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Giovanni Brambilla - One of the best experts on this subject based on the ideXlab platform.

  • arylamine drugs genotoxic Carcinogenic Activity of no derivatives
    Frontiers in Bioscience, 2012
    Co-Authors: Antonietta Martelli, Giovanni Brambilla
    Abstract:

    This review provides information on arylamine drugs which have been tested for the formation of N-nitroso compounds (NOC) by reacting with nitrite, and on the genotoxic-Carcinogenic effects of their nitrosation products. In an extensive search we have found that 109 arylamine drugs were examined for their ability to react with nitrite, and 105 of them (96.3 %) were found to form NOC or in some cases other reactive species. Moreover, 78 arylamine drugs were examined in short-term genotoxicity tests and/or in long-term Carcinogenicity assays, either in combination with nitrite or using their nitrosation product; 67 of them (85.9 %) have been found to give at least one positive response. Only a small fraction, the 19.1 % of theoretically nitrosatable arylamine drugs, has been examined for the possible formation of genotoxic-Carcinogenic NOC, guidelines for genotoxicity testing of pharmaceuticals do not indicate the need of appropriate tests, and patients are not informed that the drug-nitrite interaction and the consequent risk can be reduced to a large extent by consuming the nitrosatable drug with ascorbic acid.

  • genotoxicity and Carcinogenicity testing of pharmaceuticals correlations between induction of dna lesions and Carcinogenic Activity
    Mutation Research-reviews in Mutation Research, 2010
    Co-Authors: Giovanni Brambilla, Francesca Mattioli, Luigi Robbiano, Antonietta Martelli
    Abstract:

    This survey is a compendium of the results of DNA lesions assays (DNA adducts, DNA strand breaks, DNA repair synthesis) and of the results of Carcinogenicity assays of 146 pharmaceuticals. Of these drugs, 55 (37.7%) tested negative in both DNA lesions assay(s) and in Carcinogenicity assay(s); 65 (44.5%) tested negative in DNA lesions assay(s), but gave a positive response in at least one Carcinogenicity assay; 6 (4.1%) tested positive in at least one DNA lesions assay, but negative in Carcinogenicity assay(s); 20 (13.7%) tested positive in at least one DNA lesions assay and in at least one Carcinogenicity assay. Concerning the predictivity of DNA lesions assays findings for the results of long-term carcinogenesis assays performed in mice, rats or other species, concordance was found to exist for the 46.2% of pharmaceuticals in the case of DNA adducts, for 63.1% in the case of DNA strand breaks, and for 47.3% in the case of DNA repair synthesis (UDS).

  • correlation between induction of dna fragmentation in lung cells from rats and humans and Carcinogenic Activity
    Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2006
    Co-Authors: Luigi Robbiano, Debora Baroni, Luca Novello, Giovanni Brambilla
    Abstract:

    Abstract Six chemicals, known to induce lung tumors in rats, were examined for their ability to induce DNA fragmentation in primary cultures of rat and human lung cells, and in the lung of intact rats. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measured by the single-cell gel electrophoresis (Comet) assay, were obtained in primary lung cells from male rats with the following, minimally toxic, concentrations of the six test compounds: N-nitrosodimethylamine (NDMA; 2.5–10 mM), hydrazine (HZ; 0.5–4 mM), cadmium sulfate (CD; 31.2 and 62.5 μM), 4,4′-methylene bis (2-chloroaniline) (MOCA; 31.2–125 μM), isobutyl nitrite (IBN; 7.8–31.2 μM) and tetranitromethane (TNM; 1.9–15.6 μM). Similar degrees of DNA fragmentation were obtained in primary human lung cells; however, due to inter-donor differences, the minimum effective concentrations were in some donors lower and in others higher than in rats, and IBN induced DNA damage only in one of three donors. The DNA-damaging potency of HZ was higher in rats than in humans, and the opposite was true for MOCA. In agreement with these findings, statistically significant increases in the average frequency of DNA breaks were obtained in the lung of rats given a single oral dose (1/2 LD50) of the six test compounds. These findings give evidence that genotoxic lung carcinogens may be identified by use of the DNA fragmentation/Comet assay on rat lung cells as targets cells, and show that the six compounds tested produce in primary cultures of lung cells from human donors DNA-damaging effects substantially similar to those observed in rats.

