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Chloroquinoxaline Sulfonamide (NSC 339004) Is a Topoisomerase II/ß Poison¹

Departments of Radiology [H. G., E. F. Y., R. M. S.]; Molecular Virology, Immunology and Medical Genetics [H. G., R. M. S.]; College of Medicine [H. G., E. F. Y., R. M. S., K. K. C.]; and College of Pharmacy [K. K. C.], Ohio State University, Columbus, Ohio 43210, and Abbott Laboratories, Abbott Park, Illinois 60064 [L. L. S.]

	ABSTRACT

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Chloroquinoxaline sulfonamide (chlorosulfaquinoxaline, CQS, NSC 339004) is active against murine and human solid tumors. On the basis of its structural similarity to the topoisomerase IIß-specific drug XK469, CQS was tested and found to be both a topoisomerase-II and a topoisomerase-IIß poison. Topoisomerase II poisoning by CQS is essentially undetectable in assays using the common protein denaturant SDS, but easily detectable with strong chaotropic protein denaturants. The finding that detection of topoisomerase poisoning can be so dependent on the protein denaturant used in the assay has implications for drug discovery efforts and for our understanding of topoisomerase poisons.

	Introduction

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CQS³ is a structural analogue of sulfaquinoxaline, a compound used to control coccidiosis in poultry, rabbit, sheep, and cattle (Fig. 1) . CQS was selected for clinical development based on good activity against human tumor cells in the human tumor colony-forming assay (1) and subsequently has shown activity against murine and human solid tumors (1 , 2) . Although CQS has been under study for over a decade and is completing Phase I trial (2) and currently moving into Phase II trial, its mechanism has not been determined (3 , 4) . Sulfaquinoxalines have been reported to possess antifolate activity (5) , but antifolate activity has been ruled out for CQS (6 , 7) . CQS was also found not to intercalate into DNA (6) . CQS bears a gross structural resemblance to another solid-tumor-specific agent, XK469 (NSC 697889), in that both possess chloroquinoxaline rings attached to a small aromatic ring with an acidic function (Fig. 1) . XK469, an herbicide analogue, is in the late stage of preclinical development. Similar to CQS, several common mechanisms of biological activity had been ruled out for XK469, including antimetabolite activity, DNA and tubulin binding, alkylation, and protein kinase inhibition (8) . Because we have recently found that XK469 is a selective topoisomerase IIß poison (9) , we tested CQS for inhibition of topoisomerases and found it to be both a topoisomerase II and topoisomerase IIß poison. Detection of topoisomerase poisoning by CQS requires strong chaotropic protein denaturants, such as GuHCl or urea, rather than the more commonly used detergent, SDS.

View larger version (24K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Structures of sulfaquinoxaline, CQS, and XK469.

	Materials and Methods

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Drugs and Enzymes.
CQS (NSC 339004) was provided by Dr. R. Shoemaker, National Cancer Institute. VM-26 (teniposide, NSC 122819) was obtained from the National Cancer Institute Division of Cancer Treatment, Natural Products Branch. DMSO was the solvent for all drug stocks. Purified human topoisomerase II was from TopoGen (Columbus, OH) and LLS (Abbott Laboratories, Abbott Park, IL). Purified topoisomerase IIß was a gift of Dr. Caroline Austin (University of Newcastle, Newcastle upon Tyne, United Kingdom).

