Evaluation of the cancer chemopreventive potency of dithiolethione analogs of oltipraz.

Oltipraz and related dithiolethiones constitute an important class of chemopreventive agents that enhance the expression of carcinogen detoxication and antioxidant genes. Dose-response studies were undertaken to characterize the cancer chemopreventive activities of several dithiolethiones that are at least as active as oltipraz as inducers. Inhibition of formation of pre-neoplastic lesions and formation of DNA adducts in livers of rats exposed to aflatoxin B1 (AFB1) was monitored.

Induction of NAD(P)H quinone: oxidoreductase1 inhibits carcinogen-induced aberrant crypt foci in colons of Sprague-Dawley rats.

Phase II detoxifying enzymes like NAD(P)H (quinone acceptor)oxidoreductase1 (NQO1), glutathione S-transferases (GST), and UDP-glucuronyltransferases (UGT) may play an important role in preventing carcinogen-induced cancers. Inducers of these enzymes have been shown to inhibit carcinogen-induced colon tumors in rat and mouse models. However, it has not been clearly demonstrated that NQO1 contributes to this effect.

Thionation with the reagent combination of phosphorus pentasulfide and hexamethyldisiloxane.

The combination of P4S10 and hexamethyldisiloxane efficiently converts esters, lactones, amides, lactams, and ketones to their corresponding thiono derivatives. In the presence of elemental sulfur, 3-oxoesters are converted to dithiolethiones by this reagent. Yields are comparable to or superior to those obtained with Lawesson's reagent.

Synthesis and biochemical properties of a new photoactivatable cholesterol analog 7,7-azocholestanol and its linoleate ester in Chinese hamster ovary cell lines.

We report the chemical synthesis of a new photoactivatable cholesterol analog 7,7-azocholestanol (AC) and its linoleate ester (ACL). We also examined the biochemical properties of the sterol and its ester by employing several different mutant Chinese hamster ovary (CHO) cell lines with defined abnormalities in cholesterol metabolism as tools. AC mimics cholesterol in supporting the growth of a mutant cell line (M19) that requires cholesterol for growth.

Chemoprotection by organosulfur inducers of phase 2 enzymes: dithiolethiones and dithiins.

One of the major mechanisms of protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by carcinogens is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases, UDP-glucuronosyl transferases, and quinone reductases. Animal studies indicate that induction of phase 2 enzymes is a sufficient condition for obtaining chemoprevention and can be achieved by administering any of a diverse array of naturally-occurring and synthetic chemopreventive agents. Alliaceous and cruciferous plants are rich in organosulfur compounds with inducer activity.

Enhanced cytotoxicity of mitomycin C in human tumour cells with inducers of DT-diaphorase.

DT-diaphorase is a two-electron reducing enzyme that activates the bioreductive anti-tumour agent, mitomycin C (MMC). Cell lines having elevated levels of DT-diaphorase are generally more sensitive to MMC. We have shown that DT-diaphorase can be induced in human tumour cells by a number of compounds, including 1,2-dithiole-3-thione.

Identification of dithiolethiones with better chemopreventive properties than oltipraz.

Oltipraz and related dithiolethiones are an important class of chemopreventive agents. Studies were undertaken to identify cancer chemopreventive dithiolethiones more active than oltipraz. Largely based upon enzyme induction activities in vitro, 17 dithiolethiones, including oltipraz, were analyzed for their ability to induce hepatic phase II enzyme activities in vivo.

Induction of DT-diaphorase by 1,2-dithiole-3-thiones in human tumour and normal cells and effect on anti-tumour activity of bioreductive agents.

DT-diaphorase is a two-electron-reducing enzyme that is an important activator of bioreductive anti-tumour agents, such as mitomycin C (MMC) and EO9, and is inducible by many compounds, including 1,2-dithiole-3-thiones (D3Ts). We showed previously that D3T selectively increased DT-diaphorase activity in mouse lymphoma cells compared with normal mouse marrow cells, and also increased MMC or EO9 cytotoxic activity in the lymphoma cells with only minor effects in the marrow cells. In this study, we found that D3T significantly increased DT-diaphorase activity in 28 of 38 human tumour cell lines representing ten tissue types with no obvious relationships between the tumour type, or the base level of DT-diaphorase activity, and the ability of D3T to increase the enzyme activity.

