Abstract
Purpose
To characterize the cellular action mechanism of Debio 0507, we compared the major DNA adducts formed by Debio 0507- and oxaliplatin-treated HCT116 human colon carcinoma cells by a combination of inductively coupled plasma mass spectrometry (ICP-MS) and ultraperformance liquid chromatography mass spectrometry (UPLC-MS/MS).
Methods
HCT116 cells were treated with IC50 doses of Debio 0507 or oxaliplatin for 3 days. Total cellular Pt–DNA adducts were determined by ICP-MS. The DNA was digested, and the major Pt–DNA adducts formed by both drugs were characterized by UPLC/MS/MS essentially as described previously for cisplatin (Baskerville-Abraham et al. in Chem Res Toxicol 22:905–912, 2009).
Results
The Pt level/deoxynucleotide was 7.4/104 for DNA from Debio 0507-treated cells and 5.5/104 for oxaliplatin-treated cells following a 3-day treatment at the IC50 for each drug. UPLC-MS/MS in the positive ion mode confirmed the major Pt–DNA adducts formed by both drugs were dach-Pt-d(GpG) (904.2 m/z → 610 m/z and 904.2 m/z → 459 m/z) and dach-Pt-d(ApG) (888.2 m/z → 594 m/z and 888.2 m/z → 459 m/z).
Conclusions
These data show that the major DNA adducts formed by Debio 0507 are the dach-Pt-d(GpG) and dach-Pt-d(ApG) adducts and at equitoxic doses Debio 0507 and oxaliplatin form similar levels of dach-Pt-d(GpG) and dach-Pt-d(ApG) adducts. This suggests that the action mechanisms of Debio 0507 and oxaliplatin are similar at a cellular level.
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References
Mani S, Graham MA, Bregman DB, Ivy P, Chaney SG (2002) Oxaliplatin: a review of evolving concepts. Cancer Invest 20:246–263
Cabral H, Nishiyama N, Okazaki S, Koyama H, Kataoka K (2005) Preparation and biological properties of dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt)-loaded polymeric micelles. J Control Release 101:223–232
Mignard C, Bari V, Bichat F, Cicurel, L, Vaugniaux G, Barbier M (2010) PK and antitumor activity of DEBIO 0507, a new platinum derivative, in preclinical tumor models. American Association For Cancer Research annual meeting, Abstract 571: http://www.educationbook.aacrjournals.org/archive/2010.dtl
Cabral H, Nishiyama N, Kataoka K (2007) Optimization of (1,2-diamino-cyclohexane)platinum(II)-loaded polymeric micelles directed to improve tumor targeting and enhanced antitumor activity. J Control Release 121:146–155
Chaney SG, Campbell SL, Bassett E, Wu Y (2005) Recognition and processing of cisplatin- and oxaliplatin-DNA adducts. Crit Rev Oncol Hematol 53:L3–L11
Jennerwein MM, Eastman A, Khokhar AR (1989) Characterization of adducts produced in DNA by isomeric 1,2-diaminocyclohexaneplatinum(II) complexes. Chem-Biol Interact 70:39–49
Page JD, Husain I, Sancar A, Chaney SG (1990) Effect of the diaminocyclohexane carrier ligand on platinum adduct formation, repair, and lethality. Biochemistry 29:1016–1024
Springler B, Whittington DA, Lippard SJ (2001) 2.4 A crystal structure of an oxaliplatin 1,2-d(GpG) intrastrand crosslink in a DNA dodecamer duplex. Inorg Chem 40:5596–5602
Wu Y, Pradham P, Havener J, Boysen G, Swenberg JA, Campbell SL, Chaney SG (2004) NMR solution structure of an oxaliplatin 1,2-d(GpG) intrastrand crosslink in a DNA dodecamer duplex. J Mol Biol 341:1251–1269
Sharma S, Gong P, Temple B, Bhattacharyya D, Dokholyan NV, Chaney SG (2007) Molecular dynamic simulations of cisplatin- and oxaliplatin-d(GG) intrastrand crosslinks reveal differences in their conformational dynamics. J Mol Biol 373:1123–1140
Treiber DK, Zhai X, Jantzen HM, Essigmann JM (1994) Cisplatin-DNA adducts are molecular decoys for the ribosomal RNA transcription factor hUBF. Proc Natl Acad Sci USA 91:5672–5676
Ohndorf U-M, Rould MA, He Q, Pabo CO, Lippard SJ (1999) Basis for recognition of cisplatin-modified DNA by high-mobility-group proteins. Nature 399:708–712
