Skip to main content

Advertisement

SpringerLink
Log in

Human Multidrug Resistance Associated Protein 4 Confers Resistance to Camptothecins

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Purpose

The multidrug resistance associated protein (MRP) 4 is a member of the adenosine triphosphate (ATP)-binding cassette transporter family. Camptothecins (CPTs) have shown substantial anticancer activity against a broad spectrum of tumors by inhibiting DNA topoisomerase I, but tumor resistance is one of the major reasons for therapeutic failure. P-glycoprotein, breast cancer resistance protein, MRP1, and MRP2 have been implicated in resistance to various CPTs including CPT-11 (irinotecan), SN-38 (the active metabolite of CPT-11), and topotecan. In this study, we explored the resistance profiles and intracellular accumulation of a panel of CPTs including CPT, CPT-11, SN-38, rubitecan, and 10-hydroxy-CPT (10-OH-CPT) in HepG2 cells with stably overexpressed human MRP4. Other anticancer agents such as paclitaxel, cyclophosphamide, and carboplatin were also included.

Methods

HepG2 cells were transfected with an empty vehicle plasmid (V/HepG2) or human MRP4 (MRP4/HepG2). The resistance profiles of test drugs in exponentially growing V/HepG2 and MRP4/HepG2 cells were examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) assay with 4 or 48 h exposure time of the test drug in the absence or presence of various MRP4 inhibitors. The accumulation of CPT-11, SN-38, and paclitaxel by V/HepG2 and MRP4/HepG2 cells was determined by validated high-performance liquid chromatography methods.

Results

Based on the resistance folds from the MTT assay with 48 h exposure time of the test drug, MRP4 conferred resistance to CPTs tested in the order 10-OH-CPT (14.21) > SN-38 carboxylate (9.70) > rubitecan (9.06) > SN-38 lactone (8.91) > CPT lactone (7.33) > CPT-11 lactone (5.64) > CPT carboxylate (4.30) > CPT-11 carboxylate (2.68). Overall, overexpression of MRP4 increased the IC50 values 1.78- to 14.21-fold for various CPTs in lactone or carboxylate form. The resistance of MRP4 to various CPTs tested was significantly reversed in the presence of dl-buthionine-(S,R)-sulfoximine (BSO, a γ-glutamylcysteine synthetase inhibitor), MK571, celecoxib, or diclofenac (all MRP4 inhibitors). In addition, the accumulation of CPT-11 and SN-38 over 120 min in MRP4/HepG2 cells was significantly reduced compared to V/HepG2 cells, whereas the addition of celecoxib, MK571, or BSO significantly increased their accumulation in MRP4/HepG2 cells. There was no significant difference in the intracellular accumulation of paclitaxel in V/HepG2 and MRP4/HepG2 cells, indicating that P-glycoprotein was not involved in the observed resistance to CPTs in this study. MRP4 also conferred resistance to cyclophosphamide and this was partially reversed by BSO. However, MRP4 did not increase resistance to paclitaxel, carboplatin, etoposide (VP-16), 5-fluorouracil, and cyclosporine.

Conclusions

Human MRP4 rendered significant resistance to cyclophosphamide, CPT, CPT-11, SN-38, rubitecan, and 10-OH-CPT. CPT-11 and SN-38 are substrates for MRP4. Further studies are needed to explore the role of MRP4 in resistance, toxicity, and pharmacokinetics of CPTs and cyclophosphamide.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

ABC:

ATP-binding cassette

BCRP:

breast cancer resistance protein

BSO:

dl--buthionine-(S,R)-sulfoximine

CPT:

camptothecin

DMEM:

Dulbecco's modified Eagle's medium

DMSO:

dimethyl sulfoxide

E217βG:

17-β-d-estradiol-glucuronide

GSH:

glutathione

HPLC:

high-performance liquid chromatography

MRP:

multidrug resistance associated protein

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide

MTX:

methotrexate

OATP:

organic anion transporting polypeptide

PgP:

P-glycoprotein

PMEA:

9-(2-phosphonylmethoxyethyl)adenine

UGT:

uridine diphosphate glucuronosyltransferase

References

  1. J. Wang (1996) ArticleTitleDNA topoisomerases Annu. Rev. Biochem. 65 635–692 Occurrence Handle10.1146/annurev.bi.65.070196.003223 Occurrence Handle8811192

    Article  PubMed  Google Scholar 

  2. K. R. Hande (2003) ArticleTitleTopoisomerase II inhibitors Cancer Chemother. Biol. Response Modif. 21 103–125 Occurrence Handle15338742