Induction of DT-diaphorase in cancer chemoprevention and chemotherapy.

DT-diaphorase (EC 1.6.99.

Protection against aflatoxin B1-induced hepatic toxicity as short-term screen of cancer chemopreventive dithiolethiones.

Dithiolethiones are an important class of cancer chemopreventive agents. More than 50 new dithiolethione analogs were synthesized for structure-activity studies. Using selected dithiolethiones, studies were designed to measure protection against the hepatotoxicity of aflatoxin B1 (AFB1) and relate it to the protection against carcinogenicity.

Induction of DT-diaphorase by 1,2-dithiole-3-thione and increase of antitumour activity of bioreductive agents.

Bioreductive antitumour agents are an important new class of anticancer drugs that require activation by reduction. The two-electron reducing enzyme, DT-diaphorase, has been shown to be an important activating enzyme for the bioreductive agents, mitomycin C (MMC) and EO9. Incubation of L5178Y murine lymphoma cells in vitro with 1,2-dithiole-3-thione (D3T) increased the level of DT-diaphorase activity in these cells 22-fold.

Formation of immunochemical advanced glycosylation end products precedes and correlates with early manifestations of renal and retinal disease in diabetes.

Elevated levels of advanced glycosylation end products (AGEs) have been found in multiple tissues in association with diabetic vascular complications and during the microalbuminuric phase of diabetic nephropathy. In this study, we have used an AGE-specific enzyme-linked immunosorbent assay (ELISA) to measure skin AGEs to determine whether elevated levels can be detected before the onset of overt microangiopathy. Subjects with type I diabetes (n = 48) were graded for the degree of nephropathy (normal [23], microalbuminuria [12], or macroalbuminuria [12]) and retinopathy (none [13], background [20], or proliferative [15]).

Regulation of phase 2 enzyme induction by oltipraz and other dithiolethiones.

4-Methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz) and several other dithiolethiones protect against the acute toxicities of many xenobiotics and are effective inhibitors of experimental carcinogenesis. These protective effects are mediated, in part, through elevation of glutathione S-transferase, NAD(P)H: quinone reductase and UDP-glucuronosyltransferase activities in the liver and other target tissues. The induction of these phase 2 enzymes by oltiprax results from enhanced transcription.

Increased collagen-linked pentosidine levels and advanced glycosylation end products in early diabetic nephropathy.

Rationale: Advanced glycosylation end products (AGEs) may play an important role in the development of diabetic vascular sequelae. An AGE cross-link, pentosidine, is a sensitive and specific marker for tissue levels of AGEs.

Objectives: To evaluate the role of AGEs in the development of diabetic nephropathy and retinopathy, we studied pentosidine levels and the clinical characteristics of 48 subjects with insulin-dependent diabetes mellitus.

Relationship between glycemic control and collagen-linked advanced glycosylation end products in type I diabetes.

Objective: To evaluate the relationship between glycemic control over a 3-yr period and tissue levels of advanced glycosylation end products. The development of renal failure, blindness, and generalized vascular occlusion continue to be the most serious ravages of diabetes. Tissue glycosylation and AGEs are felt to play an important role in the development of these sequelae, but no data are available on the relationship between AGEs and long-term glycemic control.

Potent inhibition of aflatoxin-induced hepatic tumorigenesis by the monofunctional enzyme inducer 1,2-dithiole-3-thione.

1,2-Dithiole-3-thiones are five-membered cyclic sulfur-containing compounds with antioxidant, chemotherapeutic, radioprotective and chemoprotective properties. Several substituted 1,2-dithiole-3-thiones are used medicinally and one of these, oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione], has been recently shown to be an inhibitor of aflatoxin B1 (AFB1) hepatocarcinogenesis in the rat. Structure-activity studies have been undertaken to probe the mechanisms by which dithiolethiones inhibit carcinogenesis.

Mechanisms of chemoprotection by oltipraz.

