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Mutagenic activity of idarubicin and epirubicin in the bacterium Salmonella typhimurium.

Abstract. -- Idarubicin (structural analogue of daunomycin) and epirubicin (epimer of adriamycin) are two "second-generation" anthracyclines that are widely used in chemotherapy against leukemias and metastatic breast tumors, respectively. This study shows that using the Salmonella Mutagenicity Assay that idarubicin, like daunomycin, can induce frameshift (TA98; 16.1 fold), GC to AT (TA7004; 8.7 fold), and AT to GC base-substitution transition mutations (TA7001; 2.8 fold). Epirubicin, like adriamycin, can also induce frameshift (19.7 fold) and GC to AT transition mutations (14.6 fold) in this assay. Interestingly, epirubicin, but not adriamycin, can induce AT to GC mutations (2.9 fold) in this assay.

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Anthracycline antibiotics, primarily daunomycin and adriamycin, have been utilized in clinical practice since the 1960's and represent one of the most commonly used classes of anticancer drugs against leukemias and solid tissue tumors (reviewed by Sinha & Politi 1990; Hande 1998; Gewirtz 1999; Ogura 2001; Felix 2001). However, these highly active chemotherapeutic agents are also associated with acute cardiotoxic effects and a dose-related cardiomyopathy (reviewed by Hortobagyi 1997; Keefe 2001). Extensive efforts since 1972 have resulted in the replacement of these parent compounds with less toxic "second-generation" structural analogues (reviewed by Arcamone 1984; Carella et al. 1990; Fields & Koeller 1991; Hollingshead & Faulds 1991; Borchmann et al. 1997; Platel et al. 1999). Among these new compounds, 4-methoxy-daunorubicin (idarubicin), a structural analogue of daunomycin, was shown to be effective against acute nonlymphocytic leukemias with reduced cardiotoxic effects in clinical trials (Cersosimo 1992; Bogush & Robert 1996; Andersson et al. 1999; Lee et al. 2001). Similarly, 4'-epidoxorubicin (epirubicin), a 4'-epimer of adriamycin, is now widely used against early and metastatic breast cancers (Ganzina 1983; Weiss 1992; reviewed by Hortabagyi 2000; Razis & Fountzilas 2001; Trudeau & Pagani 2001).

It is known that anthracyclines (particularly the sugar moiety of the compound) can interfere with a number of biochemical and biological functions in the cell. Several studies strongly suggest that membrane binding and poisoning of topoisomerase II activity are possible modes of action for these anticancer antibiotics (Binaschi et al. 1998; Arcamone et al. 1999; Guano et al. 1999; Zunino at al. 2001). However, numerous studies also suggest that the biological activity of these drugs correlate with DNA binding with a preference to the GC bases (Fenick et al. 1997; Taatjes et al. 1997; Davies et al. 2000; Eaton et al. 2000; Qu et al. 2001). Several studies have demonstrated that anthracyclines are mutagenic in prokaryotic and eukaryotic cells (Marzin et al. 1983; Babudri et al. 1984; Olinski et al. 1997; El-Mahdy & Othman 2000; Mackay et al. 2000; Mackay & Phelps 2001). However, the mutagenicity of anthracyclines has been underestimated in the past, partly since these drugs are only "slightly" mutagenic in microbial assays (Kaldor et al. 1986; Tominaga 1986; Bokemeyer & Schmoll 1995). More recently, however, it has been suggested that the mutagenic properties of anthracyclines during tumor treatment may result in secondary cancers following chemotherapy (Olinski et al. 1997; 1998; Baguley & Ferguson 1998; Vakeva et al. 2000). Thus, it is very important to fully characterize both the mutational spectrum and the mutagenic specificity of anthracyclines as a first step to better understand the antitumor and possible precarcinogenic effects of these compounds.

