Sodium thiosulfate administered six hours after cisplatin does not compromise antineuroblastoma activity.
OBJECTIVE
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.


METHODS
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% O(2)) and in physiologic hypoxia (2% O(2)). 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).


CONCLUSIONS
These preclinical data suggest that the use of STS 6 h after cisplatin for otoprotection is unlikely to compromise the antineuroblastoma activity of cisplatin.
Harned
Theresa M
TM
Developmental Therapeutics Program, USC-CHLA Institute for Pediatric Clinical Research, Keck School of Medicine, University of Southern California and Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Kalous
Ondrej
O
Neuwelt
Alexander
A
Loera
Jason
J
Ji
Lingyun
L
Iovine
Peter
P
Sposto
Richard
R
Neuwelt
Edward A
EA
Reynolds
C Patrick
CP
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D016190:Carboplatin / Q000627:therapeutic use / Q000633:toxicity; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use / Q000633:toxicity; D013885:Thiosulfates / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D013885:Thiosulfates; D016190:Carboplatin; C017717:sodium thiosulfate; D002945:Cisplatin