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


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.
Keshelava
N
N
Division of Hematology-Oncology, Children's Hospital Los Angeles, CA 90027, USA.
Groshen
S
S
Reynolds
C P
CP
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D000077146:Irinotecan; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D019772:Topotecan / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D000077146:Irinotecan; D019772:Topotecan; D002166:Camptothecin