Toxicological Sciences 69, 16-22 (2002)
Copyright © 2002 by the Society of Toxicology
CARCINOGENICITY |
Inhibition of Human Topoisomerase II
by Fluoroquinolones and Ultraviolet A Irradiation
* Department of Pathology, New York Medical College, Valhalla, New York 10595; and
Department of Biology, Mount Holyoke College, South Hadley, Massachusetts 01075
Received January 9, 2002; accepted April 26, 2002
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Some fluoroquinolone antibiotics (FQs) become toxic and mutagenic upon exposure to ultraviolet radiation (UV). Topoisomerase inhibition has been proposed as one possible mechanism involved in this photochemical genotoxicity. To study this reaction, inhibition of the human topoisomerase II
enzyme by four FQs varying in photochemical genotoxic potency (Bay y3118 [y3118] > Lomefloxacin [Lmx] > Ciprofloxacin [Cpx] > Moxifloxacin [Mox]) was measured in vitro in the presence of UVA irradiation. None of the FQs inhibited topoisomerase II in the absence of irradiation. In contrast, with irradiation at 365 nm, the potent photochemically genotoxic y3118 produced strong inhibition of the enzyme by 15% and Cpx caused a weak 5% inhibition, but the more photochemically genotoxic Lmx only showed a transient inhibitory effect at one concentration and one irradiation dose. The photostable Mox had no effect with irradiation. Topoisomerase II inhibition by y3118 only occurred when the FQ, DNA, and enzyme were simultaneously present in the UVA-irradiated reaction mixture and was abolished in the absence of ATP, indicating the possible formation of a ternary structure. The y3118 photochemical topoisomerase inhibition correlated with the increased irradiation-mediated binding of radiolabeled FQ to DNA:topoisomerase complexes and was irreversible, like that of the topoisomerase poison, etoposide, without irradiation. The inhibitory effect of photoactivated y3118 on topoisomerase II was also observed in the presence of the antioxidant TEMPO, indicating that reactive oxygen species were not involved in the inhibition. These observations demonstrate that some but not all photochemically genotoxic FQs inhibit human topoisomerase II, possibly by UV-induced affinity of FQs to DNA:topoisomerase complexes.
Key Words: human topoisomerase II; fluoroquinolones; photogenotoxicity.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Fluoroquinolones (FQs) are highly effective antibiotics derived from the prototype nalidixic acid, and they possess a broad antibacterial spectrum (Appelbaum et al., 2000; Bakshi et al., 2001
). In the presence of ultraviolet irradiation (UV), a number of FQs exert photochemical toxic and mutagenic effects (Chételat et al., 1996; Jeffrey et al., 2000; Marrot et al., 2000; Martínez et al., 1998; Rosen et al., 1996; Snyder et al., 1999; Spratt et al., 1999). Our laboratory has previously reported that photoactive FQs produce oxidative DNA damage as a consequence of the formation of reactive oxygen species (Rosen et al., 1996; Spratt et al., 1999; Verna et al., 1998). This property was associated with the presence of a halogen in the C8 position (Rosen et al., 1997), which has been related to phototoxicity (Domagala, 1994). Although oxygen radical scavengers such as catalase, superoxide dismutase, and N, N`-dimethylurea were reported to modulate the phototoxic effects of the FQs lomefloxacin, ciprofloxacin and fleroxacin, they were unable to ameliorate their photogenotoxic effects (Chételat et al., 1996). Furthermore, levels of reactive oxygen species generated during the photoactivation of FQs were not found to correlate to the genotoxic effects (Martínez et al., 1998; Umezawa et al., 1997). Alternatively, Martínez and Chignell (1998) reported that the DNA photocleavage activity of FQs is independent from the generation of reactive oxygen species and may result from the formation of a carbene intermediate at the C-8 position resulting from the loss of fluoride upon exposure to ultraviolet irradiation (UVA). However, not all quinolones form the carbene intermediate during photodegradation (Martínez et al., 1997). While these aspects remain to be resolved, other possible mechanisms have been postulated to be responsible for the photogenotoxicity of FQs.
