Evaluation of chemopreventive agents for genotoxic activity

SRI International, Biosciences Division, Menlo Park, CA 94025, USA.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (Impact Factor: 3.68). 06/2007; 629(2):148-60. DOI: 10.1016/j.mrgentox.2007.02.004
Source: PubMed


We conducted genetic toxicity evaluations of 11 candidate chemopreventive agents with the potential for inhibiting carcinogenesis in humans at increased risk of cancer. The compounds were evaluated for bacterial mutagenesis in the Salmonella-E. coli assay, for mammalian mutagenesis in mouse lymphoma cells, for chromosome aberrations in Chinese Hamster Ovary (CHO) cells, and for micronucleus induction in mouse bone marrow. Tested agents were indole 3-carbinol (I3C), bowman-birk inhibitor concentrate (BBIC), black tea polyphenols (BTP), farnesol, geraniol, l-Se-methylselenocysteine (SeMC), 5,6-dihydro-4H-cyclopenta[1,2]-dithiol-3-thione(DC-D3T), 4'-bromoflavone, 2,5,7,8-tetramethyl-(2R-[4R,8R,12-trimethyltridecyl] chroman-6-yloxy) acetic acid (alpha-TEA), SR13668 (2,10-dicarbethoxy-6-methoxy-5,7-dihydro-indolo[2,3-b] carbazole and SR16157 (3-O-sulfamoyloxy-7alpha-methyl-21-(2-N,N-diethylaminoethoxy)-19-norpregna-1,3,5(10)-triene). All these agents, except I3C and BTP, were negative in the Salmonella-E. coli assay in the presence and absence of metabolic activation (S9). I3C and BTP induced a weak mutagenic response in the presence and absence of S9 with strains TA100 and TA98, respectively. Of the three compounds tested in the mouse lymphoma assay (I3C, BBIC, and BTP), only BTP was mutagenic in the presence of S9. In the chromosomal aberration assay, of the 8 compounds that were tested, 4'-bromoflavone elicited a positive response in the absence of S9 only, while SR16157 was positive in the presence of S9. The results with geraniol remain inconclusive. I3C, BBIC and BTP were not tested in the chromosomal aberration assay. None of the 11 agents induced micronuclei in mouse bone marrow erythrocytes.

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Available from: Rupa S Doppalapudi, Feb 11, 2014
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    • "The use of mutagenic drugs for cancer chemotherapy, with cyclophosphamide (CPA), is a routine practice (Doppalapudi et al., 2007). Therefore, identifying chemopreventive agents is important for the risk/benefit assessment of their potential use in humans. "
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    ABSTRACT: Rubus imperialis Cham. Schl. (Rosaceae) is frequently used in traditional medicine as hypoglycemic, antinociceptive and antiviral remedy. The aim of this study was to determine the in vivo genotoxic potential of Rubus imperialis aerial parts extract in cells of mice, and its possible antigenotoxic effect against cyclophosphamide (CPA)-induced DNA damage. In addition, the phytochemicals constituents in the extract were determined. Swiss albino mice were distributed in eight groups for acute treatment with R. imperialis extract (24h). The extract doses selected were 50, 250 and 500mg/kg b.w. administered by gavage alone or plus to CPA (50mg/kg b.w.) administered by intraperitoneal injection. The control groups were treated in a similar way. Analyses were performed using the comet assay, on leukocytes (collected 4 and 24hours after treatment) and liver (collected 24hours after treatment), and using the micronucleus test (MN) in bone marrow cells. Cytotoxicity was assessed by scoring 200 consecutive polychromatic (PCE) and normochromatic (NCE) erythrocytes (PCE/NCE ratio). The main compounds identified in the R. imperialis extract were saponins and steroidal compounds, being niga-ichigoside and tormentic acid the major compounds. The tested doses of R. imperialis extract showed no genotoxic effects in leukocytes from peripheral blood or liver cells by the comet assay. However, the MN test showed an increase in the frequency of micronucleated cells at the two higher doses tested, indicating that this extract have clastogenic/aneugenic effects in bone marrow cells at higher doses. On the other hand, for all cells evaluated, the three tested doses of the R. imperialis extract promoted inhibition of DNA damage induced by CPA. Despite the chemoprevention observed, the clastogenicity/aneugenicity observed suggest caution about either continuous or high-dose use of R. imperialis aerial parts extract by humans.
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    • "One type of terpenoid, namely farnesol, is considered to be an allergen by patch testing with fragrance mix (Schnuch et al., 2004; Frosch et al., 2005), but it is not believed to present a hazard to health: material safety data sheet (MSDS) states that the lethal dose 50% (LD50) is 6000 mg kg À1 by oral administration to rat. In addition, farnesol could be a candidate chemopreventive agent: it does not show any genetic toxicity when evaluated in Salmonella-Escherichia coli assay or mouse lymphoma cell (Doppalapudi et al., 2007). Farnesol was found to intensify the antimicrobial susceptibility of S. aureus (Akiyama et al., 2002; Brehm-Stecher & Johnson, 2003; Inoue et al., 2004; Jabra-Rizk et al., 2006), and we previously demonstrated that farnesol inhibits the recycling of the C 55 lipid carrier of the murein monomer precursor for subsequent peptidoglycan synthesis, leading to increased antimicrobial susceptibility, particularly to b-lactams (Kuroda et al., 2007). "
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