    PubMed  Google Scholar 

  3. J. F. Pizzolato L. B. Saltz (2003) ArticleTitleThe camptothecins Lancet 361 2235–2242 Occurrence Handle10.1016/S0140-6736(03)13780-4 Occurrence Handle12842380

    Article  PubMed  Google Scholar 

  4. M. R. Redinbo L. Stewart P. Kuhn J. J. Champoux W. G. Hol (1998) ArticleTitleCrystal structures of human topoisomerase I in covalent andnoncovalent complexes with DNA Science 279 1504–1513 Occurrence Handle10.1126/science.279.5356.1504 Occurrence Handle9488644

    Article  PubMed  Google Scholar 

  5. L. Stewart M. R. Redinbo X. Qiu W. G. Hol J. J. Champoux (1998) ArticleTitleA model for the mechanism of human topoisomerase I Science 279 1534–1541 Occurrence Handle10.1126/science.279.5356.1534 Occurrence Handle9488652

    Article  PubMed  Google Scholar 

  6. L. L. Jung W. C. Zamboni (2001) ArticleTitleCellular, pharmacokinetic, and pharmacodynamic aspects of response to camptothecins: can we improve it Drug Resist. Updat. 4 273–288 Occurrence Handle10.1054/drup.2001.0222 Occurrence Handle11998845

    Article  PubMed  Google Scholar 

  7. F. Goldwasser T. Shimizu J. Jackman Y. Hoki P. M. O'Connor K. W. Kohn Y. Pommier (1996) ArticleTitleCorrelations between S and G2 arrest and the cytotoxicity of camptothecin in human colon carcinoma cells Cancer Res.. 56 4430–4437 Occurrence Handle8813137

    PubMed  Google Scholar 

  8. M. Wall M. C. Wani C. E. Cook K. H. Palmer A. T. Mcphail G. A. Sim (1966) ArticleTitlePlant antitumor agents: 1, the isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata J. Am. Chem. Soc. 88 3888–3890 Occurrence Handle10.1021/ja00968a057

    Article  Google Scholar 

  9. J. Fassberg V. J. Stella (1992) ArticleTitleA kinetic and mechanistic study of the hydrolysis of camptothecin and some analogues J. Pharm. Sci. 81 676–684 Occurrence Handle1403703

    PubMed  Google Scholar 

  10. B. A. Chabner (1992) ArticleTitleCamptothecins J. Clin. Oncol. 10 3–4 Occurrence Handle1727922

    PubMed  Google Scholar 

  11. W. J. Slichenmyer E. K. Rowinsky R. C. Donehower S. H. Kaufmann (1993) ArticleTitleThe current status of camptothecin analogues as antitumor agents J. Natl. Cancer Inst. 85 271–291 Occurrence Handle8381186

    PubMed  Google Scholar 

  12. R. P. Hertzberg R. W. Busby M. J. Caranfa K. G. Holden R. K. Johnson S. M. Hecht W. D. Kingsbury (1990) ArticleTitleIrreversible trapping of the DNA–topoisomerase I covalent complex. Affinity labelling of the camptothesin binding site J. Biol. Chem. 265 19287–19295 Occurrence Handle2172250

    PubMed  Google Scholar 

  13. M. L. Rothenberg J. R. Eckardt J. G. Kuhn H. A. Burris SuffixIII J. Nelson S. G. Hilsenbeck G. I. Rodriguez A. M. Thurman L. S. Smith S. G. Eckhardt G. R. Weiss G. L. Elfring D. A. Rinaldi L. J. Schaaf D. D. Hoff ParticleVon (1996) ArticleTitlePhase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer J. Clin. Oncol. 14 1128–1135 Occurrence Handle8648367

    PubMed  Google Scholar 

  14. W. Bokkel Huinink Particleten M. Gore J. Carmichael A. Gordon J. Malfetano I. Hudson C. Broom C. Scarabelli N. Davidson M. Spanczynski G. Bolis H. Malmstrom R. Coleman C. Fields J. F. Heron (1997) ArticleTitleTopotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer J. Clin. Oncol. 15 2183–2193 Occurrence Handle9196130

    PubMed  Google Scholar 

  15. M. Ciotti N. Basu M. Brangi I. S. Owens (1999) ArticleTitleGlucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38) by the human UDP-glucuronosyltransferases encoded at the UGT1 locus Biochem. Biophys. Res. Commun. 260 199–202 Occurrence Handle10.1006/bbrc.1999.0453 Occurrence Handle10381366

    Article  PubMed  Google Scholar 

  16. Y. Kawato M. Aonuma Y. Hirota H. Kuga K. Sato (1991) ArticleTitleIntracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11 Cancer Res. 51 4187–4191 Occurrence Handle1651156

