Journal article
PAK-104P, a pyridine analogue, reverses paclitaxel and doxorubicin resistance in cell lines and nude mice bearing xenografts that overexpress the multidrug resistance protein
Clinical cancer research, Vol.2(2), pp.369-377
1996
PMID: 9816180
Abstract
Multidrug resistance (MDR) is considered multifactorial and has been associated with overexpression of the multidrug resistance protein (MRP). However, effective compounds for reversal of MRP-related MDR are limited. In the present study, the modulatory activity of the novel pyridine analogue PAK-104P on MRP-mediated resistance to doxorubicin and paclitaxel was investigated in two doxorubicin-selected human tumor cell lines [HT1080/DR4 (sarcoma) and HL60/ADR (leukemia)] and compared with the nonimmunosuppressive cyclosporine analogue PSC-833. In cell lines HT1080/DR4 (MRP/lung resistance-related protein phenotype) and HL60/ADR (MRP phenotype), doxorubicin resistance was significantly higher (250-fold and 180-fold, respectively) than that to paclitaxel (6-fold and 9-fold, respectively). With noncytotoxic concentrations of PAK-104P (1 and 5 microM), the reversal of doxorubicin resistance was significant but partial in HT1080/DR4 and HL60/ADR cells (dose-modifying factor for 5.0 microM PAK-104P, 25.0 and 31.2, respectively), whereas complete reversal of paclitaxel resistance was achieved in HL60/ADR cells. In contrast, PSC-833 modulation of doxorubicin and paclitaxel resistance was modest. Cellular drug uptake and retention studies by flow cytometry analysis demonstrated that PAK-104P was effective in restoring cellular doxorubicin concentrations in resistant cells to levels comparable to those obtained in parental cells. In athymic nude mice, PAK-104P significantly potentiated the therapeutic efficacy of doxorubicin and paclitaxel against resistant HT1080/DR4 xenografts. Of significance is that the maximum tolerated doses of doxorubicin and paclitaxel were administered in combination with PAK-104P, documenting improvement in the therapeutic index of these agents. In addition to reversing P-glycoprotein-mediated MDR, the pyridine analogue PAK-104P provides an example of an effective in vivo modulator of MRP-mediated MDR.
Details
- Title: Subtitle
- PAK-104P, a pyridine analogue, reverses paclitaxel and doxorubicin resistance in cell lines and nude mice bearing xenografts that overexpress the multidrug resistance protein
- Creators
- U Vanhoefer - Roswell Park Cancer InstituteSHOUSONG Cao - Roswell Park Cancer InstituteH Minderman - Roswell Park Cancer InstituteK Toth - Roswell Park Cancer InstituteR. J Scheper - Roswell Park Cancer InstituteM. L Slovak - Roswell Park Cancer InstituteY. M Rustum - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.2(2), pp.369-377
- Publisher
- American Association for Cancer Research
- PMID
- 9816180
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Language
- English
- Date published
- 1996
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359892802771
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