  • correlation between induction of dna fragmentation in urinary bladder cells from rats and humans and tissue specific Carcinogenic Activity
    Toxicology, 2002
    Co-Authors: Luigi Robbiano, Roberto Carrozzino, Marianna Bacigalupo, C Corbu, Giovanni Brambilla
    Abstract:

    Seven chemicals, six of which are known to induce epithelial neoplasms of the urinary bladder in rats, were assayed for their ability to induce DNA damage in primary cultures of rat and human cells from urinary bladder mucosa, and in urinary bladder, liver and kidney of intact rats. Significant dose-dependent increases of DNA fragmentation, as measured by the Comet assay, were obtained in cells from both rats and humans with the following concentrations of five test compounds: 2-naphthylamine and N-nitrosodi-n-butylamine 0.5 and 1 mM, phenacetin 2 and 4 mM, cyclophosphamide from 2 to 8 mM, and o-toluidine 16 and 32 mM. Nitrilotriacetic acid (1-4 mM), a rat bladder carcinogen, and 4-aminobiphenyl (0.125-0.5 mM), a bladder carcinogen in humans but not in rats, gave a weak positive response in rats cells and a more marked response in humans cells. In terms of DNA-damaging potency, 4-aminobiphenyl, cyclophosphamide, phenacetin and 4 nitrilotriacetic acid were more active in human than in rat cells, whereas the converse occurred with 2-naphthylamine. Consistently with the results observed in vitro statistically significant dose-dependent increases in the average frequency of DNA breaks were detected in the urinary bladder mucosa of rats given p.o. single doses corresponding to 14 and 12 LD50 of six of the seven test compounds; the only one which gave a substantially negative response was 4-aminobiphenyl. With the exception of N-nitrosodi-n-butylamine which caused DNA damage in liver and of phenacetin and nitrilotriacetic acid which caused damage in kidney in agreement with their tumorigenic Activity, any substantial evidence of DNA lesions in these two organs was absent in rats treated with 12 LD50 of the other 4 test compounds. These findings give evidence that urinary bladder genotoxic carcinogens may be identified by the DNA damage/Comet assay using as targets cells of urinary bladder mucosa, and show that the effect may be quantitatively different in cells from rats and from human donors.

  • correlation between induction of dna fragmentation and micronuclei formation in kidney cells from rats and humans and tissue specific Carcinogenic Activity
    Toxicology and Applied Pharmacology, 1999
    Co-Authors: Luigi Robbiano, Roberto Carrozzino, C Corbu, Porta C Puglia, Giovanni Brambilla
    Abstract:

    Abstract Five chemicals, known to induce kidney tumors in rats, were assayed for their ability to induce DNA damage and formation of micronuclei in primary cultures of rat and human kidney cells and in the kidney of intact rats. Significant dose-dependent increases of DNA fragmentation, as measured by the Comet assay, and of micronuclei frequency were obtained in primary kidney cells from both rats and humans with the following concentrations of the five test compounds: lead acetate (not tested for micronuclei induction) and potassium bromate from 0.56 to 1.8 mM, phenacetin from 1 to 3.2 mM, and 1,4-dichlorobenzene and nitrilotriacetic acid from 1.8 to 5.6 mM. In terms of DNA-damaging potency all the five chemicals were more active in rat than in human kidney cells, whereas the potencies in inducing micronuclei formation were similar in the two species with the exception of 1,4-dichlorobenzene, which was slightly more potent in human than in rat cells. Consistently with the results observed in vitro, statistically significant increases in the average frequency of both DNA breaks and micronucleated cells were detected in the kidney of rats given po a single ( 1 2 LD50) or three successive daily doses ( 1 3 LD50) of the five test compounds. 4,4′-Methylenedianiline, a carcinogen which does not induce kidney tumors in rats, gave negative responses in both in vitro and in vivo assays. These findings give evidence that kidney carcinogens may be identified by short-term genotoxicity assays using as target kidney cells and show that the five chemicals tested produce in primary cultures of kidney cells from human donors effects similar to those observed in rats.

