Predicting resistance or response to chemotherapy by proton magnetic resonance spectroscopy in neuroblastoma.
BACKGROUND
We previously showed that proton magnetic resonance spectroscopy (1H-MRS) enables estimation of neuroblastoma tumor viability. Here we investigated if 1H-MRS can predict response or resistance to chemotherapy in neuroblastoma.


METHODS
Neuroblastoma cell lines with various drug sensitivities were treated with cytotoxic drugs (cisplatin, etoposide, and irinotecan) and examined by 1H-MRS. Viability was assessed by trypan blue staining and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Nude rats carrying drug-sensitive or drug-resistant neuroblastoma xenografts were treated for 4 days with irinotecan (n = 11) or saline (n = 11) and were examined with 1H-MRS at 4.7 T before and during treatment. The Wilcoxon matched-pairs test was used to test statistical significance of difference within treatment groups. Independent groups were compared using the Mann-Whitney U test. Correlation was assessed with Spearman's rank correlation. All statistical tests were two-sided.


RESULTS
Cytotoxic drug treatment of drug-sensitive SH-SY5Y neuroblastoma cells resulted in increased methylene and polyunsaturated fatty acid resonances and decreased choline resonance. The methylene/choline ratio correlated with cell death (r(s) = .94, P<.001) and was increased in cisplatin-treated drug-sensitive (SH-SY5Y, IMR-32) but not drug-resistant [SK-N-BE2, SK-N-FI, SK-N-AS] cell lines. No changes were observed in SK-N-BE2 cells treated with irinotecan or cisplatin, whereas circumvention of the resistance by arsenic trioxide treatment led to lipid accumulation and choline depletion. Irinotecan therapy of rats carrying drug-sensitive xenografts caused the methylene/choline ratio of tumors to increase eightfold after 3 days (95% confidence interval [CI] = fivefold to 12-fold; P = .005 compared with pretreatment spectra at day 0) and caused tumors to regress statistically significantly on day 10 compared with pretreatment volume on day 0 (difference = -60%, 95% CI = -12% to -100%, n = 6; P = .012). The methylene/choline ratio of nonregressing drug-resistant xenografts was unaffected. No differences were observed after saline treatment.


CONCLUSIONS
Response or resistance to chemotherapy is accurately predicted by 1H-MRS in experimental neuroblastoma models in vivo.
Lindskog
Magnus
M
Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden. magnus.lindskog@kbh.ki.se.
Spenger
Christian
C
Jarvet
Jüri
J
Gräslund
Astrid
A
Kogner
Per
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002794:Choline / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006838:Hydrocarbons; D000077146:Irinotecan; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D016555:Matched-Pair Analysis; D008697:Methane / Q000031:analogs & derivatives* / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011237:Predictive Value of Tests; D011522:Protons; D051381:Rats; D011923:Rats, Nude; D015203:Reproducibility of Results; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D006838:Hydrocarbons; D011522:Protons; C030011:carbene; D005047:Etoposide; D000077146:Irinotecan; D002794:Choline; D008697:Methane; D002945:Cisplatin; D002166:Camptothecin