Activate the endogenous Cu2+ switch for Zn(DDC)2 liposomes conversion: Providing a safer and less toxic alternative in cancer therapy.

The ancient anti-alcohol drug disulfiram (DSF) has gained widespread attention for its highly effective anti-tumor effects in cancer treatment. Our previous studies have developed liposome of Cu (DDC)2 to overcome the limitations, like the poor water solubility. However, Cu (DDC)2 liposomes still have shown difficulties in severe hemolytic reactions at high doses and systemic toxicity, which have limited their clinical use. Therefore, this study aims to exploratively investigate the feasibility of using DSF or DDC in combination also can chelate Zn2+ to form zinc diethyldithiocarbamate (Zn (DDC)2). Furthermore, this study prepared stable and homogeneous Zn (DDC)2 liposomes, which were able to be released in the tumor microenvironment (TME). The released Zn (DDC)2 was converted to Cu (DDC)2 with the help of endogenous Cu2+-switch enriched in the TME, which has a higher stability constant compared with Zn (DDC)2. In other words, the Cu2+-switch is activated at the tumor site, completing the conversion of the less cytotoxic Zn (DDC)2 to the more cytotoxic Cu (DDC)2 for effective tumor therapy so that the Zn (DDC)2 liposomes in vivo achieved the comparable therapeutic efficacy and provided a safer alternative to Cu (DDC)2 liposomes in cancer therapy.

Improved freeze-dried kit for the preparation of 188ReN-DEDC/lipiodol for the therapy of unresectable hepatocellular carcinoma.

Rhenium-188-N-(DEDC)2/lipiodol (abbreviated as 188ReN-DEDC, where DEDC = monoanionic diethyldithiocarbamate) is a clinically proven radiopharmaceutical for the therapy of unresectable hepatocellular carcinoma (HCC) through trans arterial radioembolization (TARE). A two-vial freeze-dried kit for the preparation of [188ReN(DEDC)2] complex using sodium perrhenate (Na188ReO4) obtained from a commercial Tungsten-188/Rhenium-188 generator had been reported earlier. This method required addition of stipulated volume of glacial acetic acid into vial 1 by the user for efficient preparation of [188ReN]2+ intermediate. An error in this step can result in low radiochemical yield of [188ReN]2+ intermediate as well as sub-optimal pH of the reaction mixture for the second step, leading to poor radiochemical purity of 188ReN-DEDC complex. In the present work, a solution to this problem was found by including an oxalate buffer of pH = 3 in vial 1, eliminating the need for the addition of glacial acetic acid by the user. This modification not only made the kits more user-friendly, it resulted in significant improvement in the kinetics of formation of [188ReN]2+ intermediate, wherein > 95% radiochemical purity could be achieved within 5 min incubation at ambient temperature. Moreover, the novel route for the preparation of [188ReN]2+ intermediate may be applied to any radiopharmaceutical based on 188ReN-core.

Effect of NF-κB inhibition on chemoresistance in biliary-pancreatic cancer.

Biliary cancer and pancreatic cancer are considered to be difficult diseases to cure. Although complete resection provides the only means of curing these cancers, the rate of resectability is not high. Therefore, chemotherapy is often selected in patients with advanced unresectable biliary-pancreatic cancer. Many combination chemotherapy regimens have been applied in clinical trials. However, the survival time is not satisfactory. On the other hand, most chemotherapeutic agents induce anti-apoptotic transcriptional factor nuclear factor kappa b (NF-κB) activation, and agent-induced NF-κB activation is deeply involved in the onset of chemoresistance. Recently, novel approaches to potentiating chemosensitivity in cases of biliary-pancreatic cancer using NF-κB inhibitors with cytotoxic agents have been reported, most of which comprise translational research, although some clinical trials have also been conducted. Nevertheless, to date, there is no breakthrough chemotherapy regimen for these diseases. As some reports show promising data, combination chemotherapy consisting of a NF-κB inhibitor with chemotherapeutic agents seems to improve chemosensitivity and prolong the survival time of biliary-pancreatic cancer patients.

[AIDS: ethics and scientific investigation on human beings]. / Sida: éthique et investigation scientifique sur l'être humain.

