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Efficient Nucleotide Excision Repair of Cisplatin, Oxaliplatin, and Bis-aceto-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) PlatinumIntrastrand DNA Diadducts¹

Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7260

	ABSTRACT

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Tumors exhibit a spectrum of cellular responses to chemotherapy ranging from extreme sensitivity to resistance, either intrinsic or acquired. These variable responses are both patient and tumor specific. For platinum DNA-damaging agents, drug resistance depends on the carrier ligand of the platinum complex and is due to a combination of mechanisms including DNA repair. Nucleotide excision repair is the only known mechanism by which bulky adducts, including those generated by platinum chemotherapeutic agents, are removed from DNA in human cells. In this report, we show that the types of DNA lesions generated by three platinum drugs, cisplatin, oxaliplatin, and (Bis-aceto-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216), are repaired in vitro with similar kinetics by the mammalian nucleotide excision repair pathway.

	INTRODUCTION

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Nucleotide excision repair is a major pathway used by human cells for the removal of damaged or inappropriate bases from DNA (1 , 2) . In mammalian cells, this repair pathway is the only known mechanism for the removal of bulky, helix-distorting DNA adducts, such as those generated by certain chemotherapeutic agents, and it serves as a backup repair system for the removal of other lesions from DNA (3) . XP³ is a human disease caused by mutations in any of seven genes, XP-A through XP-G, and patients are predisposed to cancer due to specific defects in nucleotide excision repair (4) . Cell lines derived from XP patients are sensitive to UV light and to treatment with cisplatin (5) . The human nucleotide excision repair pathway uses 14 polypeptides purified as six repair factors for the initial steps of repair: XPA, RPA, XPC·HR23B, TFIIH, XPG, and XPF·ERCC1 (1, 2, 3) . These initial steps include: (a) damage recognition; (b) dual incisions both 5' and 3' to the damaged base(s); and (c) excision of 22–32 nucleotide-long oligomers containing the damage. Subsequent steps include resynthesis of DNA to fill-in the gap generated by damage excision and ligation of the newly synthesized DNA to the parental molecule.

Cisplatin is an effective chemotherapeutic agent for the treatment of testicular cancer and is used in combination regimens for a variety of other tumors, including ovarian, cervical, bladder, lung, and those of the head and neck (6) . Although many patients initially respond to treatment, a common problem is acquired resistance. This, as well as the intrinsic resistance observed in some patients, is multifactorial in nature and includes contributions from differential drug uptake, cellular detoxification systems, and DNA repair mechanisms (7 , 8) . The need for improved clinical protocols has prompted a search for new chemotherapeutic agents as well as a more complete understanding of the cellular mechanisms underlying resistance. Two new platinum compounds, oxaliplatin and JM216, show promise for the treatment of cisplatin-resistant tumors and are presently in clinical trials (6) . A recent report correlated the loss of DNA mismatch repair activity with enhanced sensitivity to cisplatin but not oxaliplatin or JM216 (9) . Nucleotide excision repair is also a major mechanism contributing to cisplatin resistance, and so we were curious as to whether this pathway discriminates between cisplatin, oxaliplatin, and JM216 adducts.

Several reports, using uniquely damaged circular or linear DNA as substrate and CFEs or highly purified proteins as the source of repair factors, have demonstrated that cisplatin adducts are removed from DNA during in vitro repair reactions (10, 11, 12) . In this study, we wanted to directly compare the in vitro repair of cisplatin, oxaliplatin, and JM216 lesions. To this end, we used a 140-bp linear duplex with a centrally located diadduct as substrate, CFE prepared from either human or rodent cell lines, and the excision assay to examine the repair of cisplatin, oxaliplatin, and JM216 diadducts. Excision assay substrate DNA has a ³²P label near the lesion, and following incubation with the full complement of repair factors, damage-containing oligomers are released as radiolabeled DNA fragments that are visualized after gel electrophoresis and autoradiography. The results presented here demonstrate that both the kinetics of repair and the mechanistic details of excision are similar for all three platinum lesions.

	MATERIALS AND METHODS

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Materials.
Cisplatin was obtained from Sigma Chemical Co. (St. Louis, MO), Pt(dach)Cl₂ was provided by Dr. S. D. Wyrick (School of Pharmacy, University of North Carolina), and JM118 was provided by Dr. C. F. J. Barnard (Johnson Matthey Technology Center, London, United Kingdom). Oligonucleotides for excision repair substrate preparation were obtained from Operon Technologies (Alameda, CA) or the Lineberger Comprehensive Cancer Center Nucleic Acids Core Facility (Chapel Hill, NC). T4 polynucleotide kinase and T4 DNA ligase were purchased from New England Biolabs (Beverly, MA), T4 DNA polymerase was from Roche Molecular Biochemicals (Indianapolis, IN), ATP and deoxyribonucleoside triphosphates were from Amersham Pharmacia Biotech (Piscataway, NJ), and [-³²P]ATP (7000 Ci/mmol; 1Ci = 37 GBq) was obtained from ICN (Irvine, CA).