Filter Assay for in Vitro Topoisomerase-DNA Cross-links.
The GF/C filter assay for protein-SV40 DNA cross-links is used to measure topoisomerase poisoning in vitro with purified enzymes and DNA substrates (9) . SV40-infected cells were labeled with [³ H]dThd (Amersham Pharmacia Biotech, Piscataway, NJ) at 36 h postinfection (100 µCi/ml, 2 h). Labeled SV40 DNA was isolated using a Midi Plasmid isolation kit (QIAGEN, Valencia, CA). DNA (12,000 dpm) was equilibrated with or without drugs in 10 mM Tris-HCl, 50 mM KCl, 5 mM MgCl₂, 0.1 mM EDTA, 15 µg/ml BSA and 1 mM ATP for 5 min at 37°C. The reactions were started by addition of the topoisomerase II or topoisomerase IIß and were incubated 30 min at 37°C. Various amounts of CQS were included in separate reactions, keeping the solvent volume constant. Reactions were stopped by adding SDS (1% final concentration), GuHCl (0.4 M final concentration), or urea (0.8 M final concentration). These protein denaturants inactivate topoisomerases trapped in topoisomerase-DNA cleavage complexes by topoisomerase poisons and thus render the covalent topoisomerase-DNA cross-links irreversible. To assay protein cross-links to SV40 DNA, duplicate aliquots of the reaction were mixed with 0.4 M GuHCl buffer [0.4 M GuHCl, 10 mM Tris-HCl, (pH 8.0), 10 mM NaEDTA, 0.01% sarkosyl, and 0.3 M NaCl] and 4.0 M GuHCl, respectively, and then filtered through prewetted GF/C glass fiber filters (Whatman, Clifton, NJ; Ref. 9 ). In 4.0 M GuHCl (DNA-binding conditions), all nucleic acids bind to the filter. The radioactivity retained on the filter under DNA binding conditions gives the value for total labeled DNA in the aliquot. In 0.4 M GuHCl buffer (protein-binding conditions), the labeled DNA retained on the filter is DNA cross-linked to the topoisomerase. The ratio of the radioactivity retained on GF/C filters in 0.4 M GuHCl buffer to the radioactivity retained on filters in 4.0 M GuHCl gives the fraction of labeled DNA that is cross-linked to the topoisomerase. A single covalently cross-linked protein is sufficient to cause the retention of a DNA molecule as large as the adenovirus genome (35,937 bp) on the filter under protein-binding conditions (10) . In the absence of added topoisomerase or drugs (reaction buffer with [³ H]dThd-labeled SV40 DNA), approximately 1–2% of the substrate DNA is retained on the filters in 0.4-M GuHCl buffer (protein-binding conditions). Because as there is some variability in the specific activity of topoisomerase preparations, the assay is adjusted for each batch of topoisomerase. Sufficient topoisomerase II is added to the reaction for 2–3% SDS-induced topoisomerase-DNA cross-linking in the presence of the drug solvent (DMSO) alone. This concentration of topoisomerase thus results in steady-state levels of topoisomerase-DNA cleavage complexes sufficient for detection in the absence of topoisomerase poisons. A value of 4–5% cross-linking in the absence of added topoisomerase poisons is thus attributable to 1–2% nonspecific DNA binding to the filter and 2–3% background topoisomerase II-DNA cleavage complexes. Drug-induced topoisomerase-DNA cross-links above this value are taken as a measure of topoisomerase poisoning. Each drug studied is also tested in reaction buffer without topoisomerase to ensure that it does not cause DNA binding to the GF/C filter in 0.4 M GuHCl buffer. When GuHCl is used to stop the topoisomerase reaction, the topoisomerase-DNA cross-linking value for the "solvent only" (i.e., no drug) control is always slightly higher than it is for an identical reaction stopped by the addition of SDS. This may be attributable to more rapid protein denaturation by the chaotropic denaturant GuHCl, resulting in more efficient trapping of topoisomerase-DNA cleavage complexes.