Efforts in this laboratory have focused primarily in defining the mutagenic specificity of anthracyclines using prokaryotic genotoxicity assays. The use of bacterial mutation assays is now firmly established both for fundamental studies in mutagenesis and carcinogenesis, and for screening chemicals and environmental samples for genotoxic properties. The most used and validated bacterial reverse-mutation assay is the Salmonella Mutagenicity Assay (reviewed by Mortelmans & Zeiger 2000). The original Ames tester strains (i.e., TA98, TA100, etc.) identified mutagens which reverted point mutations in the his operon of Salmonella typhimurium. Although the Salmonella Mutagenicity Assay has been widely used to screen chemicals for potential genotoxicity, it was not originally designed to yield information about the precise nature of the hi[s.sup.+] revertants that were obtained. For example, TA100 detects primarily GC to AT events, but this strain can also detect GC to TA and extragenic tRNA suppressor mutations (Koch et al. 1994). TA98 is a tester strain that detects compounds that induce frameshift mutations (Maron & Ames 1983). A new set of Salmonella strains was subsequently generated to identify specific base-substitution events (Gee et al. 1994; 1998). Since each strain can only revert by a single specific mutational event, it is not necessary to further classify or sequence the resulting revertants in order to know the mutation that has occurred.

Previous studies in this laboratory have shown that daunomycin can induce both frameshift and base-substitution transition mutations in Salmonella typhimurium (Mackay et al. 2000), while adriamycin induces frameshift and GC to AT transition events (Mackay & Phelps 2001). Interestingly, although adriamycin is structurally very similar to daunomycin, it does not induce AT to GC mutations in this assay (Mackay & Phelps 2001). The present study was initiated to examine if the "second-generation" structural analogues of daunomycin and adriamycin, namely idarubicin and epirubicin, could induce frameshift and transition mutations. This report demonstrates that both compounds can induce frameshift, GC to AT, and AT to GC transition events in Salmonella typhimurium.

MATERIALS AND METHODS

Bacterial strains. -- The strains and their genotypes used in this study are listed in Table 1. TA98 detects frameshift mutations (Maron & Ames 1983). TA7001 and TA7004 are base-substitution specific strains, which carry a target missense mutation in the hisG gene. The latter two strains revert to a prototrophic hi[s.sup.+] phenotype via a specific base-substitution event (TA7001, AT to GC, and TA7004, GC to AT) (Gee et al. 1994; 1998).

Chemicals. -- Adriamycin (doxorubicin hydrochloride), dimethyl sulfoxide (DMSO), ICR 191 acridine mutagen (6-chloro-9-[3-(2-chloroethylamino)propylamino]-2-methoxyacridine), [N.sup.4]-aminocytidine (N4AC), 4-nitroquinoline-N-oxide (4NQO) and streptonigrin (STN) were obtained from Sigma Chemical Co. (St. Louis). Idarubicin (Idamycin[R]) and epirubicin (Ellence[TM]) were obtained from the Erie Cancer Research Center.

Mutation assays. -- The his reversion assays (triplicate assays were conducted for each strain) followed a modified version of the traditional Ames "plate-incorporation" test (Maron & Ames 1983) which utilized a pre-incubation step in order to increase the sensitivity of the strains to each anthracycline compound and has been previously described (Mackay et al. 2000; Mackay & Phelps 2001). Very briefly, 110 [micro]L (approximately 2.0 X 1[0.sup.8] cells) of a stationary phase S. typhimurium culture (TA98, TA7001, TA7004) was exposed to either daunomycin, idarubicin, adriamycin, or epirubicin (120 [micro]g/mL) for 30 minutes in a shaking incubator (250 rpm) at 37[degrees]C. 100 [micro]L of this culture was plated onto minimal agar plates that contained 2% glucose, 0.05 mM L-histidine, and 0.005 mM biotin. These selective plates were incubated at 37[degrees]C, and the numbers of hi[s.sup.+] revertants were scored after 48 hr. For each strain, a "zero" control (culture that was not exposed to the experimental chemical) was included in order to estimate the number of spontaneous hi[s.sup.+] revertants in each experiment. The total number of viable cells in each experiment was determined by plating serial dilutions onto nonselective plates (Luria-Bertani, DIFCO). Mutation frequency is expressed as the average number of hi[s.sup.+] revertants on selective plates divided by the total number of viable cells (determined by the number of colonies on the non-selective plates).