CFEs.
The HeLa S3 cell line was from the stock of Lineberger Comprehensive Cancer Center (Chapel Hill, NC). CHO cell lines were from the American Type Culture Collection (Manassas, VA): CRL 1859 (AA8, wild-type, parental); CRL 1860 (UV41, ERCC4, XP-F); and CRL 1867 (UV135, ERCC5, XP-G). CFEs (10–20 mg/ml) were prepared as described (13) from two to three liters of cultured cells in exponential growth phase and kept at -80°C in storage buffer [25 mM HEPES-KOH (pH 7.9), 100 mM KCl, 12 mM MgCl₂, 0.5 mM EDTA, 2 mM DTT, and 12.5% (v/v) glycerol].

DNA Substrates.
Oxaliplatin and JM216 react poorly with DNA in vitro, but their biotransformation products, Pt(dach)Cl₂ and JM118 (Fig. 1) , react more readily with DNA in vitro and form adducts with the same carrier ligands as those formed by oxaliplatin and JM216 in vivo. To further facilitate their reaction with DNA, cisplatin, Pt(dach)Cl₂, and JM118 were converted to their aquated derivatives (Fig. 1) by overnight stirring with a 2:1 ratio of AgNO₃ at room temperature in the dark. A 12-mer (5'-TCTAGGCCTTCT) was incubated for 2 h at 37°C in the dark with aquated derivatives of cisplatin, Pt(dach)Cl₂, or JM118 at a 10:1 drug:nucleotide ratio. Under these conditions, the major reaction product formed with all three platinum complexes contained a single Pt adduct located at the GG sequence. Complete details of platination reactions and purification of oligonucleotides containing a single Pt adduct will be presented elsewhere.⁴ These singly platinated oligomers were used for preparation of linear 140-bp duplexes with centrally located diadducts at nucleotides 69–70 (14) . Uniquely modified 12-mers were end-labeled with T4 polynucleotide kinase and [-³²P]ATP to introduce a radiolabel at the fifth phosphodiester bond 5' to the GG diadduct, annealed with a set of five complementary and partially overlapping oligomers, and ligated with T4 DNA ligase. Full-length substrate was separated from unligated products in a 6% denaturing polyacrylamide gel, purified by electroelution, reannealed, and stored in annealing buffer [50 mM Tris-HCl (pH 7.9), 100 mM NaCl, 10 mM MgCl₂, and 1 mM DTT] at -20°C.

View larger version (23K): [in this window] [in a new window]   Fig. 1. Structures of the drugs, biotransformation products and aquated derivatives for the platinum compounds used in this study. Pt(dach)Cl2 and JM118 are thought to be the active metabolites of oxaliplatin and JM216, respectively. Aquated derivatives of these complexes and cisplatin were used to modify oligonucleotides used in the preparation of in vitro excision repair substrates.

Mapping of Incision Sites.
T4 DNA polymerase 3'5' exonuclease activity was used to map the primary sites of incision. If a DNA adduct is a block to the exonuclease activity, limited digestion with T4 DNA polymerase serves two purposes: (a) it demonstrates that the damaged base(s) is in the excised oligomer; and (b) it is used to map the 3' incision site. Excision assays were conducted with 50–150 fmol of radiolabeled DNA and 125 µg of CHO AA8 CFE in 25 µl of reaction buffer for 45 min at 30°C. Gel-purified excision products were incubated for 10 min at 30°C with T4 DNA polymerase (0.25 unit) in 10 µl of buffer provided by the manufacturer [50 mM Tris (pH 8.8), 15 mM (NH₄)₂SO₄, 7 mM MgCl₂, 0.1 mM EDTA, 50 mM ß-mercaptoethanol, and 20 µg/ml BSA] supplemented with 0.5 µg HaeIII digested DNA and visualized by autoradiography following resolution in 10% denaturing polyacrylamide gels. Similar analyses using radiolabeled, platinated 12-mers were used to identify the nucleotide(s) at which the exonuclease activity of T4 DNA polymerase is blocked 3' to the lesion. The location of the 5' incision site made by the excinuclease was determined by comparison of the primary 3' incision site with the length of excision products observed in the absence of T4 DNA polymerase digestion.