    PubMed  Google Scholar 

  17. R. H. J. Mathijssen R. J. Alphen Particlevan J. Verweij W. J. Loos K. Nooter G. Stoter A. Sparreboom (2001) ArticleTitleClinical pharmacokinetics and metabolism of irinotecan (CPT-11) Clin. Cancer Res. 7 2182–2194 Occurrence Handle11489791

    PubMed  Google Scholar 

  18. J. A. Ellerhorst A. Y. Bedikian T. M. Smith N. E. Papadopoulos C. Plager O. Eton (2002) ArticleTitlePhase II trial of 9-nitrocamptothecin (RFS 2000) for patients with metastatic cutaneous or uveal melanoma Anticancer Drugs 13 169–172 Occurrence Handle10.1097/00001813-200202000-00009 Occurrence Handle11901310

    Article  PubMed  Google Scholar 

  19. H. A. Burris SuffixIII S. Rivkin R. Reynolds J. Harris A. Wax H. Gerstein K. L. Mettinger A. Staddon (2005) ArticleTitlePhase II trial of oral rubitecan in previously treated pancreatic cancer patients Oncologist 10 183–190 Occurrence Handle10.1634/theoncologist.10-3-183 Occurrence Handle15793221

    Article  PubMed  Google Scholar 

  20. Z. A. Rasheed E. H. Rubin (2003) ArticleTitleMechanisms of resistance to topoisomerase I-targeting drugs Oncogene 22 7296–7304 Occurrence Handle10.1038/sj.onc.1206935 Occurrence Handle14576839

    Article  PubMed  Google Scholar 

  21. E. Gupta R. Mick J. Ramirez X. Wang T. M. Lestingi E. E. Vokes M. J. Ratain (1997) ArticleTitlePharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients J. Clin. Oncol. 15 1502–1510 Occurrence Handle9193346

    PubMed  Google Scholar 

  22. S. Kudoh Y. Fujiwara Y. Takada H. Yamamoto A. Kinoshita Y. Ariyoshi K. Furuse M. Fukuoka (1998) ArticleTitlePhase II study of irinotecan combined with cisplatin in patients with previously untreated small-cell lung cancer. West Japan Lung Cancer Group J. Clin. Oncol. 16 1068–1074 Occurrence Handle9508192

    PubMed  Google Scholar 

  23. F. R. Luo P. V. Paranjpe A. Guo E. Rubin P. Sinko (2002) ArticleTitleIntestinal transport of irinotecan in Caco-2 cells and MDCK II cells overexpressing efflux transporters Pgp, cMOAT, and MRP1 Drug Metab. Dispos. 30 763–770 Occurrence Handle10.1124/dmd.30.7.763 Occurrence Handle12065434

    Article  PubMed  Google Scholar 

  24. X. Y. Chu Y. Kato Y. Sugiyama (1997) ArticleTitleMultiplicity of biliary excretion mechanisms for irinotecan, CPT-11, and its metabolites in rats Cancer Res. 57 1934–1938 Occurrence Handle9157988

    PubMed  Google Scholar 

  25. X. Y. Chu Y. Kato K. Ueda H. Susuki K. Niinuma C. A. Tyson V. Weizer J. E. Dabbs R. Froehlich C. E. Green Y. Sugiyama (1998) ArticleTitleBiliary excretion mechanism of CPT-11 and its metabolites in humans: involvement of primary active transporters Cancer Res. 58 5137–5143 Occurrence Handle9823324

    PubMed  Google Scholar 

  26. E. Gupta A. R. Safa X. Wang M. J. Ratain (1996) ArticleTitlePharmacokinetic modulation of irinotecan and metabolites by cyclosporin A Cancer Res. 56 1309–1314 Occurrence Handle8640819

    PubMed  Google Scholar 

  27. X. Y. Chu Y. Kato Y. Sugiyama (1999) ArticleTitlePossible involvement of P-glycoprotein in biliary excretion of CPT-11 in rats Drug Metab. Dispos. 27 440–441 Occurrence Handle10101137

    PubMed  Google Scholar 

  28. M. D. Norris J. Smith K. Tanabe P. Tobin C. Flemming G. L. Scheffer P. Wielinga S. L. Cohn W. B. London G. M. Marshall J. D. Allen M. Haber (2005) ArticleTitleExpression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro Mol. Cancer Ther. 4 547–553 Occurrence Handle10.1158/1535-7163.MCT-04-0161 Occurrence Handle15827327

    Article  PubMed  Google Scholar 

  29. C. J. Yang J. K. Horton K. H. Cowan E. Schneider (1995) ArticleTitleCross-resistance to camptothecin analogues in a mitoxantrone-resistant human breast carcinoma cell line is not due to DNA topoisomerase I alterations Cancer Res. 55 4004–4009 Occurrence Handle7664272