The experimentation on human beings of one or several therapeutic molecules discovered in laboratory is necessary and important because it helps to find new treatments or new diagnostic methods. But, it presents serious ethical problems. In this article we are analysing the example of the HIV infection. We are succinctly describing the research methods in laboratory for therapeutic molecules, first the experimentation on animals and then on human being in clinical trials. We will then try to show, with several examples, how during these last 25 years of HIV infection, the research of new molecules has not always respected the ethical rules set out in Helsinki declaration, "Code de la santé publique" or "Guide de bonnes pratiques cliniques-ICH" etc. We are discussing here the way to avoid these irregularities.

Modulation of heat-induced cell death in PC-3 prostate cancer cells by the antioxidant inhibitor diethyldithiocarbamate.

OBJECTIVE: To examine the relationships between the form of cell death (apoptosis or necrosis), reactive oxygen species (ROS) generation, superoxide dismutase (SOD) activity and the level of heat-shock protein 70 (hsp 70) expression after thermotherapy of PC-3 prostate cancer cells; also assessed were the tumoricidal effects of combined treatment with both heat and the antioxidant inhibitor diethyldithiocarbamate (DDC). MATERIALS AND METHODS: PC-3 cells were treated with thermotherapy at 42, 43 or 44 degrees C for 30, 60, 90 or 120 min. Cell proliferation, ROS generation, SOD activity and cellular hsp 70 level were determined using tetrazolium-based cytotoxicity, fluorescent dichlorofluorescein (DCF) and nitroblue tetrazolium assays, Western blot analysis and flow cytometry, respectively. The apoptotic and necrotic cells were determined by staining with propidium iodide and fluorescein isothiocyanate-labelled annexin V. These variable were also measured after combined treatment of PC-3 cells with 1 mmol/L DDC and thermotherapy at 43 or 44 degrees C for 60 min. RESULTS: Cell survival was significantly lower after heating cells at 43 degrees C for 60, 90 and 120 min and at 44 degrees C for all periods tested (P<0.05). At 43 degrees C apoptosis increased with the duration of heating and was similarly enhanced after heating at 44 degrees C for 30 min. Necrosis was not increased by heating at 42 or 43 degrees C, but was markedly enhanced after heating at 44 degrees C with both the duration of heating and with time after heating. Significant increases in DCF production were induced by heating at 43 degrees C for 60, 90 and 120 min (P<0.05) and at 44 degrees C at all times (P<0.010-0.005). There was a significant correlation between the level of ROS generation and necrosis (P<0.001) but no correlation between the ROS level and apoptosis. SOD activity increased in cells after heating at 43 degrees C, with significant differences among cells heated for 60, 90 and 120 min (P<0.05). After heating at 44 degrees C, SOD activity was maximal in cells heated for 30 min (P<0.005), by 30 min and then decreased with time after heating. There were significant increases in hsp 70 level in cells heated at 43 degrees C for 90 and 120 min (P<0.05) and at 44 degrees C for 30 and 60 min (P<0.05 and <0.025, respectively). Hsp 70 levels decreased after heating at 44 degrees C for 90 and 120 min. The combination of DDC and heating significantly increased ROS generation and the percentage of cell death, and decreased SOD activity (P<0.05). CONCLUSION: These findings show a qualitative change in the form of cell death induced by thermotherapy of PC-3 cells, which changed from apoptosis to necrosis according to the degree and duration of heating. Mild thermotherapy induced marginally low occurrence of apoptosis of PC-3 cells and DDC may represent a useful future strategy for the treatment of prostate carcinoma.

Modification of radiation response in mice by Panax ginseng and diethyldithiocarbamate.