Wei M, Cohen SM, Silverman AP, Lippard SJ (2001) Effects of spectator ligands on the specific recognition of intrastrand platinum-DNA cross-links by high mobility group box and TATA-binding proteins. J Biol Chem 276:38774–38780
Zdraveski ZZ, Mello JA, Farinelli CK, Essigmann JM, Marinus MG (2002) MutS preferentially recognizes cisplatin- over oxaliplatin-modified DNA. J Biol Chem 277:1255–1260
Jung Y, Lippard SJ (2003) Nature of full length HMGB1 binding to cisplatin-modified DNA. Biochemistry 42:2664–2671
Malina J, Novakova O, Vojtiskova M, Natille G, Brabek V (2007) Conformation of DNA intrastrand cross-links of antitumor oxaliplatin and its enantiomeric analog. Biophys J 93:3950–3962
Chvalova K, Sari MA, Bombard S, Kozelka J (2008) LEF-1 recognition of platinated DNA sequences within double stranded DNA. Influence of flanking bases. J Inorg Biochem 102:242–250
Huang JC, Zamble DB, Reardon JT, Lippard SJ, Sancar A (1994) HMG-domain proteins inhibit the repair of the major DNA adduct of the anticancer drug cisplatin by human excision nuclease. Proc Natl Acad Sci USA 91:10394–10398
Fink D, Nebel S, Aebi S, Zheng H, Cenni B et al (1996) The role of mismatch repair in platinum drug resistance. Cancer Res 56:4881–4886
Vaisman A, Varchenko M, Umar A, Kunkel TA, Risinger JI, Barrett JC, Hamilton TC, Chaney SG (1998) The role of hMLH1, hMSH3 and hMSH6 defects in cisplatin and oxaliplatin resistance: correlation with replicative bypass of platinum-DNA adducts. Cancer Res 58:3579–3585
Zhai X, Beckmann H, Jantzen HM, Essigmann JM (1998) Cisplatin-DNA adducts inhibit ribosomal RNA synthesis by hijacking the transcription factor human upstream binding factor. Biochemistry 37:16307–16315
Vaisman A, Lim SE, Patrick SM, Copeland WC, Hinkle DC, Turchi JJ, Chaney SG (1999) Effect of DNA polymerases and high mobility group protein 1 on the carrier ligand specificity for translesion synthesis past platinum-DNA adducts. Biochemistry 38:11026–11039
Butour J-L, Johnson NP (1986) Chemical reactivity of monofunctional platinum-DNA adducts. Biochemistry 25:4534–4539
Bancroft DP, Lepre CA, Lippard SJ (1990) 195Pt NMR kinetic and mechanistic studies of cis- and trans-diamminedichloroplatinum(II) binding to DNA. J Am Chem Soc 112:6860–6871
Johnson NP, Mazard AM, Escalier J, Macquet JP (1985) Mechanism of the reaction between cis-[PtCl2(NH3)2] and DNA in vitro. J Am Chem Soc 107:6376–6380
Butour JL, Mazard AM, Macquet JP (1985) Kinetics of the reaction of cis-platinum compounds with DNA in vitro. Biochem Biophys Res Commun 133:347–353
Knox RJ, Friedlos F, Lydall DA, Roberts JJ (1986) Mechanism of cytotoxicity of anticancer platinum drugs: evidence that cis-diamminedichloroplatinum(II) and cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) differ only in the kinetics of their interaction with DNA. Cancer Res 46:1972–1979
Mauldin SK, Plescia M, Richard FA, Wyrick SD, Voyksner RD, Chaney SG (1988) Displacement of the bidentate malonate ligand from (d, l-trans-1,2-diaminocyclohexane)malonatoplatinum(II) by physiologically important compounds in vitro. Biochem Pharmacol 37:3321–3333
Mauldin SK, Gibbons G, Wyrick SD, Chaney SG (1988) Intracellular biotransformation of platinum compounds with the 1,2-diaminocyclohexane carrier ligand in the L1210 cell line. Cancer Res 48:5136–5144
Luo FR, Wyrick SD, Chaney SG (1999) Biotransformations of oxaliplatin in rat blood in vitro. J Biochem Molec Toxicol 13:159–169
Luo FR, Wyrick SD, Chaney SG (1998) Cytotoxicity, cellular uptake, and cellular biotransformations of oxaliplatin in human colon carcinoma cells. Oncol Res 10:595–603
Segal E, Le Pecq J-B (1985) Role of ligand exchange processes in the reaction kinetics of the antitumor drug cis-diamminedichloroplatinum(II) with its targets. Cancer Res 45:492–498