    PubMed  Google Scholar 

  30. R. Rajendra M. K. Gounder A. Saleem J. H. Schellens D. D. Ross S. E. Bates P. Sinko E. H. Rubin (2003) ArticleTitleDifferential effects of the breast cancer resistance protein on the cellular accumulation and cytotoxicity of 9-aminocamptothecin and 9-nitrocamptothecin Cancer Res. 63 3228–3233 Occurrence Handle12810652

    PubMed  Google Scholar 

  31. T. Nozawa H. Minami S. Sugiura A. Tsuji I. Tamai (2005) ArticleTitleRole of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms Drug Metab. Dispos. 33 434–439 Occurrence Handle10.1124/dmd.104.001909 Occurrence Handle15608127

    Article  PubMed  Google Scholar 

  32. P. Borst R. O. Elferink (2002) ArticleTitleMammalian ABC transporters in health and disease Annu. Rev. Biochem. 71 537–592 Occurrence Handle10.1146/annurev.biochem.71.102301.093055 Occurrence Handle12045106

    Article  PubMed  Google Scholar 

  33. Q. Tian J. Zhang E. Chan W. Duan S. F. Zhou (2005) ArticleTitleMultidrug resistance proteins (MRPs) and implication in drug development Drug Dev. Res. 51 1–18 Occurrence Handle10.1002/ddr.10427

    Article  Google Scholar 

  34. M. Kool M. Linden Particlevan der M. Haas Particlede G. L. Scheffer J. M. Vree Particlede A. J. Smith G. Jansen G. J. Peters N. Ponne R. J. Scheper R. P. Elferink F. Baas P. Borst (1999) ArticleTitleMRP3, an organic anion transporter able to transport anti-cancer drugs Proc. Natl. Acad. Sci. USA 96 6914–6919 Occurrence Handle10.1073/pnas.96.12.6914 Occurrence Handle10359813

    Article  PubMed  Google Scholar 

  35. H. Zeng L. J. Bain M. G. Belinsky G. D. Kruh (1999) ArticleTitleExpression of multidrug resistance protein-3 (multispecific organic anion transporter-D) in human embryonic kidney 293 cells confers resistance to anticancer agents Cancer Res. 59 5964–5967 Occurrence Handle10606242

    PubMed  Google Scholar 

  36. J. D. Allen A. H. Schinkel (2002) ArticleTitleMultidrug resistance and pharmacological protection mediated by the breast cancer resistance protein (BCRP/ABCG2) Mol. Cancer Ther. 1 427–434 Occurrence Handle12477055

    PubMed  Google Scholar 

  37. P. K. Smitherman J. ldridge E. L. Volk E. Schneider A. J. Townsend C. S. Morrow (2001) ArticleTitleResistance to mitoxantrone in multidrug-resistant MCF7 breast cancer cells: evaluation of mitoxantrone transport and the role of multidrug resistance protein family proteins Cancer Res. 61 5461–5467 Occurrence Handle11454692

    PubMed  Google Scholar 

  38. L. Lai T. M. Tan (2002) ArticleTitleRole of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)-mediated efflux of cAMP and resistance to purine analogues Biochem. J. 361 497–503 Occurrence Handle10.1042/0264-6021:3610497 Occurrence Handle11802779

    Article  PubMed  Google Scholar 

  39. M. Leggas M. Adachi G. L. Scheffer D. Sun P. Wielinga G. Du K. E. Mercer Y. Zhuang J. C. Panetta B. Johnston R. J. Scheper C. F. Stewart J. D. Schuetz (2004) ArticleTitleMrp4 confers resistance to topotecan and protects the brain from chemotherapy Mol. Cell. Biol. 24 7612–7621 Occurrence Handle10.1128/MCB.24.17.7612-7621.2004 Occurrence Handle15314169

    Article  PubMed  Google Scholar 

  40. G. Lee M. Piquette-Miller (2001) ArticleTitleInfluence of IL-6 on MDR and MRP-mediated multidrug resistance in human hepatoma cells Can. J. Physiol. Pharmacol. 79 876–884 Occurrence Handle10.1139/cjpp-79-10-876 Occurrence Handle11697747

    Article  PubMed  Google Scholar 

  41. G. Lee M. Piquette-Miller (2003) ArticleTitleCytokines alter the expression and activity of the multidrug resistance transporters in human hepatoma cell lines; analysis using RT-PCR and cDNA microarrays J. Pharm. Sci. 92 2152–2163 Occurrence Handle10.1002/jps.10493 Occurrence Handle14603501