Filter Assay for Cellular Protein-DNA Cross-links.
CV-1 cells in early confluence were labeled with [³ H]dThd (1.0 µCi/ml, 43 h) by adding label directly to the medium. Drug treatments were carried out for 15 min on the cells. Then the medium was removed, and the cells were lysed with 6 M GuHCl. The lysate (500 µl) was transferred to a 1.5-ml microcentrifuge tube containing a small stainless steel nut, the tube capped securely, and the DNA sheared by vortexing for 15 s. The lysate then was heated at 65°C for 10 min to ensure denaturation and removal of noncovalently attached proteins from the DNA. After cooling to room temperature, aliquots of the lysate were assayed with the GF/C filter assay for the percentage of labeled DNA that is cross-linked to protein as in the assay for protein-SV40 DNA cross-links. As in the in vitro assay for topoisomerase-DNA cross-links (above), GF/C glass fiber filter binding in 4 M GuHCl gives a value for the total radiolabeled DNA in the aliquot, and the filter-binding in 0.4 M GuHCl buffer gives a value for protein-DNA cross-links. A variation of this assay, in which SDS is used to lyse the cells and render topoisomerase-DNA cleavage complexes irreversible, has been described (9) . In the SDS-lysis-based assay, the level of protein-DNA cross-linking in the absence of added topoisomerase poisons is typically 5–10%. Proteinase K digestion of such lysates reduces the level of cross-linking to 1–2%. This suggests that a 5–10% value for protein-DNA cross-linking in the absence of added topoisomerase poisons represents 1–2% because of nonspecific DNA binding to filters (similar to the in vitro assay described above) and 3–8% because of trapping of endogenous topoisomerase-DNA cleavage complexes. In contrast to the in vitro assay, where a single purified topoisomerase is added to the reaction mix, the background protein-DNA cross-linking value in cells is assumed to represent trapped topoisomerase-DNA cleavage complexes of a number of different type-I and type-II topoisomerases active in the intact cells. Thus, topoisomerase poisoning measured in this in vivo assay may represent poisoning of more than one topoisomerase isozyme.

Topoisomerase II-Induced DNA Cleavage Reaction.
A 516-bp DNA substrate (residues 3846–4362 in pBR322) was labeled on one end as follows: pBR322 plasmid DNA was digested with EcoRI and ScaI to generate a fragment with one blunt end and one sticky end. The DNA fragment was purified by agarose gel electrophoresis, band excision, and a Gel Extraction kit (QIAGEN). The overhang end was labeled with ³²P in a 40-µl reaction containing 50 mM Tris-HCl (pH 7.5), 10 mM MgCl₂, 1 mM DTT, 50 µg/ml acetylated BSA, 0.25 mM of each deoxynucleotide (dGTP, dCTP, dTTP), and 70 µCi [-³²P]dATP (800 Ci/mmol) and Klenow fragment (5 units, USB Corp. Cleveland, OH). After a 15-min incubation at 37°C, unlabeled dCTP, dGTP, dTTP, and dATP were added (10 nM of each), and the incubation was continued for an additional 15 min before termination by heating at 70°C for 10 min. The end-labeled DNA fragment was then purified with a mini-Quick Spin DNA column (Roche, Indianapolis, IN).

For assay of topoisomerase II-dependent DNA cleavage, reactions contained end-labeled DNA fragments (50,000 dpm/reaction), 10 mM Hepes-HCl (pH 7.9), 50 mM KCl, 5 mM MgCl₂, 50 mM NaCl, 0.1 mM Na₂EDTA, and 1 mM ATP. After a 5-min preincubation at 37°C, the reaction was started by addition of 1.2 µg of purified human topoisomerase II (total reaction volume, 20 µl). The reaction mix was incubated at 37°C for 30 min before being terminated by the addition of 2 µl of 4 M GuHCl. The DNA was purified by ethanol precipitation, then resuspended in 28 µl of proteinase K solution (0.2 mg/ml, 2 h, 45°C). The DNA was repurified by ethanol precipitation before resuspension in 4 µl of loading buffer (80% formamide, 10 mM NaOH, 1 mM EDTA, 0.1% xylene cyanol, and 0.1% bromphenol blue). Samples were heated to 95°C for 5 min, cooled to room temperature, and then loaded onto a DNA sequencing gel (8% polyacrylamide, 19:1 acrylamide/bisacrylamide) containing 7 M urea in 1 x Tris-borate/EDTA buffer (11) . Electrophoresis was performed at 1,400 V for 1.5 h. The gel was transferred to Whatman No. 3 MM paper and exposed to Hyperfilm-MP (Amersham Pharmacia Biotech).