At high concentrations, some FQs have been reported to exhibit genotoxic effects in eukaryotic systems as a result of topoisomerase inhibition (Kohlbrenner et al., 1992; Robinson et al., 1991). The FQs CP-67,804 and CP-115,953 were shown to induce topoisomerase II-mediated DNA cleavage by enhancing pre- and post-strand DNA breaks (Robinson et al., 1991). Ciprofloxacin and CP-67,015 were also found to inhibit the catalytic DNA strand passage activity (Barrett et al., 1989). Since FQs can associate with mammalian topoisomerases, it is possible that this interaction could be enhanced by UV irradiation. In support of this, the phototoxic effects of several FQs, including lomefloxacin, were almost completely inhibited in Chinese hamster V79 cells pretreated with sodium azide, which is reported to inactivate the catalytic activity of topoisomerase II (Ju et al., 2001; Snyder and Cooper, 1999). Based on this observation, it was proposed that UV-dependent toxicities of FQs involve a common mechanism of topoisomerase II-induced DNA double strand breaks (Snyder and Cooper, 1999). However, sodium azide is not a specific inhibitor of topoisomerase II, since it has been shown to interfere with the mitochondrial electron transport chain depleting cells of ATP (Muneyuki et al., 1993). To examine directly whether the photochemical genotoxicity of FQs involves topoisomerase II inhibition, the UV-dependent inhibition of human topoisomerase II activity was measured in vitro for a spectrum of FQs with different UV-dependent genotoxicities (Jeffrey et al., 2000; Spratt et al., 1999). While one potent photogenotoxic FQ induced UV-mediated inhibition of topoisomerase II, another did not, indicating that topoisomerase inhibition does not appear to be the only mechanism of FQ photogenotoxicity.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Chemicals.
The pBR322 plasmid was purchased from Life Technologies (Grand Island, NY). Human topoisomerase II
and anti-topo II antibody were obtained from Topogen, Inc. (Columbus, OH). The FQ antibiotics (Fig. 1) ciprofloxacin (Cpx), lomefloxacin (Lmx), moxifloxacin (Mox), Bay y3118 (y3118), [14C] y3118, and [14C] Mox were kindly provided by Bayer Pharmaceuticals, Wüppertal, Germany. All other reagents were from Sigma-Aldrich (St. Louis, MO).
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Topoisomerase II
-mediated DNA cleavage/religation equilibrium.The effects of the FQ antibiotics Mox, Lmx, Cpx, and y3118 on the human topoisomerase II
-mediated cleavage/religation equilibrium were followed using the cleavage reaction (Robinson et al., 1991). Briefly, 5 nM pBR322 was incubated at 37°C with 2 units of human topoisomerase II in cleavage buffer consisting of 50 mM Tris-HCl pH 7.9, 25 mM NaCl, 50 mM KCl, 5 mM MgCl2, 0.1 mM EDTA, 2.5% glycerol, 1 mM ATP, and various concentrations of FQ antibiotics (0–10 µM range) in a 20 µl final volume. The reaction was carried out in the dark or under 60, 120, 240, and 360 mJ/cm2 UVA irradiation. A Spectroline lamp, model ENFL 280 C, was used as the source of UVA, and the intensity of UVA irradiation was measured using a Spectroline radiometer model DSE-100X with a DIX-365 UVA sensor. The cleaved products were trapped with the addition of 2 µl of 10% SDS and the enzyme was digested with 2 µl of 0.6 mg/ml proteinase K at 37°C for 30 min. Following the enzyme digestion, 2 µl loading buffer consisting of 0.25% bromophenol blue, 0.25% xylene cyanol, and 40% sucrose was added to the samples, which were then heated at 70°C for 1 min, loaded in a 1% agarose gel, and electrophoresed for 1 hour at 100 V using TAE buffer (40 mM Tris acetate and 10 mM EDTA, pH 8.0). The gels were stained with ethidium bromide and densitometry of the reaction products was measured from the agarose gels, using a CCD camera adapted to an AlphaImager 2000 system (Imgen, Alexandria, Virginia). Etoposide (100 µM) was utilized as positive control.