    Article  PubMed  Google Scholar 

  42. T. R. Jones R. Zamboni M. Belley E. Champion L. Charette A. W. Ford-Hutchinson R. Frenette J. Y. Gauthier S. Leger P. Masson C. S. McFarlane H. Piechuta J. Rokach H. Williams R. N. Young N. Haven Particlede S. S. Pong (1989) ArticleTitlePharmacology of L-660,711 (MK-571): a novel potent and selective leukotriene D4 receptor antagonist Can. J. Physiol. Pharmacol. 67 17–28 Occurrence Handle2540892

    PubMed  Google Scholar 

  43. J. Bai L. Lai H. C. Yeo B. C. Goh T. M. Tan (2004) ArticleTitleMultidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane–glutathione Int. J. Biochem. Cell Biol. 36 247–257 Occurrence Handle10.1016/S1357-2725(03)00236-X Occurrence Handle14643890

    Article  PubMed  Google Scholar 

  44. J. Carmichael W. G. DeGraff A. F. Gazdar J. D. Minna J. B. Mitchell (1987) ArticleTitleEvaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing Cancer Res. 47 936–942 Occurrence Handle3802100

    PubMed  Google Scholar 

  45. S. Zhou X. Feng P. Kestell J. W. Paxton B. C. Baguley E. Chan (2005) ArticleTitleTransport of the investigational anti-cancer drug 5, 6-dimethylxanthenone-4-acetic acid and its acyl glucuronide by human intestinal Caco-2 cells Eur J. Pharm. Sci. 24 513–524 Occurrence Handle10.1016/j.ejps.2005.01.006 Occurrence Handle15784341

    Article  PubMed  Google Scholar 

  46. M. T. Huizing H. Rosing F. Koopman A. C. Keung H. M. Pinedo J. H. Beijnen (1995) ArticleTitleHigh-performance liquid chromatographic procedures for the quantitative determination of paclitaxel (Taxol) in human urine J. Chromatogr. B Biomed. Appl. 664 373–382 Occurrence Handle10.1016/0378-4347(94)00477-M Occurrence Handle7780590

    Article  PubMed  Google Scholar 

  47. K. Lee A. J. Klein-Szanto G. D. Kruh (2000) ArticleTitleAnalysis of the MRP4 drug resistance profile in transfected NIH3T3 cells J. Natl. Cancer Inst. 92 1934–1940 Occurrence Handle10.1093/jnci/92.23.1934 Occurrence Handle11106685

    Article  PubMed  Google Scholar 

  48. S. Dallas L. Schlichter R. Bendayan (2004) ArticleTitleMRP4- and MRP5-mediated efflux of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) by microglia J. Pharmacol. Exp. Ther. 309 1221–1229 Occurrence Handle10.1124/jpet.103.063966 Occurrence Handle14762102

    Article  PubMed  Google Scholar 

  49. R. Evers M. Haas Particlede R. Sparidans J. Beijnen P. R. Wielinga J. Lankelma P. Borst (2000) ArticleTitleVinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export Br. J. Cancer 83 375–383 Occurrence Handle10.1054/bjoc.2000.1262 Occurrence Handle10917554

    Article  PubMed  Google Scholar 

  50. C. C. Paulusma M. A. Geer Particlevan R. Evers M. Heijn R. Ottenhoff P. Borst R. P. Oude Elferink (1999) ArticleTitleCanalicular multispecific organic anion transporter/multidrug resistance protein 2 mediates low-affinity transport of reduced glutathione Biochem. J. 338 IssueIDPt2 393–401 Occurrence Handle10.1042/0264-6021:3380393 Occurrence Handle10024515

    Article  PubMed  Google Scholar 

  51. L. S. Gan M. A. Moseley B. Khosla P. F. Augustijns T. P. Bradshaw R. W. Hendren D. R. Thakker (1996) ArticleTitleCYP3A-like cytochrome P450-mediated metabolism and polarized efflux of cyclosporin A in Caco-2 cells Drug Metab. Dispos. 24 344–349 Occurrence Handle8820426

    PubMed  Google Scholar 

  52. P. F. Augustijns T. P. Bradshaw L. S. Gan R. W. Hendren D. R. Thakker (1993) ArticleTitleEvidence for a polarized efflux system in Caco-2 cells capable of modulating cyclosporin A transport Biochem. Biophys. Res. Commun. 197 360–365 Occurrence Handle10.1006/bbrc.1993.2487 Occurrence Handle7903526

    Article  PubMed  Google Scholar 

  53. U. K. Walle T. Walle (1998) ArticleTitleTaxol transport by human intestinal epithelial Caco-2 cells Drug Metab. Dispos. 26 343–346 Occurrence Handle9531522

