Effects of Orally Active Taxanes on P-Glycoprotein Modulation and Colon and Breast Carcinoma Drug Resistance
| Autor: | Kristin Kee, Peter Kanter, Jean M. Veith, Fernando Cabral, William R. Greco, Amarnath Sharma, Iwao Ojima, Michael R. Vredenburg, Paula Pera, Ralph J. Bernacki |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Bridged-Ring Compounds
Male Cancer Research medicine.medical_specialty Paclitaxel medicine.medical_treatment Transplantation Heterologous Administration Oral Breast Neoplasms Rhodamine 123 Fluorescence chemistry.chemical_compound In vivo Internal medicine Tumor Cells Cultured polycyclic compounds medicine Animals Humans Tissue Distribution Doxorubicin ATP Binding Cassette Transporter Subfamily B Member 1 P-glycoprotein Chemotherapy Antibiotics Antineoplastic Taxane biology business.industry Flow Cytometry Antineoplastic Agents Phytogenic Endocrinology Oncology chemistry Colonic Neoplasms Cancer cell Cancer research biology.protein Female Taxoids Drug Screening Assays Antitumor business medicine.drug |
| Zdroj: | JNCI Journal of the National Cancer Institute. 93:1234-1245 |
| ISSN: | 1460-2105 0027-8874 |
| Popis: | 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/LCC6 mdr1 and MDA435/LCC6 breast carcinoma cells, which express and do not express Pgp, respectively, were incubated with [ 3 H]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, DLD 1 , 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 DLD 1 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 doxo-rubicin (P = .001), respectively, than cells treated with paclitaxel. Non-Pgp-expressing cells treated similarly demonstrated no increased retention of either substrate. MDA435/ LCC6 mdr1 cells retained 5.3-fold more [ 3 H]IDN-5109 than [ 3 H]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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|