The aim of this study was to determine the effect of Panax ginseng and its fractions on jejunal crypt survival, endogenous spleen colony formation and apoptosis in jejunal crypt cells of mice irradiated with high- and low-dose of gamma-irradiation. The radioprotective effect of ginseng was compared with the effect of diethyldithiocarbamate (DDC). Ginseng administration before irradiation protected the jejunal crypts (p < 0.005), increased the formation of endogenous spleen colony (p < 0.005) and reduced the frequency of radiation-induced apoptosis (p < 0.05). The radioprotective effect on jejunal crypts and apoptosis in the DDC-treated group appeared similar to that in the ginseng--treated groups. Treatment with DDC showed no significant modifying effects on the formation of endogenous spleen colony. In the experiment on the effect of fractions of ginseng, the result indicated that the lipophilic non-polar compounds (Fraction 1), lipophilic-acidic compounds (Fraction 2), free sugars (Fraction 7) and saponin compounds (Fraction 8) might have a major radioprotective effect. Although the mechanisms of this inhibitory effect remain to be elucidated, these results indicated that ginseng might be a useful radioprotector, especially since it is a relatively nontoxic natural product. Further studies are needed to fully characterize the protective nature of ginseng extract and its components.

Effect of protective agents against cisplatin ototoxicity.

HYPOTHESIS: The goals of this investigation were to compare the efficacy of three protective agents against cisplatin-induced elevation of auditory brainstem response (ABR) thresholds and to examine whether these protective agents prevent cisplatin-induced alterations of the antioxidant defense system in the cochlea of the rat. BACKGROUND: Cisplatin is an ototoxic antitumor agent. Previous animal studies have shown that cisplatin administration causes an elevation of ABR thresholds. These auditory changes are accompanied by alterations in the concentration of glutathione and the antioxidant enzymes in the cochlea. The authors' previous work has indicated that the protective agent diethyldithiocarbamate (DDTC) prevents decrease in glutathione (GSH), alteration of antioxidant enzyme activity, and disruption of cochlear function with cisplatin administration. METHODS: Wistar rats were sedated and underwent pretreatment ABR testing using clicks and tone burst stimuli at 8, 16, and 32 kHz. Control rats received saline by intraperitoneal (i.p.) injection. Positive control rats were administered cisplatin 16 mg/kg i.p. Three groups of rats received protective agents in combination with cisplatin. The DDTC-protected rats were given 600 mg/kg of DDTC subcutaneously 1 hour after cisplatin. Animals protected by 4-methylthiobenzoic acid (MTBA) were given 250 mg/kg of this agent i.p. 30 minutes before cisplatin. Animals protected with ebselen were given 16 mg/kg i.p. one hour before cisplatin. The ABR thresholds were recorded 72 hours after cisplatin administration in all groups. Cochleas were removed, and extracts of the tissues were analyzed for GSH, activities of antioxidant enzymes (superoxide dismutase [SOD], catalase, glutathione peroxidase, and glutathione reductase) and malondialdehyde (MDA) (as an index of lipid peroxidation). RESULTS: Cisplatin-treated rats had significant ABR threshold shifts, ranging from 27 to 40 dB. Rats administered each of the three protective agents in combination with cisplatin had ABR threshold shifts of <10 dB. The cochleae of rats administered cisplatin alone had nearly a 50% depletion of glutathione and about a 50% reduction in the activities of SOD, glutathione peroxidase, and glutathione reductase, while catalase activity was reduced to 70% of control values. These changes were accompanied by a reciprocal elevation of MDA of 165%. These changes, namely, the depletion of GSH and antioxidant enzyme activity and the elevation of MDA in the cochlea, were largely attenuated by the administration of the protective agents tested. CONCLUSION: These findings suggest that cisplatin ototoxicity is related to lipid peroxidation and that the use of protective agents prevents hearing loss and lipid peroxidation by sparing the antioxidant system in the cochlea. These results suggest the possibility that the clinical use of protective agents could effectively reduce or prevent damage to the inner ear of patients receiving cisplatin chemotherapy, provided that the antitumor effect is not altered.

Effect of diethyldithiocarbamate on Cryptosporidium parvum infection in immunosuppressed rats.

Diethyldithiocarbamate was the only immune modulator of 7 evaluated to show activity against Cryptosporidium parvum in immunosuppressed rats. The model was then used to assess the drug's activity further. When administered prophylactically, oral doses > or = 75 mg/kg/day significantly (P < or = 0.05) reduced the severity of ileal infection and doses > or = 300 mg/kg/day significantly (P < or = 0.05) inhibited infection of the biliary tract. When administered to rats with established infection, the drug significantly (P < or = 0.05) reduced the parasite burden in the ileum but was ineffective against biliary tract infection. The data suggest that diethyldithiocarbamate is effective for treating cryptosporidiosis of the small intestine but is probably ineffective against chronic cryptosporidiosis involving the large intestine or biliary tract.