Luigi Robbiano - One of the best experts on this subject based on the ideXlab platform.

  • genotoxicity and Carcinogenicity testing of pharmaceuticals correlations between induction of dna lesions and Carcinogenic Activity
    Mutation Research-reviews in Mutation Research, 2010
    Co-Authors: Giovanni Brambilla, Francesca Mattioli, Luigi Robbiano, Antonietta Martelli
    Abstract:

    This survey is a compendium of the results of DNA lesions assays (DNA adducts, DNA strand breaks, DNA repair synthesis) and of the results of Carcinogenicity assays of 146 pharmaceuticals. Of these drugs, 55 (37.7%) tested negative in both DNA lesions assay(s) and in Carcinogenicity assay(s); 65 (44.5%) tested negative in DNA lesions assay(s), but gave a positive response in at least one Carcinogenicity assay; 6 (4.1%) tested positive in at least one DNA lesions assay, but negative in Carcinogenicity assay(s); 20 (13.7%) tested positive in at least one DNA lesions assay and in at least one Carcinogenicity assay. Concerning the predictivity of DNA lesions assays findings for the results of long-term carcinogenesis assays performed in mice, rats or other species, concordance was found to exist for the 46.2% of pharmaceuticals in the case of DNA adducts, for 63.1% in the case of DNA strand breaks, and for 47.3% in the case of DNA repair synthesis (UDS).

  • correlation between induction of dna fragmentation in lung cells from rats and humans and Carcinogenic Activity
    Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2006
    Co-Authors: Luigi Robbiano, Debora Baroni, Luca Novello, Giovanni Brambilla
    Abstract:

    Abstract Six chemicals, known to induce lung tumors in rats, were examined for their ability to induce DNA fragmentation in primary cultures of rat and human lung cells, and in the lung of intact rats. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measured by the single-cell gel electrophoresis (Comet) assay, were obtained in primary lung cells from male rats with the following, minimally toxic, concentrations of the six test compounds: N-nitrosodimethylamine (NDMA; 2.5–10 mM), hydrazine (HZ; 0.5–4 mM), cadmium sulfate (CD; 31.2 and 62.5 μM), 4,4′-methylene bis (2-chloroaniline) (MOCA; 31.2–125 μM), isobutyl nitrite (IBN; 7.8–31.2 μM) and tetranitromethane (TNM; 1.9–15.6 μM). Similar degrees of DNA fragmentation were obtained in primary human lung cells; however, due to inter-donor differences, the minimum effective concentrations were in some donors lower and in others higher than in rats, and IBN induced DNA damage only in one of three donors. The DNA-damaging potency of HZ was higher in rats than in humans, and the opposite was true for MOCA. In agreement with these findings, statistically significant increases in the average frequency of DNA breaks were obtained in the lung of rats given a single oral dose (1/2 LD50) of the six test compounds. These findings give evidence that genotoxic lung carcinogens may be identified by use of the DNA fragmentation/Comet assay on rat lung cells as targets cells, and show that the six compounds tested produce in primary cultures of lung cells from human donors DNA-damaging effects substantially similar to those observed in rats.