Positive control chemicals. -- The Salmonella strains TA98, TA7001, and TA7004 were tested using positive control chemicals that are known to be mutagenic in this assay (Maron & Ames 1983; Gee et al. 1998; Christopher Sommers pers. comm.). ICR 191 was prepared in DMSO (4.0 [micro]g/plate) and used as a positive control for TA98. STN, dissolved in DMSO (50 [micro]g/plate), and N4AC, prepared in sterile deionized water (10 [micro]g/plate) were used as positive controls for TA7001. 4NQO, dissolved in DMSO (0.4 [micro]g/plate), and N4AC (10 [micro]g/plate) were used as positive controls for TA7004.

RESULTS AND DISCUSSION

Previous studies in this laboratory have shown that daunomucin and adriamycin can induce frameshift (i.e., TA98) and GC to AT base-substitution mutations (i.e., TA7004) in the bacterium Salmonella typhimurium (Mackay et al. 2000; Mackay & Phelps 2001). Daunomycin also can induce AT to GC events (i.e., TA7001) in this assay (Mackay et al. 2000). However, adriamycin, a compound that is structurally very similar to daunomycin, did not induce AT to GC mutations in Salmonella (Mackay & Phelps 2001). This current study demonstrates that idarubicin and epirubicin, "second-generation" structural analogues of daunomycin and adriamycin, respectively, can induce frameshift and specific base-substitution transition events.

The Ames tester strains are listed in Table 1. Each Salmonella strain (i.e., TA98, TA7001, TA7004) was first verified using selected positive control chemicals, which have been shown to be mutagenic by Gee et al. (1994; 1998; Sommers, pers. comm.).

Strains TA98, TA7001 and TA7004 were exposed to daunomycin, idarubicin, adriamycin, or epirubicin (120 [micro]g/ml). The number of hi[s.sup.+] revertants were monitored on selective minimal glucose plates and total number of cells on nonselective plates. Following the calculation of the total number of viable cells, it was possible to calculate a mutation frequency for each strain tested (in triplicate). Mutation frequency is expressed as the average number of hi[s.sup.+] revertants on selective plates divided by the total number of viable cells. The results of this study are summarized in Tables 2 and 3. TA98 was highly mutable (mutation induction folds ranged from 15.4 to 44.5; [chi square]: p<0.005) when exposed to daunomycin, idarubicin, adriamycin, or epirubicin in this assay. These results demonstrate that the "second-generation" structural analogues, idarubicin and epirubicin, also induced frameshift mutations in this assay. The two base-substitution Ames strains (TA7001, AT to GC; TA7004, GC to AT) were mutable in the presence of daunomycin (mutation induction folds ranged from 7.3 to 7.6; [chi square]: p<0.005), while TA7004 was mutable in the presence of adriamycin (mutation induction fold 7.8; [chi square]: p<0.005). As expected from previous studies, adriamycin did not induce AT to GC (TA7001) mutations (mutation induction fold 1.1; [chi square]: p>0.10) in this assay. Mutation frequencies were also determined for TA7001 and TA7004 in the presence of the "second-generation" anthracycline structural analogues, idarubicin and epirubicin. Both strains were mutable in the presence of either compound (mutation induction folds ranged from 2.8 to 14.6; [chi square]: P<0.01). Thus, while adriamycin does not induce AT to GC mutations in Salmonella, the 4'-epimer of this compound, epirubicin, is mutagenic for this transition event.

