Modulation of apoptosis by cancer chemopreventive agents.

A review of almost 2000 studies showed that the large majority of 39 putative cancer chemopreventive agents induced "spontaneous" apoptosis. Inhibition of the programmed cell death triggered by a variety of stimuli was consistently reported only with ascorbic acid, alpha-tocopherol, and N-acetylcysteine (NAC). We performed experimental studies in rodents exposed to cigarette smoke, either mainstream (MCS) or environmental (ECS), and UV-A/B-containing light.

The epidemiological revolution of the 20th century.

Until 100 years ago the epidemiological scenario of human diseases had substantially remained unchanged. The 20th century has been characterized by a fantastic advance in life expectancy and by a shift from infectious to chronic degenerative diseases as prevailing causes of death. As an example of the epidemiological revolution in a developed country, we reconstructed, year by year from 1901 to 2000, the situation in Italy.

Induction and modulation of lung tumors: genomic and transcriptional alterations in cigarette smoke-exposed mice.

Cigarette smoke plays a major role in the epidemiology of lung cancer, and smoke components have extensively been investigated in carcinogenicity and chemoprevention studies in experimental animals. However, it is much more difficult to reproduce the tumorigenicity of the whole complex mixture in preclinical models. The authors review here some results obtained in their laboratories, dealing with the induction of lung tumors, and genomic and transciptional alterations in smoke-exposed mice.

Modulation of cigarette smoke-related end-points in mutagenesis and carcinogenesis.

The epidemic of lung cancer and the increase of other tumours and chronic degenerative diseases associated with tobacco smoking have represented one of the most dramatic catastrophes of the 20th century. The control of this plague is one of the major challenges of preventive medicine for the next decades. The imperative goal is to refrain from smoking.

Molecular alterations and lung tumors in p53 mutant mice exposed to cigarette smoke.

Mutations and deletions in p53 are the most common genetic lesions in human cancer,and an extraordinarily high incidence of lung cancer occurs in smokers suffering from Li-Fraumeni syndrome, which is characterized by germ-line inactivation of one p53 allele. In contrast, p53 mutations are infrequent in lung tumors formed in A/J mice. Moreover, despite the dominant role of cigarette smoke in the epidemiology of human lung cancer, it is very difficult to reproduce the lung tumorigenicity of this complex mixture in animal models.

Induction of apoptosis in the lung but not in the liver of rats receiving intra-tracheal instillations of chromium(VI).

Several studies have shown that hexavalent chromium [Cr(VI)] induces apoptosis in a variety of in vitro test systems. We instilled intra-tracheally either saline or sodium dichromate (0.25 mg/kg body weight), for three consecutive days, to Sprague-Dawley rats.

Oltipraz chemoprevention trial in Qidong, People's Republic of China: results of urine genotoxicity assays as related to smoking habits.

A Phase II chemoprevention trial was carried out in Qidong, Jiangsu Province, People's Republic of China. The recruited subjects, all of whom were positive for serum aflatoxin-albumin adducts, were divided into three treatment arms: placebo; oltipraz ([5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione]) given daily at 125 mg p.o.

Modulation of biomarkers by chemopreventive agents in smoke-exposed rats.

Chemoprevention opens new perspectives in the prevention of cancer and other chronic degenerative diseases associated with tobacco smoking, exploitable in current smokers and, even more, in exsmokers and passive smokers. Evaluation of biomarkers in animal models is an essential step for the preclinical assessment of efficacy and safety of potential chemopreventive agents. Groups of Sprague Dawley rats were exposed whole body to a mixture of mainstream and sidestream cigarette smoke for 28 consecutive days.

Pilot studies evaluating the lung tumor yield in cigarette smoke-exposed mice.

In spite of the major role played by cigarette smoking in the epidemiology of lung cancer, it is very difficult to reproduce the carcinogenicity of this complex mixture in animal models. We implemented a series of pilot experiments in three mouse strains, exposed either to environmental cigarette smoke (ECS) or mainstream cigarette smoke (MCS) or its condensate (MCSC). The whole-body exposure of Aroclor-treated A/J mice to ECS resulted in a rapid and potent induction of micronuclei in peripheral blood erythrocytes.

Rationale and mechanisms of cancer chemoprevention.

