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REVIEW Genotoxic and Carcinogenic Effects of Gastrointestinal Drugs Mutagenesis vol. 25 no. 4 pp. 315–326, 2010 doi:10.1093/mutage/geq025 Advance Access Publication 17 May 2010 REVIEW Genotoxic and carcinogenic effects of gastrointestinal drugs Giovanni Brambilla*, Francesca Mattioli and a further in vivo test using a tissue other than the bone marrow/ Antonietta Martelli peripheral blood should be done. Guidelines for carcinogenic- Department of Internal Medicine, Division of Clinical Pharmacology and ity testing of pharmaceuticals (4,5) indicate that a long-term Toxicology, University of Genoa, Viale Benedetto XV 2, I-16132 Genoa, Italy carcinogenicity study plus a short- or medium-term in vivo system should be performed for all pharmaceuticals whose expected clinical use is continuous for at least 6 months as *To whom correspondence should be addressed. Tel: +39 010 353 8800; well as for pharmaceuticals used frequently in an intermittent Fax: þ39 010 353 8232; Email: [email protected] manner in the treatment of chronic recurrent conditions. In the Received on January 28, 2010; revised on March 23, 2010; absence of clear evidence favouring one species, the rat should accepted on April 13, 2010 be selected. In long-term carcinogenicity assays, the highest This review provides a compendium of retrievable results dose should be at least .25-fold, on a milligram per square of genotoxicity and carcinogenicity assays performed on meter basis, than the maximum recommended human daily marketed gastrointestinal drugs. Of the 71 drugs consid- dose or represent a 25-fold ratio of rodent to human area under ered, 38 (53.5%) do not have retrievable data, whereas the curve. The maximum tolerated dose (MTD) or a limit dose the other 33 (46.5%) have at least one genotoxicity or of 2000 mg/kg can be used as alternatives. Downloaded from carcinogenicity test result. Of these 33 drugs, 15 tested From the 2007 edition of the Martindale-The Complete Drug positive in at least one genotoxicity assay and 13 in at Reference (6), it can be inferred that 71 gastrointestinal drugs least one carcinogenicity assay; 8 of them gave a positive of long-term or intermittent frequent use are on the market, and response in both at least one genotoxicity assay and at least the majority of them are used in several countries. In a review mutage.oxfordjournals.org one carcinogenicity assay. Concerning the predictivity of of Snyder and Green (7), on the genotoxicity of marketed genetic toxicology findings for the result(s) of long-term pharmaceuticals, there are only 15 gastrointestinal drugs, but carcinogenesis assays, of 21 drugs with both genotoxicity no data are reported for 3 of them and for some of the and carcinogenicity data: 6 (28.6%) are neither genotoxic remaining, the information is quite limited. The International nor carcinogenic, 2 (9.5%) tested positive in at least one Agency for Research on Cancer (8) in the 91 volumes of by guest on September 18, 2011 genotoxicity assay but were non-carcinogenic, 5 (23.8%) International Agency for Research on Cancer (IARC) Mono- tested negative in genotoxicity assays but were carcino- graphs on the Evaluation of Carcinogenic Risks to Humans genic and 8 (38.1%) gave a positive response in at least one published in the years from 1972 to 2007 examined more than genotoxicity assay and in at least one carcinogenicity assay. 200 drugs, but these included only three gastrointestinal drugs: Only 12 (16.9%) of the 71 drugs examined have all data danthron and phenolphthalein classified as possibly carcino- required by present guidelines for testing of pharmaceut- genic to humans (Group 2B) and cimetidine considered non- icals, but a large fraction of them were developed and classifiable as to its carcinogenicity in humans (Group 3). marketed prior the present regulatory climate. These premises suggest that in prescribing most gastrointestinal drugs, the evaluation of the benefit:genotoxic–carcinogenic risk ratio is impossible. Therefore, we deemed useful to assess whether data allowing a more extensive information can be Introduction retrieved. Drugs for the treatment of gastrointestinal disorders are used by This review is a compendium of all the genotoxicity and numberless patients for long periods of time or frequently in an carcinogenicity data that have been found in an extensive intermittent manner. Among the various adverse reactions that search. This search was conducted primarily in peer-reviewed these drugs may cause, the occurrence of a genotoxic and/or journals using Medline, Toxline and the Registry of Toxic carcinogenic effect cannot be excluded, and it should be Effects of Chemicals Substances (9). Additional unpublished considered in the evaluation of the benefit:risk ratio. Therefore, data were obtained from the following Websites: http:/www we deemed useful to examine to what extent the drugs of this .toxnet.nlm.nih.gov, http://www.ntp.server.niehs.nih.gov,http: family underwent testing for their genotoxic and carcinogenic //www.potency.berkeley.edu, http://www.fda.gov/cder and activity. Present guidelines for