	RESULTS

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Repair of 1,2-d(GpG) Platinum Adducts by Mammalian CFEs.
Efficient repair of 1,2-d(GpG) cisplatin diadducts has been reported (10 , 11) . The results presented here (Fig. 2) confirm these reports and also demonstrate that the oxaliplatin and JM216 lesions are repaired as efficiently as cisplatin diadducts by both the human and rodent excinucleases (HeLa and AA8 CFE, respectively). The excision repair assay detects radiolabeled fragments resulting from dual incisions both 5' and 3' to the lesion, and for the platinated substrates, the excised fragments were primarily 23–28 nucleotides in length, although 22–31 nucleotide-long fragments were also observed (Fig. 2A) . This range of product sizes reflects variability at both the 3' and 5' incision sites (16) ; smaller excision products are due to degradation of the primary excision products by exonucleases present in the extracts, and in this experiment, the degradation is most evident when DNA was incubated with CHO AA8 CFE (Fig. 2A , Lanes 2, 5 and 8). Because the human and CHO excision repair proteins are interchangeable (1, 2, 3) , we conducted complementation experiments with CHO wild-type and mutant CFEs because of the higher quality extracts obtainable from these cells relative to human cell lines. When platinated substrates were incubated with CFEs prepared from mutant CHO cell lines belonging to complementation groups 4 and 5, equivalent to human XPF and XPG, excision products were not observed (Fig. 2B , Lanes 2, 3, 6, 7, 10, and 11). Repair activity, as evidenced by the generation of radiolabeled excision products, was restored to wild-type levels (Fig. 2B , Lanes 1, 5, and 9) when a mixture of CFEs from two complementation groups was incubated with substrate DNA (Fig. 2B , Lanes 4, 8, and 12). Other radiolabeled fragments that appear as a DNA ladder are caused by low levels of nicking at random positions; this activity is not associated with repair. We observed this ladder with all three platinated DNA substrates, and in this experiment, it is most pronounced for the cisplatin substrate incubated with CHO-XPG CFE (Fig. 2B , Lane 3) due to sample overloading.

View larger version (86K): [in this window] [in a new window]   Fig. 2. Excision of 1,2-d(GpG) platinum adducts by human and rodent excinucleases. A, substrates containing cisplatin, oxaliplatin, or JM216 lesions were incubated with either AA8 or HeLa CFEs. Excision products released during the reaction are primarily 23–28 nucleotides in length and are not observed in the absence of CFEs (Lanes 1, 4, and 7). In this experiment, the percentages of excision by AA8 CFE were 7.6, 5.5, and 8.0 for cisplatin, oxaliplatin, and JM 216 diadducts, respectively; for HeLa CFEs, these values were 2.1, 1.1, and 2.3. Note that the low efficiency of excision by HeLa CFE is a property of this particular extract as, in general, HeLa and AA8 CFEs have comparable excision activities. B, dual incisions require the functional excinuclease present in wild-type AA8 CFE, and excision products are not observed when substrates are incubated with mutant CFEs from either complementation group 4, CHO-XPF, or complementation group 5, CHO-XPG. Excision is reconstituted when mutant CFEs are mixed together in the reaction (Lanes 4, 8, and 12). The percentage of excision observed with AA8 CFE or for complementation were 8.0 and 6.8 for cisplatin, 6.8 and 6.0 for oxaliplatin, and 7.1 and 9.8 for JM216. The percentage of excision was calculated by dividing the cpm in the 22–31-nucleotide region by the total cpm loaded in the lane. For both panels, the location of full-length 140-bp substrate is identified by an arrow; brackets, the major excision products. The fragments migrating immediately below the 140-mer are a combination of incomplete ligation products present in the substrate and fragments generated by nonspecific nucleases in the CFEs. Degradation of primary excision products (A, Lanes 2, 5, and 8) and the ladder generated by random nicking (B, Lane 3) are discussed in the text.

View larger version (39K): [in this window] [in a new window]   Fig. 3. Kinetics of removal of 1,2-d(GpG) cisplatin, oxaliplatin, and JM216 diadducts by HeLa excinuclease. A–C, after the excision reaction, DNA was resolved in 10% denaturing polyacrylamide gels to separate excision products from substrate DNA and visualized by autoradiography. The entire autorad is shown in A for the cisplatin substrate; only the excision product regions of autorads are shown in B and C for oxaliplatin and JM216 lesions, respectively. D, quantitative analysis of the kinetic experiments. , cisplatin repair; , oxaliplatin lesions; , JM216 lesions. Data points are the average of two independent experiments done under the same conditions; bars, range of excision; where no error bars are seen, they are smaller than the size of the symbols.

View larger version (32K): [in this window] [in a new window]   Fig. 4. Mapping of incision sites. A, time course analyses with T4 DNA polymerase and platinated 12-mers were used to identify sites(s) of inhibition of T4 DNA polymerase exonuclease activity. At all time points, this exonuclease activity was primarily blocked at the fourth nucleotide 3' to the diadduct, resulting in migration of platinated 12-mers as platinated 10-mers; this same pattern of exonuclease stop sites was observed for cisplatin (data not shown). B, limited (10-min) T4 DNA polymerase digestion was used to identify the 3' incision site of gel-purified oligomers released during the excision repair reaction. For both the oxaliplatin and JM216 diadducts, as well as the cisplatin adduct (data not shown), the excised 28-mer (Lanes 1 and 3) migrated as a 22-mer (Lanes 2 and 4) after treatment with T4 DNA polymerase. Thus, XPG makes the first incision at the 11th phosphodiester bond 3' to the damage and then XPF•ERCC1 incises at the 17th bond on the 5' side to generate a 28-mer excision product.

