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Sodium Thiosulfate Administered Six Hours after Cisplatin Does Not Compromise Antineuroblastoma Activity

Authors' Affiliations: ¹ Developmental Therapeutics Program, USC-CHLA Institute for Pediatric Clinical Research and Division of Hematology-Oncology Department of Pediatrics, Keck School of Medicine, University of Southern California and Children's Hospital Los Angeles, Los Angeles, California; ² Department of Chemistry, University of San Diego, San Diego, California; and ³ Department of Neurology, Oregon Health and Science University, Portland, Oregon

Requests for reprints: C. Patrick Reynolds, Developmental Therapeutics Program, USC-CHLA Institute for Pediatric Clinical Research, MS 57, Childrens Hospital Los Angeles, Los Angeles, CA 90027. Phone: 323-361-5646; Fax: 323-664-9226; E-mail: preynolds{at}chla.usc.edu.

Purpose: We determined if the potentially otoprotective agent sodium thiosulfate (STS) could be given 6 h after cisplatin without diminishing the antineuroblastoma activity of cisplatin in human neuroblastoma cell lines in vitro (including cisplatin-resistant cell lines) and in neuroblastoma xenografts in vivo.

Experimental Design: We determined the antineuroblastoma activity of cisplatin with or without the addition of STS at 0 or 6 h after cisplatin in six neuroblastoma cell lines, both in standard cell culture conditions (20% O₂) and in physiologic hypoxia (2% O₂). Drug cytotoxicity was measured using the DIMSCAN fluorescence/digital imaging microscopy assay. In vivo studies of cisplatin combined with STS used a human neuroblastoma subcutaneous xenograft model (SMS-SAN) in athymic nu/nu mice.

Results: A significant protection against cisplatin cytotoxicity was seen when the neuroblastoma cells were exposed to cisplatin directly combined with STS. However, when cisplatin was given first and STS exposure occurred 6 h later, no effect on cisplatin cytotoxicity was observed. In a subcutaneous neuroblastoma xenograft model in nu/nu mice, mice receiving cisplatin alone or cisplatin + STS at 6 h had significantly better progression-free survival rates (P < 0.03) compared with controls or mice treated with cisplatin + STS concurrently. There was no statistically significant difference in outcomes between mice treated with cisplatin alone and the group treated with cisplatin followed by STS 6 h later (P = 0.9).

Conclusion: These preclinical data suggest that the use of STS 6 h after cisplatin for otoprotection is unlikely to compromise the antineuroblastoma activity of cisplatin.

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