genotoxicity testing of pharma- http://www.scirus.com. Concerning data that are not published ceutical (1–3) indicate a standard test battery that consists of: in peer-reviewed journals, in some cases, the tests were (i) a test for gene mutation in bacteria, (ii) an in vitro test with conducted under the oversight of authoritative bodies, such as cytogenetic evaluation of chromosomal damage with mamma- the U.S. National Toxicology Program; in the other cases, the lian cells or an in vitro mouse lymphoma tk assay that genotoxicity and carcinogenicity data are those reported by the can detect both gene mutation and chromosomal damage and Physician’s Desk Reference (10) or in the final package insert (iii) an in vivo test for chromosomal damage using rodent approved by the Center for Drug Evaluation and Research haematopoietic cells. For a compound that induces a biologi- of the Food and Drug Administration. Unfortunately, this cally relevant positive result in one or more in vitro tests, additional unpublished information if often incomplete; in Ó The Author 2010. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: [email protected]. 315 G. Brambilla et al. particular, the results of genotoxicity assays are usually repair synthesis and 11 in other types of genotoxicity assays. reported without any information of the doses that have been Twelve drugs were tested for genotoxicity in human cells. tested. Moreover, often no information is given whether the Concerning carcinogenicity, 22 drugs were tested in mice and in vitro genotoxicity assays were performed in both the 25 in rats, but it should be considered that 15 drugs gave presence and the absence of an exogenous metabolic system; in negative responses at doses to various extent lower than that these cases, in the absence of a specific indication, the result is recommended by present guidelines, i.e. lower than 25-fold the reported in the tables as obtained in both these experimental maximum recommended human daily dose on a milligrams per conditions. square meter basis. However, it should be considered that four of these drugs were tested at the MTD of 2000 or 2500 mg/kg. Table III provides for each type of assay the number of drugs Results of genotoxicity and carcinogenicity assays with positive, negative and discordant results. It is worth noting Information on genotoxic and/or carcinogenic effects of that the majority of gastrointestinal drugs tested negative in the gastrointestinal drugs was retrieved for only 33 (46.5%) of various types of genotoxicity assays; the fraction of those the 71 marketed pharmaceuticals considered (Table I). Only giving a positive response being to some extent higher in gene 12 drugs can be considered, on the basis of retrieved data, mutation in mammalian cells and in in vitro cytogenetics as tested in substantial agreement with the indications of assays. Some drugs with substantial chemical similarities allow the present guidelines on genotoxicity and carcinogenicity the following considerations with respect to the relationship testing of pharmaceuticals. Of these 12 drugs: alosetron and between chemical moieties and genotoxicity. All the prazoles mesalazine gave negative responses in all genotoxicity assays (esomeprazole, lansoprazole, omeprazole, pantoprazole and and were not carcinogenic in rodents; lubiprostone, nizatidine, rabeprazole) cause chromosomal damage. Of the four sala- olsalazine and tegaserod tested negative in genotoxicity assays zines, balsalazide and sulfasalazine gave same evidence of but gave at least one positive result in carcinogenesis assays; genotoxicity, whereas mesalazine and olsalazine tested nega- lansoprazole, omeprazole, pantoprazole, phenolphthalein, rabe- tive in genotoxicity assays. Of the four histamine analogues prazole and sulfasalazine gave positive response(s) in both H2-receptor antagonists, famotidine, nizatidine and ranitidine Downloaded from genotoxicity and carcinogenicity assays. Some additional drugs tested negative in genotoxicity assays, whereas cimetidine gave were tested for both genotoxicity and carcinogenicity but not as some evidence of DNA damage in primary rat hepatocytes. recommended by present guidelines: cisapride, famotidine, With respect to carcinogenesis assays, 7 drugs (10,17,22, hyoscine and ranitidine gave negative responses in both 25,26,32,33 of Table I) were carcinogenic in mice and 11 drugs mutage.oxfordjournals.org genotoxicity and carcinogenicity assays; balsalazide and (5,8,10,17,19,23–26,29,32 of Table I) were carcinogenic in dronabinol tested positive in one and three genotoxicity assays, rats. Of the five drugs carcinogenic in both mice and rats, four respectively, but were non-carcinogenic; bisacodyl tested were carcinogenic in different organs. Two drugs (22,25) gave negative in genotoxicity assays but was carcinogenic in rats; discordant results in mice and three (23,24,29) in rats, but with cimetidine and danthron gave positive responses in both the exception of omeprazole for the other four drugs, this by guest on September 18, 2011 genotoxicity and carcinogenicity assays.
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