Chronic degenerative diseases, including cancer, have a multifactorial origin. An intricate network connects each disease with multiple risk factors and also with multiple protective factors. From the point of view of preventive medicine, this implies that removal of a single risk factor will have a beneficial impact on the epidemiology of several diseases.

Genotoxic effects in bacteria of the light emitted by halogen tungsten lamps having treated quartz bulbs.

Traditional halogen tungsten lamps, which are extensively used worldwide for the illumination of indoor environments, have a quartz bulb which transmits not only visible light but also ultraviolet (UV) light. Due to the output of far-UV wavelengths, halogen lamps were found in previous studies to be potently genotoxic in bacteria, clastogenic in cultured human cells, and carcinogenic in hairless mice. This discovery prompted the launching of new halogen lamps, known as UV-Stop, UV-Block, or similar trade names, which have the quartz glass treated in such a way to reduce its permeability to UV radiation.

Estimates of the chromium(VI) reducing capacity in human body compartments as a mechanism for attenuating its potential toxicity and carcinogenicity.

Estimates of the overall reducing capacity of hexavalent chromium(VI) in some human body compartments were made by relating the specific reducing activity of body fluids, cell populations or organs to their average volume, number, or weight. Although these data do not have absolute precision or universal applicability, they provide a rationale for predicting and interpreting the health effects of chromium(VI). The available evidence strongly indicates that chromium(VI) reduction in body fluids and long-lived non-target cells is expected to greatly attenuate its potential toxicity and genotoxicity, to imprint a threshold character to the carcinogenesis process, and to restrict the possible targets of its activity.

Smokers and urinary genotoxins: implications for selection of cohorts and modulation of endpoints in chemoprevention trials.

Urinary genotoxicity assays measure the internal dose of genotoxic carcinogens, thereby providing a particularly sensitive endpoint for selecting cohorts of individuals exposed to cigarette smoke or other mutagens excreted with urines, as well as for evaluating the modulation of this parameter after administration of chemopreventive agents. Mutagenicity of urines was investigated in smoking Italian volunteers, who received oral N-acetylcysteine (NAC) at the same doses which are usually prescribed for the long-term treatment of chronic bronchitis. The daily excretion of mutagens, concentrated on XAD-2 columns and tested in Salmonella typhimurium YG1024 with S9 mix, was significantly and remarkably decreased by NAC in the majority of the subjects examined so far.

Biotransformation of genotoxic agents in marine sponges. Mechanisms and modulation.

Marine sponges do not appear to suffer from neoplastic diseases, in spite of possible high exposures resulting from their nature as sessile bottom filter feeders which pump large volumes of sea water. The assessment of several parameters related to the biotransformation of mutagens/carcinogens showed that the metabolic machinery of sponge medulla cells is mainly oriented towards detoxification, with some differences depending on species (Geodia cydonium or Tethya aurantium). Glutathione (GSH) levels were unexpectedly high in these cells, especially in Geodia, in which the concentration of this tripeptide was more than twice that measured in liver preparations from untreated rats, at least when related to the protein content.

Chemopreventive properties and mechanisms of N-Acetylcysteine. The experimental background.

The thiol N-acetylcysteine (NAC), now under clinical trial for cancer chemoprevention both in Europe (project Euroscan) and in the US (National Cancer Institute), has been shown during the past decade to exert protective effects in a variety of experimental test systems. NAC inhibited spontaneous mutagenicity and that induced by a number of chemical compounds and complex mixtures. Moreover, NAC significantly decreased the incidence of neoplastic and preneoplastic lesions induced by several chemical carcinogens in rodents (mice, rats, hamsters), e.

Cytosolic activation of aromatic and heterocyclic amines. Inhibition by dicoumarol and enhancement in viral hepatitis B.

The aromatic amines 2-aminofluorene (2AF), 2-acetylaminofluorene, and 2-aminoanthracene, and the heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, and 3-amino-1-methyl-SH-pyrido[4,3-b]indole (Trp-P-2) were activated by rat liver cytosolic fractions to form mutagenic metabolites in Salmonella typhimurium strains TA98, TA98NR, and TA98/1,8-DNP6. In the case of the Trp-P-2, the cytosolic activation was even more potent than the microsomal activation, which is classically ascribed to N-hydroxylation and subsequent esterification. The cytosolic activation was a) NADPH-dependent, b) induced by pretreatment of rats with 3-methylcholanthrene and especially Aroclor 1254 but not by phenobarbital, and c) inhibited by dicoumarol.