To confirm whether plasmid cleavage involved the inhibition of the topoisomerase II or a UVA-mediated reaction independent from the enzyme, inhibition assays were conducted in the absence of enzyme, ATP, or magnesium. Enzyme assays were also performed in the presence of 100 µM TEMPO or under anaerobic conditions using a nitrogen atmosphere to examine whether the generation of reactive oxygen species participated in the UVA-FQ–induced topoisomerase inhibition.
Religation of cleaved pBR322.
DNA religation was followed using the heat-induced religation protocol described by Robinson et al.(1991). Briefly, DNA cleavage/religation equilibrium was established as described above in the presence of 100 µM y3118 dosed with 360 mJ/cm2 UVA. Following UVA exposure, the DNA:topoisomerase complexes were trapped with 0.8 µl of 250 mM EDTA. Following the addition of 0.6 µl of 5 M NaCl, the samples were shifted from 37° to 55°C, and the reaction was stopped at various time points by the addition of 2 µl of 10% SDS. The samples were extracted once with phenol:chloroform (1:1), ethanol-precipitated, and electrophoresed in a 1% agarose gel. The gels were stained with ethidium bromide, and densitometry of the reaction products was analyzed using the AlphaImager system.
Binding of radiolabelled FQs to pBR322 and topoisomerase II.
To examine the degree of association of photoactivated fluoroquinolones to DNA or DNA:topoisomerase complexes, [14C] y3118 (3.52 MBq/mg) or [14C] Mox (2.94 MBq/mg) were incubated in cleavage buffer containing pBR322 alone or pBR322 plus human topoisomerase II, and irradiated with 360 mJ/cm2 of UVA. Following UVA exposure, the reaction mixture was extracted with phenol:chloroform (1:1), and the DNA was precipitated in 2.5 volumes of ethanol. The DNA pellet was rinsed twice in 70% ethanol, resuspended in 0.1% SDS, and radioactivity finally measured using a Wallac scintillation counter (Perkin Elmer, Gaithersburg, MD).
[14C]-Labeled y3118 and Mox were also incubated in cleavage buffer at 37°C for 30 min with 20 picograms of human topoisomerase II, alone in the dark or under 360 mJ/cm2 UVA. Following the incubation period, the topoisomerase enzyme was immunoprecipitated using a polyclonal topoisomerase II antibody. Briefly, the reaction mixture was incubated for 1 h at 4°C with 20 picograms of antibody. Following the incubation with primary antibody, 10% protein A-agarose beads were added to the samples and the mixture was incubated at 4°C with rocking for 1 h. The antigen-antibody complexes, bound to the protein A-agarose beads, were centrifuged at 10,000 x g for 5 min at 4°C. The supernatant was discarded and the pellets were resuspended 3 times in RIPA buffer (150 nM NaCl, 1% NP40, 0.1% SDS, and 50 mM Tris–HCl pH 8.0) and centrifuged at 10,000 x g. Following the final wash, the pellets were resuspended in 0.1% SDS and boiled for 10 min, then radioactivity was measured using a Wallac scintillation counter.
Statistics.
Samples from unirradiated and irradiated groups were compared by analysis of variance (ANOVA). Unless specified, the data represent the mean ± SEM of samples obtained from three experiments.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To investigate the molecular basis for the photochemical genotoxicity and mutagenicity of FQs, we studied four FQs (Fig. 1
) differing in their photochemical properties. Bay y3118 and lomefloxacin (Lmx) were highly photoactive, whereas ciprofloxacin (Cpx) was weakly active and moxifloxacin (Mox) was photostable (Kersten et al., 1999; Snyder and Cooper, 1999; Spratt et al., 1999; Appelbaum and Hunter, 2000). Studies were first conducted to determine whether FQs could inhibit the human topoisomerase II in vitro when exposed to UVA, by following the linearization of the pBR322 plasmid.