  • correlation between induction of dna fragmentation in urinary bladder cells from rats and humans and tissue specific Carcinogenic Activity
    Toxicology, 2002
    Co-Authors: Luigi Robbiano, Roberto Carrozzino, Marianna Bacigalupo, C Corbu, Giovanni Brambilla
    Abstract:

    Seven chemicals, six of which are known to induce epithelial neoplasms of the urinary bladder in rats, were assayed for their ability to induce DNA damage in primary cultures of rat and human cells from urinary bladder mucosa, and in urinary bladder, liver and kidney of intact rats. Significant dose-dependent increases of DNA fragmentation, as measured by the Comet assay, were obtained in cells from both rats and humans with the following concentrations of five test compounds: 2-naphthylamine and N-nitrosodi-n-butylamine 0.5 and 1 mM, phenacetin 2 and 4 mM, cyclophosphamide from 2 to 8 mM, and o-toluidine 16 and 32 mM. Nitrilotriacetic acid (1-4 mM), a rat bladder carcinogen, and 4-aminobiphenyl (0.125-0.5 mM), a bladder carcinogen in humans but not in rats, gave a weak positive response in rats cells and a more marked response in humans cells. In terms of DNA-damaging potency, 4-aminobiphenyl, cyclophosphamide, phenacetin and 4 nitrilotriacetic acid were more active in human than in rat cells, whereas the converse occurred with 2-naphthylamine. Consistently with the results observed in vitro statistically significant dose-dependent increases in the average frequency of DNA breaks were detected in the urinary bladder mucosa of rats given p.o. single doses corresponding to 14 and 12 LD50 of six of the seven test compounds; the only one which gave a substantially negative response was 4-aminobiphenyl. With the exception of N-nitrosodi-n-butylamine which caused DNA damage in liver and of phenacetin and nitrilotriacetic acid which caused damage in kidney in agreement with their tumorigenic Activity, any substantial evidence of DNA lesions in these two organs was absent in rats treated with 12 LD50 of the other 4 test compounds. These findings give evidence that urinary bladder genotoxic carcinogens may be identified by the DNA damage/Comet assay using as targets cells of urinary bladder mucosa, and show that the effect may be quantitatively different in cells from rats and from human donors.

  • correlation between induction of dna fragmentation and micronuclei formation in kidney cells from rats and humans and tissue specific Carcinogenic Activity
    Toxicology and Applied Pharmacology, 1999
    Co-Authors: Luigi Robbiano, Roberto Carrozzino, C Corbu, Porta C Puglia, Giovanni Brambilla
    Abstract:

    Abstract Five chemicals, known to induce kidney tumors in rats, were assayed for their ability to induce DNA damage and formation of micronuclei in primary cultures of rat and human kidney cells and in the kidney of intact rats. Significant dose-dependent increases of DNA fragmentation, as measured by the Comet assay, and of micronuclei frequency were obtained in primary kidney cells from both rats and humans with the following concentrations of the five test compounds: lead acetate (not tested for micronuclei induction) and potassium bromate from 0.56 to 1.8 mM, phenacetin from 1 to 3.2 mM, and 1,4-dichlorobenzene and nitrilotriacetic acid from 1.8 to 5.6 mM. In terms of DNA-damaging potency all the five chemicals were more active in rat than in human kidney cells, whereas the potencies in inducing micronuclei formation were similar in the two species with the exception of 1,4-dichlorobenzene, which was slightly more potent in human than in rat cells. Consistently with the results observed in vitro, statistically significant increases in the average frequency of both DNA breaks and micronucleated cells were detected in the kidney of rats given po a single ( 1 2 LD50) or three successive daily doses ( 1 3 LD50) of the five test compounds. 4,4′-Methylenedianiline, a carcinogen which does not induce kidney tumors in rats, gave negative responses in both in vitro and in vivo assays. These findings give evidence that kidney carcinogens may be identified by short-term genotoxicity assays using as target kidney cells and show that the five chemicals tested produce in primary cultures of kidney cells from human donors effects similar to those observed in rats.

