Broad-spectrum modulation of ATP-binding cassette transport proteins by the taxane derivatives ortataxel (IDN-5109, BAY 59-8862) and tRA96023
- First Online:
- 113 Downloads
The taxanes paclitaxel and docetaxel are substrates for P-glycoprotein (Pgp), an ATP-binding cassette (ABC) transport protein associated with multidrug resistance (MDR). In contrast, the synthetic taxane ortataxel (BAY 59-8862, IDN-5109) is effective against Pgp-expressing cells by virtue of modulation of Pgp-mediated transport. The synthetic taxane tRA96023 also modulates Pgp and is noncytotoxic due to removal of the tubulin-binding side chain at the C-13 position of the taxane backbone. We studied the effects of ortataxel and tRA96023 on the other MDR-associated ABC transport proteins, multidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP, MXR, ABCG2).
Modulation of mitoxantrone, daunorubicin and doxorubicin retention and cytotoxicity by ortataxel and tRA96023 was studied in established cell lines overexpressing Pgp, MRP-1 and wild type (BCRPR482) and mutant (BCRPR482T) BCRP, and was compared with modulation by the established Pgp-, MRP-1- and BCRP-specific modulators PSC-833, probenecid and fumitremorgin C, respectively.
Ortataxel effectively modulated drug retention and cytotoxicity in cell lines overexpressing MRP-1 and BCRPR482, in addition to Pgp. tRA96023 modulated drug retention and cytotoxicity in cell lines overexpressing BCRPR482 and Pgp, but not those overexpressing MRP-1. Neither ortataxel nor tRA96023 modulated BCRPR482T.
The synthetic taxane derivatives ortataxel and tRA96023 are broad-spectrum ABC protein modulators. Further studies will seek to identify a noncytotoxic synthetic taxane that modulates Pgp, MRP-1 and BCRP.
KeywordsTaxanes P-glycoprotein Multidrug resistance protein Breast cancer resistance protein Modulation
- 1.Baer MR, George SL, Dodge RK, O’Loughlin KL, Minderman H, Caligiuri MA, Anastasi J, Powell BL, Kolitz JE, Schiffer CA, Bloomfield CD, Larson RA (2002) Phase III study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B study 9720. Blood 100:1224–1232PubMedGoogle Scholar
- 3.Casazza AM, Fairchild CR (1996) Paclitaxel (taxol) mechanisms of resistance. In: Hait WN (ed) Drug resistance. Kluwer Academic Publishers, Boston, pp 149–171Google Scholar
- 6.Creaven PJ, Eckhardt SG, Hamm J, Schwartz G, Sutton JW, Kaidbey J, Lathia C, Bernacki R, Ramnath NA (2002) Phase I and pharmacokinetic study of a novel taxane BAY-59-8862. Proc Am Soc Clin Oncol 21:100aGoogle Scholar
- 9.Gollapudi S, Kim CH, Tran BN, Sangha S, Gupta S (1997) Probenecid reverses multidrug resistance in multidrug resistance-associated protein-overexpressing HL60/AR and H69/AR cells but not in P-glycoprotein-overexpressing HL60/Tax and P388/ADR cells. Cancer Chemother Pharmacol 40:150–158CrossRefPubMedGoogle Scholar
- 13.Guerci A, Merlin JL, Missoum N, Feldmann L, Marchal S, Witz F, Rose C, Guerci O (1995) Predictive value for treatment outcome in acute myeloid leukemia of cellular daunorubicin accumulation and p-glycoprotein expression simultaneously determined by flow cytometry. Blood 85:2147–2153PubMedGoogle Scholar
- 16.Horwitz SB, Cohen D, Rao S, Ringel I, Shen H-J, Yang C-PH (1993) Taxol: mechanisms of action and resistance. Natl Cancer Inst Monogr 15:55–61Google Scholar
- 20.Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen I-M, Head DR, Appelbaum FR, Willman CL (1997) Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 89:3323–3329PubMedGoogle Scholar
- 21.Leith CP, Kopecky KJ, Chen I-M, Eijdems L, Slovak ML, McConnell TS, Head DR, Weick J, Grever MR, Appelbaum FR, Willman CL (1999) Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 94:1086–1099PubMedGoogle Scholar
- 26.Minderman H, Suvannasankha A, O’Loughlin KL, Allen J, Schinkel A, Scheper RJ, Scheffer GL, Robey R, Bates SE, Baer MR (2002) P-glycoprotein, multidrug resistance-associated protein and breast cancer resistance protein-mediated transport: substrate and modulator specificity. Proc Am Assoc Cancer Res 43:496Google Scholar
- 29.Ojima I, Slater JC, Michaud E, Kuduk SD, Bounaud PY, Vrignaud P, Bissery MC, Veith JM, Pera P, Bernacki RJ (1996) Syntheses and structure-activity relationships of the second-generation antitumor taxoids: exceptional activity against drug-resistant cancer cells. J Med Chem 39:3889–3896CrossRefPubMedGoogle Scholar
- 36.Roche Diagnostics (2003) Cell proliferation agent WST-1 (pack insert). http://www.roche-applied-science.com/pack-insert/1644807a.pdfGoogle Scholar