    PubMed  Google Scholar 

  54. A. Sparreboom J. Asperen Particlevan U. Mayer A. H. Schinkel J. W. Smit D. K. Meijer P. Borst W. J. Nooijen J. H. Beijnen O. Tellingen Particlevan (1997) ArticleTitleLimited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine Proc. Natl. Acad. Sci. USA 94 2031–2035 Occurrence Handle10.1073/pnas.94.5.2031 Occurrence Handle9050899

    Article  PubMed  Google Scholar 

  55. S. Hatse E. Clercq ParticleDe J. Balzarini (1998) ArticleTitleEnhanced 9-(2-phosphonylmethoxyethyl)adenine secretion by a specific, indomethacin-sensitive efflux pump in a mutant 9-(2-phosphonylmethoxyethyl)adenine-resistant human erythroleukemia K562 cell line Mol. Pharmacol. 54 907–917 Occurrence Handle9804626

    PubMed  Google Scholar 

  56. R. V. Srinivas B. L. Robbins M. C. Connelly Y. F. Gong N. Bischofberger A. Fridland (1993) ArticleTitleMetabolism and in vitro antiretroviral activities of bis(pivaloyloxymethyl) prodrugs of acyclic nucleoside phosphonates Antimicrob. Agents Chemother. 37 2247–2250 Occurrence Handle8257154

    PubMed  Google Scholar 

  57. B. L. Robbins M. C. Connelly D. R. Marshall R. V. Srinivas A. Fridland (1995) ArticleTitleA human T lymphoid cell variant resistant to the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine shows a unique combination of a phosphorylation defect and increased efflux of the agent Mol. Pharmacol. 47 391–397 Occurrence Handle7870049

    PubMed  Google Scholar 

  58. J. Wijnholds C. A. Mol L. Deemter Particlevan M. Haas Particlede G. L. Scheffer F. Baas J. H. Beijnen R. J. Scheper S. Hatse E. Clercq ParticleDe J. Balzarini P. Borst (2000) ArticleTitleMultidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs Proc. Natl. Acad. Sci. USA 97 7476–7481 Occurrence Handle10.1073/pnas.120159197 Occurrence Handle10840050

    Article  PubMed  Google Scholar 

  59. G. Reid P. Wielinga N. Zelcer M. Haas ParticleDe L. Deemter ParticleVan J. Wijnholds J. Balzarini P. Borst (2003) ArticleTitleCharacterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5 Mol. Pharmacol. 63 1094–1103 Occurrence Handle10.1124/mol.63.5.1094 Occurrence Handle12695538

    Article  PubMed  Google Scholar 

  60. M. A. McAleer M. A. Breen N. L. White N. Matthews (1999) ArticleTitlepABC11 (also known as MOAT-C and MRP5), a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells J. Biol. Chem. 274 23541–23548 Occurrence Handle10.1074/jbc.274.33.23541 Occurrence Handle10438534

    Article  PubMed  Google Scholar 

  61. Z. S. Chen K. Lee S. Walther R. B. Raftogianis M. Kuwano H. Zeng G. D. Kruh (2002) ArticleTitleAnalysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system Cancer Res. 62 3144–3150 Occurrence Handle12036927

    PubMed  Google Scholar 

  62. J. H. Hooijberg H. J. Broxterman M. Kool Y. G. Assaraf G. J. Peters P. Noordhuis R. J. Scheper P. Borst H. M. Pinedo G. Jansen (1999) ArticleTitleAntifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2 Cancer Res. 59 2532–2535 Occurrence Handle10363967

    PubMed  Google Scholar 

  63. I. Chourpa J. M. Millot G. D. Sockalingum J. F. Riou M. Manfait (1998) ArticleTitleKinetics of lactone hydrolysis in antitumor drugs of camptothecin series as studied by fluorescence spectroscopy Biochim. Biophys. Acta 1379 353–366 Occurrence Handle9545598

    PubMed  Google Scholar 

  64. L. P. Rivory E. Chatelut P. Canal A. Mathieu-Boue J. Robert (1994) ArticleTitleKinetics of the in vivo interconversion of the carboxylate and lactone forms of irinotecan (CPT-11) and of its metabolite SN-38 in patients Cancer Res. 54 6330–6333 Occurrence Handle7987823

    PubMed  Google Scholar 

  65. Y. Sasaki H. Hakusui S. Mizuno M. Morita T. Miya K. Eguchi T. Shinkai T. Tamura Y. Ohe N. Saijo (1995) ArticleTitleA pharmacokinetic and pharmacodynamic analysis of CPT-11 and its metabolite SN-38 Jpn. J. Cancer Res. 86 101–110 Occurrence Handle7737901

