Effects of orally active taxanes on P-glycoprotein modulation and colon and breast carcinoma drug resistance.

Abstract

BACKGROUND:

The taxane paclitaxel (Taxol) is often of limited efficacy in chemotherapeutic regimens because some cancer cells express high levels of the efflux pump, P-glycoprotein (Pgp), which removes the drug from the cells. The orally active paclitaxel analog IDN-5109 has been reported to overcome Pgp-mediated drug resistance. We tested whether IDN-5109 acts by modulating Pgp activity.

METHODS:

Human MDA435/LCC6mdr1 and MDA435/LCC6 breast carcinoma cells, which express and do not express Pgp, respectively, were incubated with [3H]IDN-5109 and paclitaxel to determine intracellular drug accumulation. Flow cytometry was used to analyze intracellular retention of two Pgp substrates, rhodamine 123 (Rh-123) and doxorubicin, in both breast carcinoma cell lines and in human colon carcinoma cells (SW-620, DLD1, and HCT-15, whose Pgp levels vary) treated with different taxanes. The effects of IDN-5109 and paclitaxel on tumor growth in vivo were studied with the use of tumors established through xenografts of Pgp-expressing SW-620 and DLD1 cells in severe combined immunodeficiency mice. All statistical tests were two-sided.

RESULTS:

Pgp-expressing cells treated with IDN-5109 or with the taxane-based drug resistance reversal agent tRA96023, which blocks Pgp activity, retained 8.1- and 9.4-fold more Rh-123 (P =.0001), respectively, and 1.7- and 1.9-fold more doxorubicin (P =.001), respectively, than cells treated with paclitaxel. Non-Pgp-expressing cells treated similarly demonstrated no increased retention of either substrate. MDA435/LCC6mdr1 cells retained 5.3-fold more [3H]IDN-5109 than [3H]paclitaxel after 2 hours (P =.01). IDN-5109 showed statistically significantly higher tumor growth inhibition than paclitaxel against the SW-620 xenograft (P =.003).

CONCLUSIONS:

IDN-5109 modulates Pgp activity, resulting in superior tumor growth inhibition against Pgp-expressing tumors as compared with paclitaxel. IDN-5109 may broaden the spectrum of taxane use to include colon tumors.

• Authors: M R Vredenburg, I Ojima, J Veith, P Pera, K Kee, F Cabral, A Sharma, P Kanter, W R Greco, R J Bernacki
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 93 Issue 16 Pg. 1234-45 (Aug 15 2001) ISSN: 0027-8874 [Print] United States
• PMID: 11504769 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antibiotics, Antineoplastic
• Antineoplastic Agents, Phytogenic
• Bridged-Ring Compounds
• Taxoids
• Doxorubicin
• IDN 5109
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (drug effects, metabolism)
• Administration, Oral
• Animals
• Antibiotics, Antineoplastic
• Antineoplastic Agents, Phytogenic (pharmacokinetics, pharmacology)
• Breast Neoplasms (drug therapy, metabolism)
• Bridged-Ring Compounds (administration & dosage, pharmacology)
• Colonic Neoplasms (drug therapy, metabolism)
• Doxorubicin (pharmacokinetics)
• Drug Screening Assays, Antitumor (methods)
• Female
• Flow Cytometry
• Fluorescence
• Humans
• Male
• Paclitaxel (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
• Taxoids
• Tissue Distribution
• Transplantation, Heterologous
• Tumor Cells, Cultured