The Single–and Repeated–dose Toxicity of Dimethyl Sulfoxide

Smith, Eric G.; Hadidian, Z.; Mason, Marcus M.

doi:10.1111/j.1749-6632.1967.tb34870.x

Cited by 93 publications

(50 citation statements)

References 8 publications

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“…The median lethal dose (LD50) of intravenous DMSO in animals ranges from about 4 to 10 g/kg body weight, depending on the species. 26,27 The maximum tolerated dose increases to 10 or more g/kg when the compound is given orally. In a series of remarkable experiments Benville, Smith, and Shanks 40 studied young salmon and trout totally immersed in DMSO solutions.…”

Section: Discussionmentioning

confidence: 99%

“…24 DMSO has the advantages of being a hydroxyl radical trap that distributes rapidly to all body fluid compartments 25 and that can be tolerated in high concentrations in vivo. 26,27 Methane sulfinic acid (MSA) is a primary and characteristic product of the trapping reaction; it is poorly metabolized by tissue; 21 and it is relatively stable as a salt at pH > 4. 28 The yield of methane sulfinic acid in gamma irradiated, aqueous solutions of DMSO matches the theoretical radiochemical yield of hydroxyl radicals; and similarly, the yield of methane sulfinic acid when Fenton's reaction is performed in aqueous DMSO solutions matches the amount of hydrogen peroxide reduced.…”

Section: Introductionmentioning

confidence: 99%

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Scatchard analysis of methane sulfinic acid production from dimethyl sulfoxide: A method to quantify hydroxyl radical formation in physiologic systems

Babbs

Griffin

1989

Free Radical Biology and Medicine

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A major impediment to the confirmation of free radical mechanisms in pathogenesis is a lack of direct, chemical evidence that oxygen centered free radicals actually arise in living tissues in quantities sufficient to cause serious damage. This investigation was conducted to validate the use of dimethyl sulfoxide (DMSO) as a quantitative molecular probe for the generation of hydroxyl radicals (HO*) under physiologic conditions. Reaction of HO* with DMSO produces methane sulfinic acid (MSA) as a primary product, which can be detected by a simple colorimetric assay. To develop a method for estimating total HO* production, we studied two model systems: the superoxide driven Fenton reaction in vitro, using xanthine oxidase as the source of superoxide, and a computer model of Fenton chemistry. Measured MSA production both in vitro and in the computer model was a predictable function of the concentrations of DMSO and competing scavengers of HO*, according to the principle of competition kinetics. Both experimental results and model calculations showed that Scatchard analysis may be used to infer total HO* generation, despite the presence of scavengers other than DMSO, such as mannitol. Thus, methane sulfinic acid production from DMSO holds promise as an easily measured marker for HO* formation in biologic systems pretreated with DMSO, and Scatchard analysis of repeated experiments with varying DMSO concentrations can yield an estimate of total HO* generation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Scatchard analysis of methane sulfinic acid production from dimethyl sulfoxide: A method to quantify hydroxyl radical formation in physiologic systems

Babbs

Griffin

1989

Free Radical Biology and Medicine

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“…1 to 1.0 M [32, 52, 53] to trap the major portion of HO radicals generated and thus estimate their true abundance. Fortunately, DMSO is an extremely nontoxic [54,55] and rapidly penetrating molecular probe that can be tolerated by living tissues in adequately high concentrations [54,[56][57][58][59][60]. It also reacts very rapidly with HO to give a single set of initial products: 7 including a chemically distinctive and stable compound, methane sulfinic acid (MSA), that is not normally present in biological specimens.…”

Section: Preliminary Tests Of the Hypothesismentioning

confidence: 99%

Free radicals and the etiology of colon cancer

Babbs

1990

Free Radical Biology and Medicine

313

174

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This hypothesis paper reviews diverse evidence suggesting that intracolonic production of oxygen radicals may play a role in carcinogenesis. The hypothesis began to evolve when the author made the chance discovery that 1/10,000 dilutions of feces generated detectable quantities of highly reactive hydroxyl radicals (HO). The rate of HO formation, detected using DMSO as a molecular probe, was quite remarkable, corresponding to that which would be produced by over 10,000 rads of gamma irradiation per day, absorbed in the periphery of the fecal mass adjacent to the mucosa. The relatively high concentrations of iron in feces, together with the ability of bile pigments to act as iron chelators that support Fenton chemistry, may very well permit efficient HO generation from superoxide and hydrogen peroxide produced by bacterial metabolism. Such free radical generation in feces could provide a missing link in our understanding of the etiology of colon cancer: the oxidation of procarcinogens either by fecal HO, or by secondary peroxyl radicals (ROO) to form active carcinogens or mitogenic tumor promotors. Intracolonic free radical formation may explain the high incidence of cancer in the colon and rectum, compared to other regions of the GI tract, as well as the observed correlations of a higher incidence of colon cancer with red meat in the diet, which increases stool iron, and with excessive fat in the diet, which may increase the fecal content of procarcinogens and bile pigments. OVERVIEW OF THE HYPOTHESIS AND RELEVANT CHEMICAL MECHANISMSMy intention in this hypothesis paper is to present a new hypothesis suggesting how oxygen derived free radicals, generated in fecal material next to colonic epithelium, may play a significant role in the etiology of colon cancer. This hypothesis derives from an earlier conjecture by Graf and Eaton [1], coupled with the serendipitous discovery in our laboratory that highly reactive HO radicals can be produced abundantly by suspensions of feces under aerobic conditions. As do many other hypotheses for the pathogenic effects of oxygen centered free radicals in biologic systems [2][3][4][5][6], this one also invokes the superoxide driven Fenton reaction:In feces a ready biologic source of superoxide is the respiratory activity of bacteria [7][8][9][10], notably E. coli [11], perhaps together with spontaneous autoxidation of ferrous iron chelates that have been previously reduced by metabolites of the anerobic subpopulation of fecal flora. Another intriguing source of colonic superoxide is the lipoxygenase activity of normal or sloughed colonic epithelial cells [12]. The necessary iron is provided from the diet, since only a small fraction of dietary iron is absorbed in upper GI tract [13,14]. Hydroxyl (HO) radicals so formed within the colon could easily trigger a variety of carcinogenic mechanisms. For example, they could participate in aromatic hydroxylation reactions [15,16] to form carcinogenic products [17]; they could abstract hydrogen atoms from indoles to form radicals t...