The prevention of nickel contact dermatitis. A review of the use of binding agents and barrier creams.

Chelating agents and other substances can be used to bind nickel or reduce its penetration through the skin, and hence to reduce the symptoms in subjects with nickel sensitivity. Topical usage is mostly described but, in some studies, chelating agents have been given systemically. The most effective ligand for nickel so far described is 5-chloro-7-iodoquinolin-8-ol. Although normally regarded as safe, its usage in some situations may be limited by concerns about its toxicity. Other ligands with demonstrable effect include ethylenediaminetetraacetic acid in various forms, diphenylglyoxime and dimethylglyoxime. Cation exchange resins can effectively bind nickel and work both in vitro and in vivo. Propylene glycol, petrolatum and lanolin reduce the absorption of nickel through the skin. Corticosteroids and cyclosporin work in nickel dermatitis by suppressing the immunological reaction rather than through an effect on nickel. Studies of the oral administration of ligands such as tetraethylthiuram disulphide have given conflicting results but the use of these agents is limited by hepatoxicity in any case. Some compounds offer potential for use in the prophylaxis of nickel dermatitis. Further work is required to develop the existing agents and to look at the use of novel combinations, such as that of a cation exchanger with a ligand.

Effects of levamisole, DTC and low-dose mechlorethamine on humoral response of SRBC-immunized rabbits exposed to cold stress.

The experiments were carried out on normothermal rabbits and rabbits exposed to cold stress (hypothermia). The animals of the latter group were submerged in ice-water for 20 s and then placed in a freezer at -15 degrees C for 8 min until their body temperature dropped by 3 degrees C. Both the normothermal and hypothermal rabbits were immunized i.p. with 3 ml of 10% sheep red blood cells (SRBC). Levamisole (2 mg/kg), DTC (sodium diethyldithiocarbamate, 20 mg/kg) or mechlorethamine (mustine; 5 micrograms/kg) were injected i.v. three times at 24-h intervals. The number of PFC, total (19S + 7S) and 2-mercapthoethanol resistant (7S) serum haemagglutination titres were determined. It was found that, in normothermal rabbits, all three agents potentiated the number of plaque-forming cells (PFC); the impact of DTC was the strongest, while the weakest influence was observed for mechlorethamine. Furthermore, DTC increased anti-SRBC haemagglutinin titre, whereas mechlorethamine did not. Levamisole, on the other hand, reduced total serum haemagglutinin titre. Cold stress reduced humoral response to SRBC, which was reflected in the decreased number of PFC and serum haemagglutination titres (19S + 7S and 7S). Each agent showed a different way of action. Pretreatment with DTC prevented the immunosuppression caused by cold stress, while levamisole and mechlorethamine only reduced the immunosuppressive effect.

Sodium dithiocarb as adjuvant immunotherapy for high risk breast cancer: a randomized study.

Sixty-four patients with non metastatic high risk breast cancer were randomized in a double blind trial of adjuvant immunotherapy with sodium dithiocarb (DDC) versus placebo. All patients underwent prior surgery (mammectomy according to Patey) then adjuvant FAC chemotherapy +/- DDC. With a median follow-up of 5 years we observed 6 relapses and 5 deaths in DDC group; 13 relapses and 12 deaths in control group. At 6 years, overall survival is 81% in DDC group versus 55%. Disease free survival (DFS) is 76% in DDC group versus 55%. DDC associated to chemotherapy and locoregional treatment can improve survival and probably DFS in this high risk breast cancer subgroup.

The current status of toxicity protectants in cancer therapy.

Current therapies for the treatment of malignancies are associated with significant toxicity, as chemotherapy and radiation therapy do not discriminate between normal and malignant cells. One approach to ameliorating the toxicity associated with therapy is through the use of chemoprotective agents. This article reviews a variety of agents that have been evaluated as possible protectants, including WR-2721 and the colony-stimulating factors. It is hoped that the understanding of how to optimally use chemoprotective agents will lead to more tolerable treatments for patients, and possibly allow for dose-escalation, which may contribute to improvement in patient survival.

