Cross-resistance of topoisomerase I and II inhibitors in neuroblastoma cell lines

Purpose: We have previously shown that neuroblastoma cell lines established from patients after intensive chemotherapy show sustained resistance to va rious drugs and especially high resistance to etoposide (up to 51 times hig her than a clinically achievable level). To determine whether topoisomerase I inhibitors (topotecan and CPT-11) are effective against etoposide-resist ant neuroblastomas, we studied the response to topotecan and the active met abolite of CPT-11 (SN-38) in 19 cell lines with a spectrum of sensitivities to etoposide. Materials and methods: The panel included cell lines establi shed at diagnosis and after disease progression either during induction che motherapy or after myeloablative therapy supported with bone marrow transpl antation. Cytotoxicities of topotecan, SN-38, and etoposide were determined using a microplate digital image microscopy (DIMSCAN) assay with a 4-log d ynamic range. Results: All six etoposide-resistant cell lines were resistan t 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 greater than or equal to 0.6) occurred between top otecan + etoposide, topotecan + SN-38, and etoposide + SN-38. Conclusions: Topotecan and CPT-11 do not have significant activity against most etoposid e-resistant neuroblastoma cell lines and this suggests that agents other th an topoisomerase inhibitors should be explored for the treatment of recurre nt neuroblastomas.