1,2-Dithiole-3-thiones are five-membered cyclic sulfur-containing compounds with antioxidant, chemotherapeutic, radioprotective and cancer chemoprotective properties. One substituted dithiolethione, oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione], originally developed as an antischistosomal agent, has recently been observed to protect against chemically induced carcinogenesis in lung, trachea, forestomach, colon, breast, skin, liver and urinary bladder in rodents. The induction of electrophilic detoxication enzymes, which result in diminished carcinogen-DNA adduct formation and reduced cytotoxicity, appears to be an important component of the anticarcinogenic action of oltipraz and other dithiolethiones.

Evaluation of promotion of pancreatic carcinogenesis in rats by benzyl acetate.

Benzyl acetate was found to induce liver tumours and gastric squamous neoplasms in mice in a chronic bioassay conducted through the National Toxicology Program. An increased incidence of acinar cell adenomas of the pancreas of F344 rats was noted in the bioassay, but the significance of these lesions was confounded because the benzyl acetate was given by gavage in corn oil. The use of corn oil as a vehicle has been shown to enhance the growth of such lesions in the rat pancreas.

Potentiation of radiation-induced bacterial cell killing by binuclear rhodium(II) complexes and their amines.

Rhodium(II) binuclear complexes were surveyed for potentiation of radiation-induced cell killing of hypoxic and fully oxic Salmonella typhimurium cells. The Rh2 tetracarbonate ion substantially potentiated hypoxic cell radiation sensitivity. Phosphate interfered with this potentiation.

Inhibition of pancreatic and liver carcinogenesis in rats by retinoid- and selenium-supplemented diets.

Chemoprevention by a synthetic retinoid, selenium, and these agents in combination during the postinitiation stages of carcinogenesis induced in rats by azaserine was evaluated. Male Lewis rats were given three weekly injections of 30 mg/kg azaserine while being fed a purified diet. One week after completion of carcinogen treatment, groups of rats were switched to the purified diet supplemented with either a retinoid, N-(2-hydroxyethyl)retinamide, at a level of 0.

Pancreatic carcinogenesis in azaserine-treated rats: inhibition by a solvent mixture in the diet.

The growth of azaserine-induced foci and nodules in a 4-month experiment and the incidence of carcinomas in a 15-month experiment were greater in LEW/CrlBR inbred rats fed a purified diet (AIN-76A) than in rats fed a natural-ingredient diet (chow). Addition of a mixture of several solvents to either diet reduced the incidence of adenocarcinomas in the pancreas in the long-term study but failed to reduce the number or size of pancreatic atypical acinar cell foci in the experiments of 4 months and 6 months (chow only) duration. Apparently, some component of the solvent mixture inhibits a late stage in the development of pancreatic carcinoma.

In vivo and in vitro genotoxicity of selected compounds toward rodent pancreas.

Using the technique of alkaline elution analysis, the ability of 11 known or suspected pancreatic carcinogens to damage the DNA of pancreatic acinar cells when administered to rats and hamsters was examined. The two species respond differently to several agents. In selected instances, DNA damage was also assessed in cultured pancreatic acinar cells exposed in vitro to the agents.

gamma-Glutamyltransferase activity in atypical acinar cell nodules of rat pancreas.

The biochemical and histochemical measurement of the enzyme gamma-glutamyltransferase (GGT) was undertaken in normal rat pancreas and in rat pancreas containing azaserine-induced preneoplastic nodules. A steady decrease in pancreatic GGT activity was observed in the normal animals as they aged from 5 to 34 weeks. The azaserine-induced nodules contained a lower average GGT activity than the control pancreas although a 10-fold variation was noted in the GGT activity of individual nodules.

Mutagenicity of L-azaserine for V79 cells in a pancreatic acinar cell-mediated mutagenesis assay.

The mutagenicity of azaserine was determined in a pancreatic acinar cell-mediated mutagenesis assay using V79 cells as the responder cell line. The mutation frequency of V79 cells was increased in direct culture with azaserine as well as in coculture with rat and hamster pancreatic acinar cells. Although slightly higher mutation frequencies were seen with coculture, the mutation frequency induced by azaserine in coculture was not significantly enhanced over that observed in direct culture.