    PubMed  Google Scholar 

  66. K. Kobayashi B. Bouscarel Y. Matsuzaki S. Ceryak S. Kudoh H. Fromm (1999) ArticleTitlepH-dependent uptake of irinotecan and its active metabolite, SN-38, by intestinal cells Int. J. Cancer 83 491–496 Occurrence Handle10.1002/(SICI)1097-0215(19991112)83:4<491::AID-IJC10>3.0.CO;2-M Occurrence Handle10508485

    Article  PubMed  Google Scholar 

  67. K. Kobayashi B. Bouscarel Y. Matsuzaki S. Ceryak H. Fromm (1998) ArticleTitleUptake mechanism of irinotecan (CPT-11) and its metabolite (SN-38) by hamster intestinal cells Gastroenterology 114 G2578

    Google Scholar 

  68. X. Y. Chu H. Suzuki K. Ueda Y. Kato S. Akiyama Y. Sugiyama (1999) ArticleTitleActive efflux of CPT-11 and its metabolites in human KB-derived cell lines J. Pharmacol. Exp. Ther. 288 735–741 Occurrence Handle9918583

    PubMed  Google Scholar 

  69. X. Y. Chu Y. Kato K. Niinuma K. I. Sudo H. Hakusui Y. Sugiyama (1997) ArticleTitleMultispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats J. Pharmacol. Exp. Ther. 281 304–314 Occurrence Handle9103511

    PubMed  Google Scholar 

  70. R. Xie R. H. Mathijssen A. Sparreboom J. Verweij M. O. Karlsson (2002) ArticleTitleClinical pharmacokinetics of irinotecan and its metabolites: a population analysis J. Clin. Oncol. 20 3293–3301 Occurrence Handle10.1200/JCO.2002.11.073 Occurrence Handle12149304

    Article  PubMed  Google Scholar 

  71. T. G. Burke Z. Mi (1994) ArticleTitleThe structural basis of camptothecin interactions with human serum albumin: impact on drug stability J. Med. Chem. 37 40–46 Occurrence Handle10.1021/jm00027a005 Occurrence Handle8289200

    Article  PubMed  Google Scholar 

  72. N. Kaneda Y. Hosokawa T. Yokokura S. Awazu (1997) ArticleTitlePlasma pharmacokinetics of 7-ethyl-10-hydroxycamptothecin (SN-38) after intravenous administration of SN-38 and irinotecan (CPT-11) to rats Biol. Pharm. Bull. 20 992–996 Occurrence Handle9331983

    PubMed  Google Scholar 

  73. M. C. Haaz L. P. Rivory C. Riche J. Robert (1997) ArticleTitleThe transformation of irinotecan (CPT-11) to its active metabolite SN-38 by human liver microsomes. Differential hydrolysis for the lactone and carboxylate forms Naunyn-Schmiedeberg's Arch. Pharmacol. 356 257–262

    Google Scholar 

  74. M. N. Tallman J. K. Ritter P. C. Smith (2005) ArticleTitleDifferential rates of glucuronidation for 7-ethyl-10-hydroxy-camptothecin (SN-38) lactone and carboxylate in human and rat microsomes and recombinant UGT isoforms Drug Metab. Dispos. 33 977–983 Occurrence Handle10.1124/dmd.104.003491 Occurrence Handle15833930

    Article  PubMed  Google Scholar 

  75. P. R. Wielinga I. Heijden Particlevan der G. Reid J. H. Beijnen J. Wijnholds P. Borst (2003) ArticleTitleCharacterization of the MRP4- and MRP5-mediated transport of cyclic nucleotides from intact cells J. Biol. Chem. 278 17664–17671 Occurrence Handle10.1074/jbc.M212723200 Occurrence Handle12637526

    Article  PubMed  Google Scholar 

  76. P. Borst R. Evers M. Kool J. Wijnholds (2000) ArticleTitleA family of drug transporters: the multidrug resistance-associated proteins J. Natl. Cancer Inst. 92 1295–1302 Occurrence Handle10.1093/jnci/92.16.1295 Occurrence Handle10944550

    Article  PubMed  Google Scholar 

  77. F. Goldwasser I. Bae M. Valenti K. Torres Y. Pommier (1995) ArticleTitleTopoisomerase I-related parameters and camptothecin activity in the colon carcinoma cell lines from the National Cancer Institute anticancer screen Cancer Res. 55 2116–2121 Occurrence Handle7743511

    PubMed  Google Scholar 

  78. E. Gupta F. Luo A. Lallo S. Ramanathan V. Vyas E. Rubin P. Sinko (2000) ArticleTitleThe intestinal absorption of camptothecin, a highly lipophilic drug, across Caco-2 cells is mediated by active transporter(s) Anticancer Res. 20 1013–1016 Occurrence Handle10810389

