PURPOSE: We have previously shown that neuroblastomal cell lines established from patients after intensive chemotherapy show sustained resistance to various drugs and especially high resistance to etoposide (up to 51 times higher than a clinically achievable level). To determine whether topoisomerase I inhibitors (topotecan and CPT- 11) are effective against etoposide-resistant neuroblastomas, we studied the response to topotecan and the active metabolite of CPT-11 (SN-38) in 19 cell lines with a spectrum of sensitivities to etoposide. MATERIALS AND METHODS: The panel included cell lines established at diagnosis and after disease progression either during induction chemotherapy or after myeloablative therapy supported with bone marrow transplantation. Cytotoxicities of topotecan, SN-38, and etoposide were determined using a microplate digital image microscopy (DIMSCAN) assay with a 4-log dynamic range. RESULTS: All six etoposide-resistant cell lines were resistant to topotecan and SN-38 (resistance defined as LC90 higher then clinically achievable levels for the drug). Significant cross-resistance by Pearson's correlation analysis (r > or = 0.6) occurred between topotecan + etoposide, topotecan + SN-38, and etoposide + SN-38. CONCLUSIONS: Topotecan and CPT-11 do not have significant activity against most etoposide-resistant neuroblastoma cell lines and this suggests that agents other than topoisomerase inhibitors should be explored for the treatment of recurrent neuroblastomas.
PURPOSE: We have previously shown that neuroblastomal cell lines established from patients after intensive chemotherapy show sustained resistance to various drugs and especially high resistance to etoposide (up to 51 times higher than a clinically achievable level). To determine whether topoisomerase I inhibitors (topotecan and CPT- 11) are effective against etoposide-resistant neuroblastomas, we studied the response to topotecan and the active metabolite of CPT-11 (SN-38) in 19 cell lines with a spectrum of sensitivities to etoposide. MATERIALS AND METHODS: The panel included cell lines established at diagnosis and after disease progression either during induction chemotherapy or after myeloablative therapy supported with bone marrow transplantation. Cytotoxicities of topotecan, SN-38, and etoposide were determined using a microplate digital image microscopy (DIMSCAN) assay with a 4-log dynamic range. RESULTS: All six etoposide-resistant cell lines were resistant to topotecan and SN-38 (resistance defined as LC90 higher then clinically achievable levels for the drug). Significant cross-resistance by Pearson's correlation analysis (r > or = 0.6) occurred between topotecan + etoposide, topotecan + SN-38, and etoposide + SN-38. CONCLUSIONS:Topotecan and CPT-11 do not have significant activity against most etoposide-resistant neuroblastoma cell lines and this suggests that agents other than topoisomerase inhibitors should be explored for the treatment of recurrent neuroblastomas.
Authors: Min H Kang; Malcolm A Smith; Christopher L Morton; Nino Keshelava; Peter J Houghton; C Patrick Reynolds Journal: Pediatr Blood Cancer Date: 2010-10-04 Impact factor: 3.167
Authors: Julie R Park; Jeffrey R Scott; Clinton F Stewart; Wendy B London; Arlene Naranjo; Victor M Santana; Peter J Shaw; Susan L Cohn; Katherine K Matthay Journal: J Clin Oncol Date: 2011-10-17 Impact factor: 44.544
Authors: Thorsten Simon; Alfred Längler; Urs Harnischmacher; Michael C Frühwald; Norbert Jorch; Alexander Claviez; Frank Berthold; Barbara Hero Journal: J Cancer Res Clin Oncol Date: 2007-05-04 Impact factor: 4.553
Authors: W Cai; N V Maldonado; W Cui; N Harutyunyan; L Ji; R Sposto; C P Reynolds; N Keshelava Journal: Br J Cancer Date: 2010-10-05 Impact factor: 7.640
Authors: Yin Liu; Hong-Wei Wu; Michael A Sheard; Richard Sposto; Srinivas S Somanchi; Laurence J N Cooper; Dean A Lee; Robert C Seeger Journal: Clin Cancer Res Date: 2013-02-01 Impact factor: 12.531
Authors: William A May; Rita S Grigoryan; Nino Keshelava; Daniel J Cabral; Laura L Christensen; Jasmine Jenabi; Lingyun Ji; Timothy J Triche; Elizabeth R Lawlor; C Patrick Reynolds Journal: PLoS One Date: 2013-12-02 Impact factor: 3.240