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“…8,11 Toxicology studies in humans and animals report numerous side-effects dependent on dose and route of administration. 7,12 Most commonly, nausea and vomiting are associated with the infusion of cryopreserved stem cells. In addition hypotension or hypertension, chest tightness, respiratory distress, bradycardia and muscle cramps have been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Less commonly reported toxicities include intravascular hemolysis, hypothermia, liver damage and central nervous system effects including sedation and seizures. [12][13][14] Following myeloablative chemotherapy, RD began to develop acute renal insufficiency as evidenced by rising serum creatinine and metabolic acidosis. At the time of her stem cell infusion, her BUN was 24 and creatinine was 1.8 mg/dl.…”

Section: Discussionmentioning

confidence: 99%

Reversible leukoencephalopathy associated with re-infusion of DMSO preserved stem cells

Higman

Port

Beauchamp

et al. 2000

Bone Marrow Transplant

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Summary:We report a case of posterior reversible leukoencephalopathy (PRL) following the infusion of dimethylsulfoxide (DMSO) cryopreserved autologous stem cells in the setting of myeloablative chemotherapy in a patient with recurrent Ewing's sarcoma. Magnetic resonance (MR) imaging revealed white matter changes which resolved over the next 2 months. Bone Marrow Transplantation (2000) 26, 797-800. Keywords: DMSO; leukoencephalopathy; MRI; stem cell infusion; reversible Reversible posterior leukoencephalopathy syndrome (RPL) is characterized by white matter edema predominantly in the posterior parietal, temporal and occipital regions of the brain with characteristic clinical symptoms of headache, altered mental status, seizures and visual changes. 1 This clinical and radiographic syndrome has been reported in association with hypertensive encephalopathy, eclampsia, renal failure with hypertension and immunosuppression most notably with cyclosporine and tacrolimus. 1-5 RPL has not previously been recognized in association with DMSO infusion. Reversible central neurotoxicity has been described in two patients with high levels of DMSO after infusion of cryopreserved autologous peripheral blood stem cells, without neuroimaging. 6 We report a case of reversible leukoencephalopathy associated with infusion of DMSOcryopreserved stem cells in which the initial leukoencephalopathy and resolution are demonstrated radiographically. Case reportRD is a 16-year-old Caucasian female diagnosed as having non-metastatic Ewing's sarcoma of the chest wall in May 1996. She was treated on the intergroup Ewing's sarcoma study (POG 9354/CCG6742 regimen A) with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide over 30 weeks and local control by surgical resection at 12 weeks. Sixteen months after the completion of her therapy, she developed a cough associated with a large pleural effusion and a 7.5 × 9-cm posterior mediastinal mass arising from the right chest wall, pathologically confirmed to be recurrent Ewing's sarcoma.She was referred for myeloablative chemotherapy with stem cell rescue. In August 1998, she received cyclophosphamide (4 g/m 2 i.v.) followed by 10 g/kg/day G-CSF to mobilize stem cells which were collected by leukapheresis. CD34 + cells were isolated using the Isolex 300i (Baxter, Deerfield, IL, USA) and preserved in 10% DMSO/17.5% Plasmalyte A/22.5% autologous irradiated plasma and stored in liquid nitrogen. Salvage chemotherapy included ifosfamide, carboplatin and etoposide with a good initial response, but the tumor progressed locally and was not operable. She received docetaxel, which produced a good partial response, and underwent a gross total resection of the residual tumor.Her pre-transplant evaluations were satisfactory with the exception of a residual pleural effusion and spirometry that showed moderate restrictive lung disease, marginal renal function with a baseline creatinine clearance of 70 ml/min/1.73 m 2 , and peripheral neuropathy attributed to vincristine and docetaxel.RD received c...

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The Single–and Repeated–dose Toxicity of Dimethyl Sulfoxide

Cited by 93 publications

References 8 publications

Scatchard analysis of methane sulfinic acid production from dimethyl sulfoxide: A method to quantify hydroxyl radical formation in physiologic systems

Scatchard analysis of methane sulfinic acid production from dimethyl sulfoxide: A method to quantify hydroxyl radical formation in physiologic systems

Free radicals and the etiology of colon cancer

Reversible leukoencephalopathy associated with re-infusion of DMSO preserved stem cells

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