    PubMed  Google Scholar 

  79. J. Ma M. Maliepaard K. Nooter W. J. Loos H. J. Kolker J. Verweij G. Stoter J. H. Schellens (1998) ArticleTitleReduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line Br. J. Cancer 77 1645–1652 Occurrence Handle9635842

    PubMed  Google Scholar 

  80. A. C. Croce G. Bottiroli R. Supino E. Favini V. Zuco F. Zunino (2004) ArticleTitleSubcellular localization of the camptothecin analogues, topotecan and gimatecan Biochem. Pharmacol. 67 1035–1045 Occurrence Handle10.1016/j.bcp.2003.10.034 Occurrence Handle15006540

    Article  PubMed  Google Scholar 

  81. J. Ark-Otte Particlevan M. A. Kedde J. Vijgh Particlevan der A. M. Dingemans W. J. Jansen H. M. Pinedo E. Boven G. Giaccone (1998) ArticleTitleDeterminants of CPT-11 and SN-38 activities in human lung cancer cells Br. J. Cancer 77 2171–2176 Occurrence Handle9649129

    PubMed  Google Scholar 

  82. J. Cummings G. Boyd B. T. Ethell J. S. Macpherson B. Burchell J. F. Smyth D. I. Jodrell (2002) ArticleTitleEnhanced clearance of topoisomerase I inhibitors from human colon cancer cells by glucuronidation Biochem. Pharmacol. 63 607–613 Occurrence Handle10.1016/S0006-2952(01)00812-7 Occurrence Handle11992628

    Article  PubMed  Google Scholar 

  83. O. C. Trifan W. F. Durham V. S. Salazar J. Horton B. D. Levine B. S. Zweifel T. W. Davis J. L. Masferrer (2002) ArticleTitleCyclooxygenase-2 inhibition with celecoxib enhances antitumor efficacy and reduces diarrhea side effect of CPT-11 Cancer Res. 62 5778–5784 Occurrence Handle12384538

    PubMed  Google Scholar 

  84. M. Kool M. Haas Particlede G. L. Scheffer R. J. Scheper M. J. Eijk Particlevan J. A. Juijn F. Baas P. Borst (1997) ArticleTitleAnalysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines Cancer Res. 57 3537–3547 Occurrence Handle9270026

    PubMed  Google Scholar 

  85. S. Jorajuria N. Dereuddre-Bosquet F. Becher S. Martin F. Porcheray A. Garrigues A. Mabondzo H. Benech J. Grassi S. Orlowski D. Dormont P. Clayette (2004) ArticleTitleATP binding cassette multidrug transporters limit the anti-HIV activity of zidovudine and indinavir in infected human macrophages Antiviral Ther. 9 519–528

    Google Scholar 

  86. R. G. Manzano K. A. Wright P. R. Twentyman (1996) ArticleTitleModulation by acrolein and chloroacetaldehyde of multidrug resistance mediated by the multidrug resistance-associated protein (MRP) Clin. Cancer Res. 2 1321–1326 Occurrence Handle9816303

    PubMed  Google Scholar 

Download references

Acknowledgments

This work is funded by the National University of Singapore Academic Research Funds (Nos. R-148-000-054-112, R-148-000-047-101, and R-183-000-105-112).

Author information

Authors and Affiliations

  1. Department of Pharmacy, Faculty of Science, National University of Singapore, Science Drive 4, Singapore, 117543, Singapore

    Quan Tian, Jing Zhang, Eli Chan, Sui Yung Chan, Urs Alex Boelsterli, Paul Chi-Lui Ho & Shufeng Zhou

  2. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Theresa May Chin Tan, Wei Duan & Hongyuan Yang

  3. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Urs Alex Boelsterli, Jin-Song Bian & Yi-Zhun Zhu

  4. Department of Clinical Pharmacology, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, China

    Min Huang

  5. ICU Unit, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangzhou, China

    Weiping Xiong

  6. Department of Maternal Medicine, Affiliated Hospital of Obstetrics and Gynaecology, Fudan University, Shanghai, China

    Xiaotian Li

Authors
  1. Quan Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Theresa May Chin Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eli Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sui Yung Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Urs Alex Boelsterli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul Chi-Lui Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hongyuan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jin-Song Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Min Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yi-Zhun Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Weiping Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xiaotian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Shufeng Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shufeng Zhou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tian, Q., Zhang, J., Tan, T.M.C. et al. Human Multidrug Resistance Associated Protein 4 Confers Resistance to Camptothecins. Pharm Res 22, 1837–1853 (2005). https://doi.org/10.1007/s11095-005-7595-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-005-7595-z

Key Words

Search

Navigation