Cytotoxicity Assay.
The MTT reduction assay (12 , 13) was used to determine the cytotoxicity of CQS for CV-1 cells. In this assay, a tetrazolium salt, MTT, was used as a colorimetric substrate for measurements of cell viability. Cells were plated at a density of 2.5 x 10⁴ cells/well in 96-well tissue culture plates, and then incubated at 37°C in MEM medium with 10% FCS. After 24 h incubation, different concentrations of drug were added, and incubation was continued for another 3 days. MTT was then added to a final concentration of 0.5 mg/ml and the incubation was continued for 5 h at 37°C. The medium was then replaced with 100% N,N-dimethylformamide (100 µl/well), and the plates were left at 37°C for another 2 h. Then, colorimetric analysis at 550 nm was done. Values in the presence of the drug solvent alone were used as the blank control.

	Results and Discussion

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CQS caused dose-dependent protein-DNA cross-links to CV-1 monkey kidney cell chromosomal DNA when drug treatment was terminated by lysis with GuHCl (Fig. 2) . The mM concentration range is achievable clinically. In an early Phase I clinical trial at an i.v. dose of 4060 mg/m² every 28 days, peak plasma concentrations of higher than 1 mM (>500 µg/ml) was achieved (14) . In a subsequent Phase I clinical trial using a 2000-mg/m² dose weekly for 4 weeks, plasma concentration at >0.3 mM (or >100 µg/ml) concentrations was found (2) . The CQS IC₅₀ for CV-1cells, obtained using an MTT cytotoxicity assay, was 1.8 mM (data not shown). CQS lacks functional groups that would make it a bifunctional protein-DNA cross-linking agent, and the short drug exposure (15 min) allows little time for metabolism. When the same assay was done using SDS for cell lysis, no CQS-induced protein-DNA cross-links were detected. Because dose-dependent protein-DNA cross-linking is also characteristic of topoisomerase poisons, we tested CQS against purified topoisomerase II and IIß in an in vitro assay for topoisomerase poisoning. As shown in Fig. 3A , CQS caused cross-linking of both human topoisomerase II isozymes to the substrate DNA in a concentration-dependent manner when GuHCl was used to terminate the reaction but not when SDS was used to terminate the reaction. Because SDS is negatively charged and GuHCl is positively charged at physiological pH, they were compared with another protein denaturant, urea, which is uncharged at physiological pH. Urea, like GuHCl, proved to be an efficient protein denaturant for detection of topoisomerase II poisoning by CQS (Fig. 3B) . For additional confirmation of topoisomerase poisoning, we tested CQS with human topoisomerase II in a DNA cleavage assay using a ³²P-end labeled DNA substrate. As shown in Fig. 4 , CQS stabilized topoisomerase II cleavages. The strong topoisomerase II/IIß poison, VM-26, at a lower concentration, stabilized topoisomerase II cleavages at more sites on the same substrate DNA.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. CQS-induced protein-DNA cross-links in CV-1 cells. CV-1 monkey kidney cells in early confluence were labeled with [3H]dThd for 43 h by adding the label directly to the medium. The cells were treated with CQS for 15 min. The medium and drug were removed and the cells lysed with 6 M GuHCl. The lysate was vortexed as described (9) to reduce the DNA size by shearing. Aliquots of the cell lysate were then assayed for protein DNA cross-links using the GF/C filter assay. A 7% background binding, seen in the absence of CQS, has been subtracted from each measurement (see "Materials and Methods").

View larger version (22K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. CQS-induced topoisomerase II-DNA cross-links. A, purified [3H]dThd-labeled SV40 DNA was incubated with purified topoisomerase II (TopoGen batch AP 159) or topoisomerase IIß in the presence of CQS at the concentrations indicated. The reactions were stopped by the addition of GuHCl (, topoisomerase II; , topoisomerase IIß) or SDS (•, topoisomerase II; , topoisomerase IIß) and assayed for topoisomerase-DNA cross-links. B, [3H]dThd-labeled SV40 DNA was incubated with purified human topoisomerase II (TopoGen batch FB 1400) either with CQS (1 µg/ml, white bars) or without CQS (black bars); the reactions were stopped with the indicated protein denaturants and assayed for topoisomerase-DNA cross-links.