Inhibition of the 'spontaneous' mutagenicity in Salmonella typhimurium TA102 and TA104.

Thirty-four compounds belonging to various chemical classes were assayed for the ability to modulate the 'spontaneous' mutagenicity in strain TA104 of S. typhimurium, and 17 of them were also assayed in TA102. All test agents, many of which were already known or suspected to act as inhibitors of induced mutagenicity, had been previously monitored in our laboratory for antimutagenicity towards either 4-nitroquinoline 1-oxide in TA100 and/or cigarette smoke in TA98 with S9 mix.

Experimental databases on inhibition of the bacterial mutagenicity of 4-nitroquinoline 1-oxide and cigarette smoke.

Two antimutagenicity databases were prepared by applying a co-treatment procedure to the Salmonella reversion assay. Ninety compounds belonging to various chemical classes were quantitatively tested for antimutagenicity towards the direct-acting mutagen 4-nitroquinoline 1-oxide (4NQO) in strain TA100 of S. typhimurium and 63 of them were additionally tested for antimutagenicity towards unfractionated mainstream cigarette smoke (CS) in strain TA98, in the presence of S9 mix.

Genotoxicity of mercury compounds. A review.

This article reviews literature data concerning the genotoxicity of 29 mercury-containing agents, including laboratory compounds as well as ingredients of preparations used as fungicides, dyes, disinfectants and drugs. A variety of genetic end-points were investigated in bacteria, yeasts, moulds, plants, insects, cultured cells from fishes, rodents or humans, aquatic organisms, amphibians, mammalia and exposed humans. The overall evaluation is quite complex.

Multiple genotoxicity biomarkers in fish exposed in situ to polluted river water.

Specimens of rainbow trout (Oncorhynchus mykiss) were either kept in an aquarium under laboratory conditions or caged in the River Po (Northern Italy), upstream or downstream the confluence with the River Lambro, a small yet heavily polluted tributary. Genotoxicity biomarkers, evaluating the internal dose or early biological effects, were monitored after 7, 15 and 30 days of in situ exposure. With the exception of a slight increase of aminopyrine-N-demethylase and uridine-5'-diphospho-glucuronosyl-transferase, no significant effect was produced in fish kept upstream the River Lambro, as compared to control fish kept in the aquarium.

[Mixed-function oxidase induction as a test for the biological monitoring of water: limitations and prospects].

The induction in fish liver of some enzyme activities, and typically of microsomal mixed-function oxidases (MFO), provides the earliest biological warning signal of exposure to pollutants. Our studies provided evidence that the basal levels of cytochrome P-450 and specific MFO activities, such as arylhydrocarbon hydroxylase (AHH) and ethoxyresorufin deethylase (EROD), were strongly influenced by the diet in freshwater fish (Oncorhynchus mykiss). The response of fish liver to a known enzyme inducer, i.

Metabolic alterations produced by cigarette smoke in rat lung and liver, and their modulation by oral N-acetylcysteine.

Male Sprague-Dawley rats were exposed whole-body to the mainstream smoke produced by a commercial filter cigarette for 8 consecutive days, accounting for a cumulative exposure to the smoke of 75 cigarettes. Liver and lung S12 fractions were used in the Salmonella mutagenicity test in order to assess either the decrease of potency of a direct-acting mutagen (sodium dichromate) or the metabolic activation of promutagens, including cigarette smoke itself and its condensate, benzo[a]pyrene and its 7,8-diol, the aromatic amine 2-aminofluorene, and the heterocyclic amine 3-amino-1-methyl-5H-pyrido(4,3)indole. Moreover, individual biochemical parameters were measured in the liver and lung of the same rats and, in the case of cytochrome P-450-dependent monooxygenases, also in the heart of untreated or Aroclor-treated rats.

Potent genotoxicity of halogen lamps, compared to fluorescent light and sunlight.

The light emitted by halogen lamps induced mutations in Salmonella typhimurium and DNA damage in Escherichia coli, as shown by the hypersensitivity of DNA repair-deficient strains. The mutagenicity of halogen lamps was considerably higher than that of fluorescent light and of sunlight, even at much lower illuminance levels. Excision mechanisms and SOS functions were involved in repairing light-induced base-pair substitutions and frameshift errors in bacterial DNA.