	DISCUSSION

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Additional subunits are recruited to the damage site and, after enzymatic unwinding of the DNA helix in the area of the lesion, dual incisions are made by XPG and XPF·ERCC1 (1, 2, 3) . On the basis of T4 DNA polymerase mapping and other experiments (14 , 16) , we have reported that, for the majority of DNA lesions [including thymine cyclobutane dimer, (6-4) photoproduct, psoralen-thymine adduct, and acetylaminofluorene guanosine adduct], the incision made by XPG is at 6 ± 3 phosphodiester bonds 3' to DNA damage, and that the incision by XPF·ERCC1 is 20 ± 5 bonds 5' to the lesion, resulting in release of damage-containing oligomers primarily 22–32 nucleotides in length. However, in the case of the 1,3-intrastrand d(GpTpG) cisplatin diadduct, the incision sites were reported to be at the extremes of the range: the 16th phosphodiester bond 5' and the 9th phosphodiester bond 3' to the lesion (13) . The major excision product size that we report (28 mer) is generated by 5' and 3' incisions at the 17th and 11th phosphodiester bonds, respectively. This suggests that "shifted" 3' incision sites may be a common phenomenon for platinum lesions, including 1,3-intrastrand d(GpTpG) cisplatin diadducts (13) and 1,2-d(GpG)-diadducts generated by cisplatin, oxaliplatin, and JM216.

With in vitro repair assays, we typically observe maximal levels of excision within 1 h compared with 6–24 h for cultured cells, and the overall level of repair is considerably lower than that observed for cultured cells, presumably because of inactivation of the enzyme in vitro and nonspecific degradation of substrate. Our finding of similar extents of repair for cisplatin, oxaliplatin, and JM216 lesions are consistent with reports that the effectiveness of Pt-dach complexes, such as oxaliplatin, in cell lines with acquired cisplatin resistance cannot be explained by differences in overall repair of cisplatin or Pt-dach adducts (19 , 20) .

A precise molecular mechanism for primary or acquired cisplatin resistance is not known, and in most cases, the resistance is multifactorial in nature. Because DNA lesions are considered to be the main lesions that cause cellular death, the efficiency of removal of cisplatin and its analogues by nucleotide excision repair is expected to play a role in drug response. It is not likely that the modest in vitro differences that we report for both the initial kinetics and the overall rate of repair would translate into more pronounced effects in vivo. We conclude that cisplatin, oxaliplatin, and JM216 lesions are removed with similar in vitro efficiencies by the nucleotide excision repair pathway, and that the mechanism of excision, as defined by the requirement for both XPF·ERCC1 and XPG and the location of 3' and 5' incision sites, is the same for all three diadducts. Thus, the effectiveness of oxaliplatin and JM216 in cisplatin-resistant cell lines is not likely to be due to the differential removal of these lesions by nucleotide excision repair enzymes.

	ACKNOWLEDGMENTS

 
We thank P. E. Juniewicz and J. Rake for critical reading of the manuscript and useful comments, and we are grateful to S. D. Wyrick and C. F. J. Barnard for gifts of Pt(dach)Cl₂ and JM118.

	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 NIH Grant GM32833 (to A. S.) and a research contract from Sanofi Pharmaceuticals (to S. G. C.).

² To whom requests for reprints should be addressed, at Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Mary Ellen Jones Building, CB # 7260, Chapel Hill, NC 27599-7260. Phone: (919) 962-0115; Fax: (919) 966-2852.

³ The abbreviations used are: XP, xeroderma pigmentosum; cisplatin, cis-diamminedichloroplatinum(II); oxaliplatin, (trans-R,R)1,2-diaminocyclohexaneoxalatoplatinum(II); Pt(dach)Cl₂, (trans-R,R)1,2-diaminocyclohexanedichloroplatinum(II); JM216, bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV); JM118, cis-amminedichloro(cyclohexylamine)platinum(II); ERCC, excision-repair cross complementing; CFE, cell-free extract; CHO, Chinese hamster ovary.

⁴ A. Vaisman, S. E. Lim, S. M. Patrick, W. C. Copeland, D. C. Hinkle, J. J. Turchi, and S. G. Chaney. The effect of DNA polymerases and HMG1 on the carrier ligand specificity for translesion synthesis past Pt-DNA adducts, in press.

Received 3/24/99. Accepted 6/17/99.

	REFERENCES

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