Y Hoki1, A Fujimori, Y Pommier. 1. Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Abstract
UNLABELLED: Camptothecin and its derivatives are specific inhibitors of eukaryotic topoisomerase I (top1) and are active in cancer patients against a variety of refractory solid tumors and leukemia. PURPOSE: The present study further investigated the relationship between multidrug resistance (MDR) mediated by P-glycoproteinMDR and potential resistance to camptothecin derivatives using two experimental systems: (1) MDR KB-V1 cells selected for vinblastine resistance, and (2) NIH3T3 cells transfected with a plasmid expressing wildtype P-glycoproteinMDR multidrug transporter (NIH-MDR-G185). RESULTS: We found that both KBV-1 and NIH-MDR-G185 cells were resistant to topotecan, and that topotecan-induced cleavable complexes were reduced in KB-V1 cells, consistent with a role of P-glycoproteinMDR in cellular resistance to topotecan. By contrast, no significant resistance to camptothecin, 9-aminocamptothecin, 10, 11-methylenedioxycamptothecin, or SN-38 (the active metabolite of CPT-11) was observed in NIH-MDR-G185 cells, while KB-V1 cells were cross-resistant to these compounds but produced cleavable complexes similar to those produced by parental KB-3-1 cells. CONCLUSIONS: These results suggest that topotecan is the only camptothecin tested with significant susceptibility to MDR in cell culture, and that multidrug resistant cells such as KBV1 probably exhibit additional resistance mechanisms to camptothecins besides P-glycoproteinMDR overexpression.
UNLABELLED: Camptothecin and its derivatives are specific inhibitors of eukaryotic topoisomerase I (top1) and are active in cancerpatients against a variety of refractory solid tumors and leukemia. PURPOSE: The present study further investigated the relationship between multidrug resistance (MDR) mediated by P-glycoproteinMDR and potential resistance to camptothecin derivatives using two experimental systems: (1) MDR KB-V1 cells selected for vinblastine resistance, and (2) NIH3T3 cells transfected with a plasmid expressing wildtype P-glycoproteinMDR multidrug transporter (NIH-MDR-G185). RESULTS: We found that both KBV-1 and NIH-MDR-G185 cells were resistant to topotecan, and that topotecan-induced cleavable complexes were reduced in KB-V1 cells, consistent with a role of P-glycoproteinMDR in cellular resistance to topotecan. By contrast, no significant resistance to camptothecin, 9-aminocamptothecin, 10, 11-methylenedioxycamptothecin, or SN-38 (the active metabolite of CPT-11) was observed in NIH-MDR-G185 cells, while KB-V1 cells were cross-resistant to these compounds but produced cleavable complexes similar to those produced by parental KB-3-1 cells. CONCLUSIONS: These results suggest that topotecan is the only camptothecin tested with significant susceptibility to MDR in cell culture, and that multidrug resistant cells such as KBV1 probably exhibit additional resistance mechanisms to camptothecins besides P-glycoproteinMDR overexpression.
Authors: T P Sajitha; B L Manjunatha; R Siva; Navdeep Gogna; Kavita Dorai; G Ravikanth; R Uma Shaanker Journal: J Chem Ecol Date: 2018-05-25 Impact factor: 2.626
Authors: Zhiyong Liao; Robert W Robey; Josée Guirouilh-Barbat; Kenneth K W To; Orsolya Polgar; Susan E Bates; Yves Pommier Journal: Mol Pharmacol Date: 2007-11-05 Impact factor: 4.436
Authors: Peng-Cheng Lv; Mohamed S A Elsayed; Keli Agama; Christophe Marchand; Yves Pommier; Mark Cushman Journal: J Med Chem Date: 2016-04-20 Impact factor: 7.446
Authors: U Vanhoefer; M R Müller; R A Hilger; B Lindtner; U Klaassen; N Schleucher; Y M Rustum; S Seeber; A Harstrick Journal: Br J Cancer Date: 1999-12 Impact factor: 7.640
Authors: Anita K Lalloo; Feng R Luo; Ailan Guo; Pankaj V Paranjpe; Sung-Hack Lee; Viral Vyas; Eric Rubin; Patrick J Sinko Journal: BMC Med Date: 2004-05-04 Impact factor: 8.775