Davies MS, Berners-Price S, Hambley TW (1998) Rates of platination of AG and GG containing double-stranded oligonucleotides: Insights into why cisplatin binds to GG and AG but not GA sequences in DNA. J Am Chem Soc 120:11380–11390
Hah SS, Stivers KM, de Vere White RW, Henderson PT (2006) Kinetics of carboplatin-DNA binding in genomic DNA and bladder cancer cells as determined by accelerator mass spectrometry. Chem Res Toxicol 19:622–626
Hah SS, Sumbad RA, de Vere White RW, Turteltaub KW, Henderson PT (2007) Characterization of oxaliplatin-DNA adduct formation in DNA and differentiation of cancer cell drug sensitivity at microdose concentrations. Chem Res Toxicol 20:1745–1751
Hah SS, Henderson PT, Turteltaub KW (2010) Towards biomarker-dependent individualized chemotherapy: exploring cell-specific differences in oxaliplatin-DNA adduct distribution using accelerator mass spectrometry. Biorg Med Chem Lett 20:2448–2451
Fichtinger-Schepman AMJ, van Dijk-Knijnenburg HCM, van der Velde-Visser SD, Berends F, Baan RA (1995) Cisplatin and carboplatin-DNA adducts: is Pt-AG the cytotoxic lesion? Carcinogenesis 16:2447–2453
Blommaert FA, van Dijk-Knijnenburg HCM, Dijt FJ, Denengelse L, Baan RA, Berends F, Fichtinger-Schepman AMJ (1995) Formation of DNA adducts by the anticancer drug carboplatin: different nucleotide sequence preferences in vitro and in cells. Biochemistry 34:8474–8480
Boudny V, Vrana O, Gaucheron F, Kleinwachter V, Leng M, Brabec V (1992) Biophysical analysis of DNA modified by 1,2-diaminocyclohexane platinum(II) complexes. Nucleic Acids Res 20:267–272
Saris CP, van de Vaart PJM, Rietbroek RC, Blommaert FA (1996) In vitro formation of DNA adducts by cisplatin, lobaplatin and oxaliplatin in calf thymus DNA in solution and in cultured human cells. Carcinogenesis 17:2763–2769
Woynarowski JM, Chapman WG, Napier C, Herzig MCS, Juniewicz P (1998) Sequence- and region-specificity of oxaliplatin adducts in naked and cellular DNA. Molec Pharmacol 54:770–777
Luo FR, Yen TY, Wyrick SD, Chaney SG (1999) High-performance liquid chromatographic separation of the biotransformation products of oxaliplatin. J Chromatog B 724:345–356
Le Pla RC, Ritchie KJ, Henderson CJ, Wolf CR, Harrington CF, Farmer PB (2007) Development of a liquid chromatography-electrospray ionization tandem mass spectrometry method for detecting oxaliplatin-DNA intrastrand cross-links in biological samples. Chem Res Toxicol 20:1177–1182
Mowaka S, Linschied M (2008) Separation and characterization of oxaliplatin dinucleotides from DNA using HPLC-ESI-ion trap mass spectrometry. Anal Bioanal Chem 392:819–830
Kerr SL, Shoeib T, Sharp BL (2008) A study of oxaliplatin-nucleobase interactions using ion trap electrospray mass spectrometry. Anal Bioanal Chem 391:2339–2348
Baskerville-Abraham IM, Boysen G, Troutman JM, Mutlu E, Collins L, deKrafft KE, Lin W, King C, Chaney SG, Swenberg JA (2009) Development of an ultraperformance liquid chromatography/mass spectrometry method to quantify cisplatin 1,2 intrastrand guanine–guanine adducts. Chem Res Toxicol 22:905–912
Eastman A (1983) Characterization of the adducts produced in DNA by cis-diamminedichloroplatinum(II) and cis-dichloro(ethylenediamine)platinum(II). Biochemistry 22:3927–3933
Eastman A (1986) Reevaluation of the interactions of cis-diamminedichloro(ethylenediamine)platinum(II) with DNA. Biochemistry 25:3912–3915
Acknowledgments
This work was supported by Research Contract Debio 0507-069 from Debiopharm SA (Lausanne, Switzerland) and P30-ES10126 from National Institute of Environmental Health Sciences.
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King, C.L., Ramachandran, S., Chaney, S.G. et al. Debio 0507 primarily forms diaminocyclohexane-Pt-d(GpG) and -d(ApG) DNA adducts in HCT116 cells. Cancer Chemother Pharmacol 69, 665–677 (2012). https://doi.org/10.1007/s00280-011-1744-3
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DOI: https://doi.org/10.1007/s00280-011-1744-3