Several biochemical analyses suggest that the interaction(s) between anthracyclines, primarily daunomycin and adriamycin, and DNA are complex in nature (Davies et al. 2000; Eaton et al 2000; Qu et al. 2001). Anthracyclines can form DNA crosslinks in vivo (Skladanowski & Konopa 1994) and with GC base pairs, specifically a (GC[).sub.4] oligo-nucleotide, in vitro with formaldehyde (Taatjes et al. 1997; Fenick et al. 1997). The primary mode of action (antitumor effect) of anthracyclines appears to be the intercalation of the aglycone portion of the compound between adjacent DNA base pairs, and this activity results in topoisomerase-induced DNA strand breaks (Liu 1989; Baguley & Ferguson 1998; Zunino et al. 2001). Alkylation of DNA and the production of reactive oxygen species have also been reported to cause DNA modifications during anthracycline chemotherapeutic treatments (Bokemeyer & Schmoll 1995; Olinski et al. 1997). This DNA damage has been found to possess premutagenic properties and, if not repaired, may contribute to carcinogenesis (Bokemeyer & Schmoll 1995; Olinski et al. 1998).

The amino sugar is recognized to be a critical determinant of the antitumor activity of daunomycin and adriamycin. In an attempt to improve the pharmacological properties of these anticancer drugs, novel anthracyclines have been designed with altered amino sugars. Epirubicin differs from adriamycin by the epimerization of the OH group in position 4' of the aminosugar moiety and has been shown to be less toxic during chemotherapeutic treatments against metastatic breast cancers (Ganzina 1983; reviewed by Hortabagyi 2000). Idarubicin, a 4-demthoxy-anthracycline analogue of daunomycin, exhibits several features, which render this drug unique among anthracyclines against acute nonlymphocyctic leukemia. Its higher lipophilicity leads to faster accumulation within the nucleus, superior DNA-binding capacity, and consequently, a greater antitumor effect when compared to daunomycin (Borchmann et al. 1997). Furthermore, idarubicin can be administered orally at effective plasma concentrations and exhibits reduced cardiotoxicity when administered at therapeutic doses (Cerosimo 1992; Weiss 1992).

These mutational analyses also suggest that the interaction(s) between these anthracyclines and the DNA helix might indeed be very complex. Daunomycin and idarubicin exhibit similar mutagenic effects in Salmonella (Table 2). However, the slight differences in structure between adriamycin and epirubicin give rise to different mutational spectra in this assay. Both compounds can induce GC to AT transition mutations (Mackay & Phelps 2001; this report). However, unlike epirubicin, which can also induce AT to GC mutations (Table 3), adriamycin is not mutagenic with TA7001 in the Salmonella Mutagenicity Assay (Mackay et al. 2000). These results suggest that there may exist small chemical differences between the binding of each antibiotic with DNA and also suggest that unique interactions of epirubicin and adriamycin with DNA might provide an explanation for the significantly different clinical activities of the two anticancer drugs.

The incidence of many secondary cancers has been linked to high doses of chemotherapy (Kaldor et al. 1987; Swendlow et al. 1992; Olinski et al. 1997, 1998; Allen et al. 1998; Baguley & Ferguson 1998; Vakeva et al. 2000). In order to improve the clinical efficacy of anti-neoplastic anthracycline compounds (i.e., daunomycin, adriamycin, epirubicin and idarubicin) during chemotherapy, it will be necessary to identify modulators of their activities that could potentially be exploited to sensitize target tissues to therapy or to protect nontarget tissues during therapy. Such modulators include metabolic activation pathways and DNA repair pathways.

Anthracyclines can induce DNA crosslinks (Cullinane & van Rosmalen 1994; Cullinane et al. 2000). All cells have base excision repair mechanisms, which can recognize and remove cross-linking base adducts. For example, 3-methyladenine DNA glycosylase (Aag) recognizes and removes a variety of these DNA adducts (e.g., groups that can attach at the N7 and N3 positions of the purine ring) (reviewed by Seeberg et al. 2000). Escherichia coli mutants (alkA tag), which lack Aag activity, are extremely sensitive to killing in the presence of monofunctional (for example, methylmethanesulfonate) and complex (for example, BCNU) alkylating agents (Evensen & Seeberg 1982; Clarke et al. 1984; Engelward et al. 1996). Furthermore, addition of a mouse gene, which encodes Aag, to alkA tag cells, restores partial resistance to cell killing in the presence of several alkylating and DNA cross-linking agents (Engelward et al. 1993). Future endeavors within this laboratory will determine if a base-excision repair pathway that includes Aag can recognize and repair anthracycline-induced DNA cross-links. Hopefully, these results may lead to a lessening of the detrimental effects of anthracycline compounds and/or increased antitumor efficacies of these drugs in future cancer chemotherapeutic treatments. These experiments are currently in progress.
Table 1. Ames Salmonella strains.