[Oxidative stress in 29 HIV seropositive patients. Two-year results of a double-blind trial of diethyldithiocarbamate versus placebo]. / Stress oxydatif chez 29 sujets séropositifs. Résultats à 2 ans d'une étude en double insu diéthyldithiocarbamate versus placebo.

Among 29 seropositive subjects who had participated in the HIV 87 therapeutic trial (Mérieux laboratories), the oxidative stress was evaluated at 24 months in 16 treated with diethyldithiocarbamate (dithiocarb) and in 13 who had received the placebo. No significant difference was found between these two groups, whereas the existence of an oxidative stress has been confirmed in seropositive subjects compared with controls.

Diethyldithiocarbamate, a novel immunomodulator, prolongs survival in autoimmune MRL-lpr/lpr mice.

MRL-lpr/lpr mice die at an early age from a spontaneously developing systemic lupus erythematosus-like disease and are characterized by massive lymphadenopathy, hyperproliferation of Lyt-2/L3T4 (null) T cells, decreased responses to mitogens, thymic atrophy, and very high serum autoantibody levels. Diethyldithiocarbamate (DTC), an immunomodulator suggested to enhance T cells, was used to treat 12-week-old female MRL-lpr/lpr mice (25 mg/kg/week). DTC treatment significantly prolonged survival (50% mortality, 43 weeks vs 20 weeks). Increased survival was associated with decreased lymphadenopathy, decreased proliferation of null cells, restoration of impaired mitogen responses, decreased thymic atrophy, and decreased serum levels of anti-DNA and anti-histone antibodies. Studies of cell surface antigen phenotype demonstrated increased expression of Lyt-2 and macrophage surface antigens. No effect on L3T4 single staining cells was observed. These results show that DTC significantly alters the disease course in these mice and suggest that DTC may be a useful treatment for autoimmune disease.

Cisplatin rescue therapy: experience with sodium thiosulfate, WR2721, and diethyldithiocarbamate.

Cisplatin has a steep dose response curve for both antitumor and adverse effects. Therapeutic strategies aimed at reducing toxicity and allowing dose escalation of intravenous cisplatin, such as administration in hypertonic saline and pharmacokinetically based dosing schedules, have been partially successful in reducing nephrotoxicity and bone marrow suppression. However, new dose-limiting toxicities consisting of peripheral neuropathy and ototoxicity have emerged, which continue to restrict potential use of high dose cisplatin therapy. Intraperitoneal administration of high dose cisplatin also offers the potential of markedly increased local drug exposure if systemic toxicity can be avoided. Proposed chemoprotective agents, including sodium thiosulfate, WR2721, and diethyldithiocarbamate (DDTC) are being extensively examined as "rescue agents" for either regional or systemic administration of cisplatin. Although each agent offers unique advantages to be considered in developing successful rescue therapy, many questions remain regarding molecular and pharmacokinetic interactions with cisplatin, appropriate dosing schedules, and effects on antineoplastic activity. We present a review of current investigations of chemoprotectors for prevention of cisplatin-related toxicities.

Effects of diethyldithiocarbamate and structural analogs in mice with systemic candidal infections.

Three different substituted dithiocarbamates: sodium diethyldithiocarbamate (DDTC), sodium dimethyldithiocarbamate (DmDTC), and sodium N-methyl-D-glucamine dithiocarbamate (NMG-DTC) were evaluated for their ability to combat the growth and development of three human pathogenic strains of Candida albicans, in vitro and in vivo, in mice. DDTC and DmDTC produced marked growth inhibition on agar plates, in vitro, of three different strains of Candida albicans, while NMG-DTC displayed little inhibitory effect. Low, nontoxic doses of each compound administered to immunosuppressed mice exhibited impressive therapeutic effects in treating candidiasis. NMG-DTC showed the best consistent therapeutic antifungal effect against Candida albicans in mice immunosuppressed with Solu-Medrol. Combinations of low doses of DDTC and Amphotericin-B appeared to be effective in treating systemic candidal infections, and the results suggested that these combinations may offer therapeutic advantages over those produced by the use of either agent alone.