View larger version (73K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. Stimulation of topoisomerase II-DNA cleavage by CQS and VM-26. A uniquely 32P-end-labeled 516-bp restriction fragment of pBR322 was incubated with human topoisomerase II alone, topoisomerase II with 100 µM VM-26, or topoisomerase II with 3.3 mM CQS (37°C, 30 min). The reactions were terminated by the addition of GuHCl. DNA was purified from each sample, denatured by heating at 95°C in 80% formamide, 10 mM NaOH, 1 mM EDTA, cooled, and loaded on a DNA sequencing gel for electrophoretic separation of cleaved DNA. Lanes marked "DNA" included the substrate DNA in identical reaction mixtures, but without topoisomerase. CQS did not cause DNA strand breaks in the absence of topoisomerase (not shown).

It is thought that topoisomerase poisons stabilize DNA strand-passing reaction intermediates in which the topoisomerase is covalently attached to the DNA at the site of a DNA strand break. Topoisomerase poison assays use protein denaturants to inactivate the topoisomerase while this reaction intermediate is stabilized by the drug. The DNA strand-passing intermediate is converted to an irreversible "protein-associated DNA strand break" by the protein denaturant. However, enzymatic inactivation of the topoisomerase by complete denaturation may not be an instantaneous process. Complete denaturation is likely to require interaction with a number of denaturant molecules. We propose that the binding of the first few molecules of SDS may alter the structure of CQS-stabilized topoisomerase II-DNA cleavage complexes so that they release the CQS molecule while retaining enough structure to carry out the religation step of the topoisomerase reaction. Denaturation caused by a stronger protein denaturant may inactivate the topoisomerases in CQS-stabilized DNA cleavage intermediates so rapidly that they cannot complete their reactions.

CQS and XK469 are both quinoxalines. Although there are significant differences in structure, there are also strong similarities that led us to test the topoisomerase activity of CQS. Both compounds share a quinoxaline ring that is linked to a parasubstituted phenyl ring with a bridge at the 2 position of the quinoxaline ring. These two compounds also possess acidic moieties. In CQS, the acidic sulfonamide function is located in the linker between the two ring systems, whereas the acidic propionic acid function of XK469 is exo to the ring system. Both molecules can adopt conformations that place the acidic function near the quinoxaline ring. CQS and XK469 also differ in the phenyl ring system, with CQS having a basic amino group that is absent in XK469.

XK469 and CQS represent the first members of a new quinoxaline class of topoisomerase II inhibitors. Because both drugs show solid tumor activity, this may be a general characteristic of the quinoxaline topoisomerase II poisons. Both drugs are very weak topoisomerase II poisons with low nonspecific cytotoxicity, so high therapeutic doses can be tolerated. Although XK469 is very selective for the ß isozyme of topoisomerase II (p180), CQS appears to target both the ß and the (p170) isozymes. The basis of isozyme selectivity for these drugs is not readily apparent, but it may be related to the differences in functionalities and/or regio-alignment with the quinoxaline ring. Additional insights into topoisomerase II isozyme selectivity may be accomplished through structure-activity studies.

	ACKNOWLEDGMENTS

 
We thank TopoGen (Columbus, Ohio) for purified human topoisomerase II and Dr. Caroline Austin (University of Newcastle, United Kingdom) for purified human topoisomerase IIß.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by grants from the Public Health Service, NCI RO1 CA80961 to R. M. S., Contract NO1-CM-57201 to K. K. C., U01CA63185 to K. K. C. and R. M. S., and P30 CA16058 to The Ohio State University Comprehensive Cancer Center.

² To whom requests for reprints should be addressed, at Ohio State University, Department of Radiology, 103 Wiseman Hall, 400 West 12^th Avenue, Columbus, OH 43210. Phone: (614) 292-9375; Fax: (614) 292-7237.

³ The abbreviations used are: CQS, chloroquinoxaline sulfonamide; GuHCl, guanidinium chloride; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide.

Received 5/22/00. Accepted 9/13/00.

	REFERENCES

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