  • studies on the mechanism of the Carcinogenic Activity of amitrole
    Toxicological Sciences, 1994
    Co-Authors: Francesca Mattioli, Luigi Robbiano, L Fazzuoli, P Baracchini
    Abstract:

    Amitrole, a widely used herbicide found to produce thyroid and liver tumors in rodents and classified as possibly Carcinogenic to humans, was investigated to acquire further information about its mechanism of action. A 20-hr exposure to amitrole concentrations ranging from 5.6 to 18 mM did not induce DNA fragmentation, as measured by the alkaline elution technique, in primary cultures of human thyroid follicular cells and of human liver cells. Under the same experimental conditions a minimal frequency of DNA breaks was detected in primary cultures of rat hepatocytes, but this event was presumably the unspecific consequence of a cytotoxic effect. In rats given amitrole with drinking water for 12 successive days at a daily dose of approximately 200 mg/kg, plasma levels of triiodothyronine and thyroxine displayed a progressive reduction, and a concurrent increase of both the mitotic index and frequency of S-phase cells revealing a clear-cut follicular cell hyperplasia was observed. In a group of these rats euthanized after 8 days of treatment any evidence of DNA fragmentation was absent in both thyroid and liver cells. Taken as a whole these results provide further evidence that the mechanism of amitrole Carcinogenic Activity is most likely nongenotoxic but due to hormone imbalance.

C Corbu - One of the best experts on this subject based on the ideXlab platform.

  • correlation between induction of dna fragmentation in urinary bladder cells from rats and humans and tissue specific Carcinogenic Activity
    Toxicology, 2002
    Co-Authors: Luigi Robbiano, Roberto Carrozzino, Marianna Bacigalupo, C Corbu, Giovanni Brambilla
    Abstract:

    Seven chemicals, six of which are known to induce epithelial neoplasms of the urinary bladder in rats, were assayed for their ability to induce DNA damage in primary cultures of rat and human cells from urinary bladder mucosa, and in urinary bladder, liver and kidney of intact rats. Significant dose-dependent increases of DNA fragmentation, as measured by the Comet assay, were obtained in cells from both rats and humans with the following concentrations of five test compounds: 2-naphthylamine and N-nitrosodi-n-butylamine 0.5 and 1 mM, phenacetin 2 and 4 mM, cyclophosphamide from 2 to 8 mM, and o-toluidine 16 and 32 mM. Nitrilotriacetic acid (1-4 mM), a rat bladder carcinogen, and 4-aminobiphenyl (0.125-0.5 mM), a bladder carcinogen in humans but not in rats, gave a weak positive response in rats cells and a more marked response in humans cells. In terms of DNA-damaging potency, 4-aminobiphenyl, cyclophosphamide, phenacetin and 4 nitrilotriacetic acid were more active in human than in rat cells, whereas the converse occurred with 2-naphthylamine. Consistently with the results observed in vitro statistically significant dose-dependent increases in the average frequency of DNA breaks were detected in the urinary bladder mucosa of rats given p.o. single doses corresponding to 14 and 12 LD50 of six of the seven test compounds; the only one which gave a substantially negative response was 4-aminobiphenyl. With the exception of N-nitrosodi-n-butylamine which caused DNA damage in liver and of phenacetin and nitrilotriacetic acid which caused damage in kidney in agreement with their tumorigenic Activity, any substantial evidence of DNA lesions in these two organs was absent in rats treated with 12 LD50 of the other 4 test compounds. These findings give evidence that urinary bladder genotoxic carcinogens may be identified by the DNA damage/Comet assay using as targets cells of urinary bladder mucosa, and show that the effect may be quantitatively different in cells from rats and from human donors.

  • correlation between induction of dna fragmentation and micronuclei formation in kidney cells from rats and humans and tissue specific Carcinogenic Activity
    Toxicology and Applied Pharmacology, 1999
    Co-Authors: Luigi Robbiano, Roberto Carrozzino, C Corbu, Porta C Puglia, Giovanni Brambilla
    Abstract:

    Abstract Five chemicals, known to induce kidney tumors in rats, were assayed for their ability to induce DNA damage and formation of micronuclei in primary cultures of rat and human kidney cells and in the kidney of intact rats. Significant dose-dependent increases of DNA fragmentation, as measured by the Comet assay, and of micronuclei frequency were obtained in primary kidney cells from both rats and humans with the following concentrations of the five test compounds: lead acetate (not tested for micronuclei induction) and potassium bromate from 0.56 to 1.8 mM, phenacetin from 1 to 3.2 mM, and 1,4-dichlorobenzene and nitrilotriacetic acid from 1.8 to 5.6 mM. In terms of DNA-damaging potency all the five chemicals were more active in rat than in human kidney cells, whereas the potencies in inducing micronuclei formation were similar in the two species with the exception of 1,4-dichlorobenzene, which was slightly more potent in human than in rat cells. Consistently with the results observed in vitro, statistically significant increases in the average frequency of both DNA breaks and micronucleated cells were detected in the kidney of rats given po a single ( 1 2 LD50) or three successive daily doses ( 1 3 LD50) of the five test compounds. 4,4′-Methylenedianiline, a carcinogen which does not induce kidney tumors in rats, gave negative responses in both in vitro and in vivo assays. These findings give evidence that kidney carcinogens may be identified by short-term genotoxicity assays using as target kidney cells and show that the five chemicals tested produce in primary cultures of kidney cells from human donors effects similar to those observed in rats.

Roberto Carrozzino - One of the best experts on this subject based on the ideXlab platform.

  • correlation between induction of dna fragmentation in urinary bladder cells from rats and humans and tissue specific Carcinogenic Activity
    Toxicology, 2002
    Co-Authors: Luigi Robbiano, Roberto Carrozzino, Marianna Bacigalupo, C Corbu, Giovanni Brambilla
    Abstract:

    Seven chemicals, six of which are known to induce epithelial neoplasms of the urinary bladder in rats, were assayed for their ability to induce DNA damage in primary cultures of rat and human cells from urinary bladder mucosa, and in urinary bladder, liver and kidney of intact rats. Significant dose-dependent increases of DNA fragmentation, as measured by the Comet assay, were obtained in cells from both rats and humans with the following concentrations of five test compounds: 2-naphthylamine and N-nitrosodi-n-butylamine 0.5 and 1 mM, phenacetin 2 and 4 mM, cyclophosphamide from 2 to 8 mM, and o-toluidine 16 and 32 mM. Nitrilotriacetic acid (1-4 mM), a rat bladder carcinogen, and 4-aminobiphenyl (0.125-0.5 mM), a bladder carcinogen in humans but not in rats, gave a weak positive response in rats cells and a more marked response in humans cells. In terms of DNA-damaging potency, 4-aminobiphenyl, cyclophosphamide, phenacetin and 4 nitrilotriacetic acid were more active in human than in rat cells, whereas the converse occurred with 2-naphthylamine. Consistently with the results observed in vitro statistically significant dose-dependent increases in the average frequency of DNA breaks were detected in the urinary bladder mucosa of rats given p.o. single doses corresponding to 14 and 12 LD50 of six of the seven test compounds; the only one which gave a substantially negative response was 4-aminobiphenyl. With the exception of N-nitrosodi-n-butylamine which caused DNA damage in liver and of phenacetin and nitrilotriacetic acid which caused damage in kidney in agreement with their tumorigenic Activity, any substantial evidence of DNA lesions in these two organs was absent in rats treated with 12 LD50 of the other 4 test compounds. These findings give evidence that urinary bladder genotoxic carcinogens may be identified by the DNA damage/Comet assay using as targets cells of urinary bladder mucosa, and show that the effect may be quantitatively different in cells from rats and from human donors.

