+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Cross-resistance to antifolates in multidrug resistant cell lines with P-glycoprotein or multidrug resistance protein expression



Cross-resistance to antifolates in multidrug resistant cell lines with P-glycoprotein or multidrug resistance protein expression



Biochemical Pharmacology 53(12): 1855-1866



Resistance to some (lipophilic) antifolates has been associated with P-glycoprotein (P-gp)mediated multidrug resistance (MDR). A possible relationship with non-P-gp MDR has not been established. We studied resistance to antifolates in SW-1573 human lung carcinoma cells, a P-gp overexpressing variant SW-1573/2R160 and a multidrug resistance protein (MRP) overexpressing variant SW-1573/2R120. In this study, thymidylate synthase (TS) inhibitors with different properties concerning the efficiency of membrane transport and the efficiency of polyglutamytation were tested for cross-resistance in SW-1573/2R120 and SW-1573/2R160 cells. Growth inhibition patterns in this cell line panel were measured by the Sulforhodamine B (SRB) assay. Resistance factors for TS inhibitors were: 2.4 and 0.4 for 5-fluorouracil (5FU), 18.8 and 8.8 for ZD1694, 17 and 0.7 for AG337, and 40 and 8.3 for BW1843U89 in SW-1573/2R160 and SW-1573/2R120, respectively. This study showed changes in the TS enzyme kinetics during the induction of doxorubicin resistance in both SW-1573 variants, resulting in 2-fold lower K-m values for 2'-deoxyuridine-5'-monophosphate (dUMP) in both resistant variants compared to the parental cell line. TS activity, TS protein induction and TS mRNA expression all had 2-fold increased in the SW-1573/2R120 compared to the SW-1573/2R160. 3H-MTX influx was 2-fold lower in SW-1573/2R160 cells compared to SW-1573/2R120 and SW-1573 cells. In the SW-1573/2R160 cell line, an aberrant intracellular trafficking towards the target TS was observed, compared to SW-1573/2R120 and SW-1573 cells as measured by the TS in situ assay. The rate of TS inhibition by the TS inhibitors used in this study was similar in all cell tines. In conclusion, collateral sensitivity to 5FU and the lipophilic AG337 and cross-resistance to other antifolates were observed in non-P-gp MDR SW-1573/2R120 cells, as well as resistance to all antifolates in P-gp SW-1573/2R160 cells. The mechanism of resistance in SW-1573/2R160 cells possibly involves reduced influx and changes in intracellular trafficking, routes. For the SW-1573/2R120 cell line, several changes related to the TS enzyme possibly play a role in the observed cross-resistance and collateral sensitivity pattern.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 008399727

Download citation: RISBibTeXText

PMID: 9256160

DOI: 10.1016/s0006-2952(97)82448-3


Related references

Expression of ATP binding cassette superfamily (multidrug resistance-1, multidrug resistance-associated protein, human canalicular multispecific organ anion transporter) mRNA in etoposide and m-AMSA resistant cell lines. Gan to Kagaku Ryoho. Cancer and ChemoTherapy 24(13): 1941-1946, 1997

Sequential gene expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and lung resistance protein: functional activity of P-gp and MRP present in the doxorubicin-resistant human K562 cell lines. Anti-Cancer Drugs 12(3): 247-258, 2001

Multidrug resistance-associated protein expression in multidrug resistant cell lines and leukemias. Blood 82(10 Suppl. 1): 258A, 1993

Comparison of furosemide and vinblastine secretion from cell lines overexpressing multidrug resistance protein (P-glycoprotein) and multidrug resistance-associated proteins (MRP1 and MRP2). Pharmacology 64(3): 126-134, 2002

Expression of multidrug resistance-associated protein (MRP), MDR1 and DNA topoisomerase II in human multidrug-resistant bladder cancer cell lines. British Journal of Cancer 71(5): 907-913, 1995

Probenecid reverses daunorubicin resistance in multidrug resistant tumor HL60/AR and H69/AR cell lines that overexpress multidrug resistance-associated protein. Proceedings of the American Association for Cancer Research Annual Meeting 36: 345, 1995

Reversion of P-glycoprotein-mediated multidrug resistance by guggulsterone in multidrug-resistant human cancer cell lines. European Journal of Pharmacology 694(1-3): 39-44, 2012

Multidrug resistance in small cell lung cancer: expression of P-glycoprotein, multidrug resistance protein 1 and lung resistance protein in chemo-naive patients and in relapsed disease. Lung Cancer 54(2): 235-240, 2006

P-glycoprotein and multidrug resistance-associated protein mediate specific patterns of multidrug resistance in malignant glioma cell lines, but not in primary glioma cells. Brain Pathology 13(4): 482-494, 2003

The activity of latent benzoperimidine esters to inhibit P-glycoprotein and multidrug resistance-associated protein 1 dependent efflux of pirarubicin from several lines of multidrug resistant tumor cells. Cancer Detection and Prevention 28(4): 283-293, 2004

Reversal of multidrug resistance by verapamil and modulation by alpha 1-acid glycoprotein in wild-type and multidrug-resistant Chinese hamster ovary cell lines. Cancer Research 50(9): 2818-2822, 1990

Expression of P-glycoprotein and multidrug resistance-associated protein in peripheral blood mononuclear cells from multidrug resistant tuberculosis patients. Zhonghua Jie he He Hu Xi Za Zhi 34(7): 520-522, 2011

Expression of multidrug resistance proteins P-glycoprotein, multidrug resistance protein 1, breast cancer resistance protein and lung resistance related protein in locally advanced bladder cancer treated with neoadjuvant chemotherapy: biological and clinical implications. Journal of Urology 170(4 Pt 1): 1383-1387, 2003

Histopathological assessment of multidrug resistance in gastric cancer: expression of P-glycoprotein, multidrug resistance-associated protein, and lung-resistance protein. Surgery Today 29(5): 401-406, 1999

Multidrug resistance-associated protein 7 expression is involved in cross-resistance to docetaxel in salivary gland adenocarcinoma cell lines. International Journal of Oncology 30(2): 393-401, 2007