The pBR322 plasmid preparation utilized in these studies contained 2 plasmid states, supercoiled (closed circular) and relaxed nicked (open circular) double stranded DNA. The closed circular DNA migrates faster in agarose gel than the open circular DNA, as shown in Fig. 2. Topoisomerases catalyze the relaxation of supercoiled DNA through the transient cleavage of DNA, mediated by covalent binding between the enzyme and DNA followed by DNA religation and dissociation of the topoisomerase (Berger, 1998; Burden et al., 1998; Ferguson et al., 1994; Jacob et al., 2001; Nitiss, 1998). In the presence of topoisomerase II, an equilibrium between the open circular and closed circular plasmids was established (Fig. 2). When treated with the topoisomerase II inhibitor etoposide, the half-life of the cleaved DNA is lengthened by preventing religation (Ferguson and Baguley, 1994). The cleaved DNA can then be identified in gels as a band that migrates between the open circular and closed circular DNA, which consists of linearized plasmid (Fig. 2).
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Increasing intensities of UVA resulted in a dose response inhibition of topoisomerase II
in the presence of y3118, with a maximal 15% enzyme inhibition at 360 mJ/cm2 of UVA (Figs. 2 and 3). A moderate 5% and 4% in topoisomearse II inhibition was also observed for 5 and 10 µM Cpx, respectively, when exposed to 360 mJ/cm2 UVA (Figs. 2 and 3). Although Lmx has been shown in our laboratory to be photochemically mutagenic in the V79 cell lines, this FQ caused no topoisomerase II inhibition at the same concentrations and UVA doses utilized for y3118, except for a single concentration at a single irradiation dose (1 µM, 240 mJ/cm2, respectively; Fig. 3). No enzyme inhibition was observed for the photostable FQ Mox (Fig. 3).
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The mechanisms of inhibition of topoisomerase II
were examined using the photoactive y3118. When DNA, y3118 or topoisomerase II were irradiated alone prior to their addition into the reaction mixture, DNA cleavage and plasmid linearization was not observed (Fig. 4). Also, DNA cleavage was not observed when combinations of y3118:DNA, topoisomerase II:DNA, or y3118:topoisomerase II (not shown) were exposed to 360 mJ/cm2 UVA before conducting the enzyme assay (Fig. 4). This suggests that topoisomerase II inhibition by photoactivated y3118 requires the presence of all 3 components (DNA, topoisomerase II, and y3118) as shown in Figure 4. To further examine whether pBR322 cleavage resulted from direct enzyme inhibition by the photoactivated y3118 rather than FQ-mediated DNA cleavage independent from topoisomerase II activity, in vitro assays were conducted in the absence of enzyme, ATP, or magnesium. In the absence of enzyme or ATP, DNA cleavage was completely absent (Fig. 5). However, a 6% enzyme inhibition was still observed with 1, 5, and 10 µM y3118 exposed to 360 mJ/cm2 UVA in the absence of magnesium (Fig. 5).
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To discriminate whether pBR322 linearization, following UVA irradiation of y3118, originated from induction in pre-/post-strand DNA cleavage or inhibition of religation, the effect of photoactivated y3118 in enzyme-mediated religation was examined. DNA religation in the presence of y3118 was not observed at 55°C, similar to the effect of etoposide (Fig. 6
). The same results were obtained when religation was conducted at 0°C (data not shown).