Strain Genotype Mutation Detected

TA7001 hisG1775 [DELTA]ara9 [DELTA]chl1004 A:T to G:C
 (bio chlD uvrB chlA) galE503
 rfa1041/pKM101

TA7004 hisG9133 [DELTA]ara9 [DELTA]chl1004 G:C to A:T
 (bio chlD uvrB chlA) galE503
 rfa1044/pKM101

TA98 hisD3052 [DELTA]ara9 [DELTA]chl1008 frameshift
 (bio chlD uvrB gal) rfa1004/pKM101
 (-1 C)

Table 2. Daunomycin/Idarubicin mutation frequencies of Ames Salmonella
stains.

Strain Spontaneous Mutation
 Frequency (S)

TA7001 0.9 ([+ or -] 0.1) X 1[0.sup.-8]
TA7004 0.8 ([+ or -] 0.1) X 1[0.sup.-7]

 TA98 1.1 ([+ or -] 0.3) X 1[0.sup.-7]

Strain Induced Mutation Induced Fold
 Frequency (I) (daunomycin)
 (120 [micro]g/ml daunomycin) (I/S)

TA7001 6.6 ([+ or -] 0.1) X 1[0.sup.-8] 7.3
TA7004 6.1 ([+ or -] 0.6) X 1[0.sup.-7] 7.6

 TA98 4.9 ([+ or -] 0.5) X 1[0.sup.-6] 44.6

Strain Induced Mutation Induced Fold
 Frequency (I) (idarubicin)
 (120 [micro]g/ml idarubicin) (I/S)

TA7001 2.6 ([+ or -] 0.1) X 1[0.sup.-8] 2.8
TA7004 7.0 ([+ or -] 0.1) X 1[0.sup.-7] 8.7

 TA98 1.8 ([+ or -] 0.3) X 1[0.sup.-6] 16.1

Table 3. Adriamycin/Epirubicin mutation frequencies of Ames Salmonella
stains.

Strain Spontaneous Mutation
 Frequency (S)

TA7001 0.9 ([+ or -] 0.1) X 1[0.sup.-8]
TA7004 0.8 ([+ or -] 0.1) X 1[0.sup.-7]
 TA98 1.1 ([+ or -] 0.3) X 1[0.sup.-7]

Strain Induced Mutation Induction Fold
 Frequency (I) (adriamycin)
 (120 [micro]g/ml adriamycin) (I/S)

TA7001 1.0 ([+ or -] 0.1) X 1[0.sup.-8] 1.1
TA7004 6.2 ([+ or -] 0.7) X 1[0.sup.-7] 7.8
 TA98 1.7 ([+ or -] 0.4) X 1[0.sup.-6] 15.4

Strain Induced Mutation Induction Fold
 Frequency (I) (epirubicin)
 (120 [micro]g/ml epirubicin) (I/S)

TA7001 2.6 ([+ or -] 0.1) X 1[0.sup.-8] 2.9
TA7004 1.2 ([+ or -] 0.1) X 1[0.sup.-6] 14.6
 TA98 2.2 ([+ or -] 0.3) X 1[0.sup.-6] 19.7


ACKNOWLEDGMENTS

The authors wish to thank Dr. Christopher Sommers for sharing his unpublished results and Dr. Susan Rosendahl for idarubicin and epirubicin. This research was partly supported by a Beta Beta Beta Foundation Research Scholarship to the senior author.

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John M. Brumfield and William J. Mackay

Edinboro University of Pennsylvania

Department of Biology & Health Services

Edinboro, Pennsylvania 16444

WJM at: bamackay@erie.net
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Author:Brumfield, John M.; Mackay, William J.
Publication:The Texas Journal of Science
Geographic Code:1U7TX
Date:Aug 1, 2002
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