  • correlation between induction of dna fragmentation and micronuclei formation in kidney cells from rats and humans and tissue specific Carcinogenic Activity
    Toxicology and Applied Pharmacology, 1999
    Co-Authors: Luigi Robbiano, Roberto Carrozzino, C Corbu, Porta C Puglia, Giovanni Brambilla
    Abstract:

    Abstract Five chemicals, known to induce kidney tumors in rats, were assayed for their ability to induce DNA damage and formation of micronuclei in primary cultures of rat and human kidney cells and in the kidney of intact rats. Significant dose-dependent increases of DNA fragmentation, as measured by the Comet assay, and of micronuclei frequency were obtained in primary kidney cells from both rats and humans with the following concentrations of the five test compounds: lead acetate (not tested for micronuclei induction) and potassium bromate from 0.56 to 1.8 mM, phenacetin from 1 to 3.2 mM, and 1,4-dichlorobenzene and nitrilotriacetic acid from 1.8 to 5.6 mM. In terms of DNA-damaging potency all the five chemicals were more active in rat than in human kidney cells, whereas the potencies in inducing micronuclei formation were similar in the two species with the exception of 1,4-dichlorobenzene, which was slightly more potent in human than in rat cells. Consistently with the results observed in vitro, statistically significant increases in the average frequency of both DNA breaks and micronucleated cells were detected in the kidney of rats given po a single ( 1 2 LD50) or three successive daily doses ( 1 3 LD50) of the five test compounds. 4,4′-Methylenedianiline, a carcinogen which does not induce kidney tumors in rats, gave negative responses in both in vitro and in vivo assays. These findings give evidence that kidney carcinogens may be identified by short-term genotoxicity assays using as target kidney cells and show that the five chemicals tested produce in primary cultures of kidney cells from human donors effects similar to those observed in rats.

Antonietta Martelli - One of the best experts on this subject based on the ideXlab platform.

  • arylamine drugs genotoxic Carcinogenic Activity of no derivatives
    Frontiers in Bioscience, 2012
    Co-Authors: Antonietta Martelli, Giovanni Brambilla
    Abstract:

    This review provides information on arylamine drugs which have been tested for the formation of N-nitroso compounds (NOC) by reacting with nitrite, and on the genotoxic-Carcinogenic effects of their nitrosation products. In an extensive search we have found that 109 arylamine drugs were examined for their ability to react with nitrite, and 105 of them (96.3 %) were found to form NOC or in some cases other reactive species. Moreover, 78 arylamine drugs were examined in short-term genotoxicity tests and/or in long-term Carcinogenicity assays, either in combination with nitrite or using their nitrosation product; 67 of them (85.9 %) have been found to give at least one positive response. Only a small fraction, the 19.1 % of theoretically nitrosatable arylamine drugs, has been examined for the possible formation of genotoxic-Carcinogenic NOC, guidelines for genotoxicity testing of pharmaceuticals do not indicate the need of appropriate tests, and patients are not informed that the drug-nitrite interaction and the consequent risk can be reduced to a large extent by consuming the nitrosatable drug with ascorbic acid.

  • genotoxicity and Carcinogenicity testing of pharmaceuticals correlations between induction of dna lesions and Carcinogenic Activity
    Mutation Research-reviews in Mutation Research, 2010
    Co-Authors: Giovanni Brambilla, Francesca Mattioli, Luigi Robbiano, Antonietta Martelli
    Abstract:

    This survey is a compendium of the results of DNA lesions assays (DNA adducts, DNA strand breaks, DNA repair synthesis) and of the results of Carcinogenicity assays of 146 pharmaceuticals. Of these drugs, 55 (37.7%) tested negative in both DNA lesions assay(s) and in Carcinogenicity assay(s); 65 (44.5%) tested negative in DNA lesions assay(s), but gave a positive response in at least one Carcinogenicity assay; 6 (4.1%) tested positive in at least one DNA lesions assay, but negative in Carcinogenicity assay(s); 20 (13.7%) tested positive in at least one DNA lesions assay and in at least one Carcinogenicity assay. Concerning the predictivity of DNA lesions assays findings for the results of long-term carcinogenesis assays performed in mice, rats or other species, concordance was found to exist for the 46.2% of pharmaceuticals in the case of DNA adducts, for 63.1% in the case of DNA strand breaks, and for 47.3% in the case of DNA repair synthesis (UDS).