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The exposure of FQs to UVA was reported to generate reactive oxygen species, which could produce oxidative DNA damage (Devasagayam et al., 1991
; Rosen et al., 1996; Spratt et al., 1999). To examine whether the generation of reactive oxygen species mediated y3118-induced topoisomerase II inhibition and consequent DNA damage, enzyme assays were conducted in the presence or absence of the reactive oxygen quencher TEMPO (100 µM). Inhibition of topoisomerase II was observed in the presence of TEMPO (Fig. 7). Similar results (data not shown) were observed when the enzyme reactions were conducted under a nitrogen atmosphere, which was shown previously to abrogate DNA oxidative damage (Spratt et al., 1999). These findings suggest that the generation of reactive oxygen following UV irradiation of FQs does not induce topoisomerase II inhibition.
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To assess whether topoisomerase II
inhibition resulted from the direct association of photoactivated y3118 to the DNA or the enzyme, studies were conducted using [14C]-labeled y3118 and Mox. In the absence of UVA, [14C]-y3118 and [14C]-Mox were found to associate to DNA and topoisomerase II (Fig. 8). Following UVA exposure, a slight, but not significant, increase in [14C]-Mox association to DNA or topoisomerase II was observed (Fig. 8). A significant 3-fold increase in [14C]-Mox association (p < 0.05) was observed when Mox, DNA, and topoisomerase II were present in the reaction mixture during UVA exposure (Fig. 8). Association of [14C]-y3118 to DNA or topoisomerase II was also observed in the absence of UVA (Fig. 8). The association of [14C]-y3118 to DNA and topoisomerase II was increased 10-and 2-fold, respectively, in the presence of UVA, whereas a 100-fold increase in [14C]-y3118 binding to DNA was observed when DNA, topoisomerase II, and y3118 were exposed together to UVA (Fig. 8), suggesting the interaction of photoactivated FQs with DNA:topoisomerase cleavage complexes.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The experiments reported here examined for the first time the effect of photoactivated FQs on the human topoisomerase II
by measuring the cleavage of the PBR322 plasmid. The findings establish the effects of four FQs differing in photochemical toxicities (y3118 > Lmx > Cpx > Mox) on the enzyme activity in the presence of UVA irradiation. By following the topoisomerase cleavage/religation equilibrium, it was observed that UVA-irradiated y3118, a potent photochemical mutagen in V79 cells (Jeffrey et al., 2000), strongly inhibited human topoisomerase II activity. A weak topoisomerase II inhibition was also observed for the photoactivated Cpx, but not for the photostable Mox. Although Lmx has been shown to be a weak photomutagen in V79 cells (Jeffrey et al., 2000), this compound, despite its increased nicking of plasmid DNA in the presence of UVA (data not shown), did not inhibit topoisomerase II activity at concentrations and UVA doses that were effective for y3118. In contrast to our study, Lmx has been reported to be clastogenic following UV exposure (Kersten et al., 1999; Snyder and Cooper, 1999), an effect attributed to topoisomerase II inhibition from experiments using sodium azide-pretreated V79 cells. However, the inability of Lmx to inhibit topoisomerase II, as found in our studies, suggests that the mechanism of photochemical mutagenesis mediated by Lmx is not identical to that of y3118 and Cpx. When exposed to UVA, Lmx increases the formation of thymidine dimers, which is correlated with its ability to initiate skin tumors (Traynor and Gibbs, 1999) and this effect could be the primary mechanism by which Lmx induces DNA damage. Thus, topoisomerase inhibition appears not to be a common mechanism by which all photoactivated FQs induce genotoxicity.
