol reaction in the treatment of Alcohol Dependence Syndrome. However disulfiram therapy is assoriated with various adverse effects and needs a structured and supervised after care program. Relapse rate is very high once disulfiram therapy Is dlscontinued. Keeping the..e facto" in mind disultlram therapy is used less often today than previously. MJAn 2001; 57: 320-321

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Long‐term Antabuse treatment: tolerance and reasons for withdrawal

Cited by 24 publications

References 2 publications

The Role of Copper in Disulfiram-Induced Toxicity and Radiosensitization of Cancer Cells

The Role of Copper in Disulfiram-Induced Toxicity and Radiosensitization of Cancer Cells

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Current Status of Disulfiram Therapy

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