Broad-spectrum modulation of ATP-binding cassette transport proteins by the taxane derivatives ortataxel (IDN-5109, BAY 59-8862) and tRA96023.
OBJECTIVE
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).


METHODS
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 (BCRP(R482)) and mutant (BCRP(R482T)) BCRP, and was compared with modulation by the established Pgp-, MRP-1- and BCRP-specific modulators PSC-833, probenecid and fumitremorgin C, respectively.


RESULTS
Ortataxel effectively modulated drug retention and cytotoxicity in cell lines overexpressing MRP-1 and BCRP(R482), in addition to Pgp. tRA96023 modulated drug retention and cytotoxicity in cell lines overexpressing BCRP(R482) and Pgp, but not those overexpressing MRP-1. Neither ortataxel nor tRA96023 modulated BCRP(R482T).


CONCLUSIONS
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.
Minderman
Hans
H
Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA.
Brooks
Tracy A
TA
O'Loughlin
Kieran L
KL
Ojima
Iwao
I
Bernacki
Ralph J
RJ
Baer
Maria R
MR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D006801:Humans; D008942:Mitoxantrone / Q000493:pharmacokinetics; D043823:Taxoids / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D043823:Taxoids; D004317:Doxorubicin; C404743:IDN 5109; D008942:Mitoxantrone; D003630:Daunorubicin