To examine the mechanism by which photoactivated FQs inhibit the human topoisomerase II enzyme, studies were conducted using the photoactive y3118, which strongly inhibited topoisomerase II in the presence of UVA. Irradiation of y3118, DNA or topoisomerase alone or combinations of y3118:DNA or y3118:topoisomerase yielded no DNA double strand breaks. DNA double strand breaks were only observed when y3118, DNA, and topoisomerase II were simultaneously present in the enzyme assay. This suggests that photoactivated y3118 could be exerting its inhibitory effects by forming a ternary FQ-enzyme-DNA complex requiring ATP, as has been described for etoposide and m-AMSA in the absence of UV irradiation (Anderson et al., 1994; Nelson et al., 1984; Robinson et al., 1990). Quinolone-induced inactivation of topoisomerase II at high concentrations was proposed to involve the direct binding of quinolones to DNA and not to the enzyme (Shen et al., 1985, 1989; Tornaletti and Pedrini, 1988). Such binding of FQs to DNA was proposed to inhibit topoisomerase II activity resulting in DNA damage (Shen and Pernet, 1985; Tornaletti and Pedrini, 1988). In contrast, our studies using radiolabeled Mox and y3118 revealed that both FQs are capable of associating with both the enzyme and the DNA. A nonsignificant association of Mox or y3118 with DNA or the human topoisomerase II incubated individually in the presence of these FQs was observed in the absence of UVA. However, in the presence of UVA, the association of the photostable FQ Mox and the highly photoreactive FQ y3118 to the DNA:topoisomerase complexes was increased 2-fold and 100-fold, respectively. This finding suggests that the degree of association of photoactive FQs to DNA:topoisomerase complexes could determine the degree of DNA damage, as proposed previously for other topoisomerase II poisons (Snyder and Cooper, 1999).
The DNA cleavage induced by photoactivated y3118 was irreversible, in contrast to studies performed by Robinson et al. using Drosophila melanogaster topoisomerase II and high concentrations of the FQs CP-115,953 and CP-67,804 without irradiation (Robinson et al., 1991). It is likely that the inability of topoisomerase II to religate the double strand breaks may result from the photomediated increase in binding of y3118 to both the topoisomerase II and the DNA. Extensive binding of y3118 not only could prevent topoisomerase II from recognizing and ligating DNA cleaved sites but could also induce a conformational change of the enzyme leading to its inactivation. Most likely, the binding of FQs to the DNA:topoisomerase complexes could result in the stabilization of the "cleavable complex," as described for a number of topoisomerase II poisons (Burden et al., 1999; Boos and Stopper, 2000; Corbett and Osheroff, 1993; Nelson et al., 1984; Robinson and Osheroff, 1990)
UVA irradiation of FQs results in the formation of reactive oxygen species, and this effect has been proposed as a possible mechanism involved in FQ photochemical toxicity (Martínez et al., 1998; Robertson et al., 1991; Umezawa et al., 1997) and genotoxicity (Rosen et al., 1996; Spratt et al., 1999). Our experiments, using the antioxidant TEMPO or conducted under a nitrogen atmosphere, excluded the involvement of this mechanism in topoisomerase inhibition and DNA cleavage by y3118. Moreover, in previous experiments using high fluences of UVA in which oxidative damage is produced, Lmx was more efficient than y3118 in producing DNA strand breaks in pBR322 (Spratt et al., 1999), in contrast to the greater inhibitory activity of y3118 in the present experiments. Nevertheless, the overall photochemical genotoxicity of a particular FQ may involve DNA oxidation as well as inhibition of topoisomerase II.
In summary, the photochemical genotoxic effects of some, but not all FQs could be attributed to their capacity to inhibit the topoisomerase II enzyme with UVA irradiation. Thus, in the elucidation of the overall mechanism of photochemical genotoxicity, investigation of DNA binding, oxidative DNA damage, and inhibition of topoisomerases and possibly other enzymes, such as DNA repair enzymes, will be required.
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ACKNOWLEDGMENTS |
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The authors thank Bayer Pharmaceuticals (Wüppertal, Germany) for providing cold and radiolabeled FQs used in this study. This project was supported by National Cancer Institute Grant No. RO1CA86056.
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NOTES |
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1 To whom correspondence should be addressed. Fax: (914) 594-3113. E-mail: carmen_perrone{at}nymc.edu.
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