Role of chemotherapy resistance genes in outcome of neuroblastoma.
BACKGROUND
Neuroblastoma is a heterogeneous pediatric disease. Most patients with localized disease usually have a favorable prognosis, but patients with advanced disease have a poor prognosis despite combination chemotherapy. Treatment failure may be attributable to resistance to cytotoxic drugs.


METHODS
Using quantitative RT-PCR, we investigated the clinical significance of the level of mRNA expression of multidrug resistance genes (MDR1, MRP1, MRP5, LRP) in a series of 29 advanced neuroblastoma samples.


RESULTS
At the end of induction chemotherapy, 48% of patients achieved a clinical complete response, 28% achieved a partial response or stable disease, and 24% presented progressive disease. MDR1 mRNA overexpression (i.e., mRNA level >2 copies of MDR1 gene) was observed in 74% of samples, and MRP1, MRP5, LRP overexpression was observed less frequently (30, 33, and 33% of samples, respectively). None of these parameters were predictive of response, relapse, or survival. However, clinical response to treatment was highly predictive of relapse-free survival and overall survival.


CONCLUSIONS
High expression of these multidrug resistance genes in advanced neuroblastoma is not the main parameter of response to cytotoxic drugs; clinical response to treatment remains the most important parameter in predicting the prognosis of patients with advanced neuroblastoma, until other relevant laboratory parameters have been identified.
de Cremoux
Patricia
P
Department of Tumor Biology, Institut Curie, 26 rue d'Ulm, Paris Cedex, France. patricia.de-cremoux@curie.net
Jourdan-Da-Silva
Nathalie
N
Couturier
Jérôme
J
Tran-Perennou
Carine
C
Schleiermacher
Gudrun
G
Fehlbaum
Pascale
P
Doz
François
F
Mosseri
Véronique
V
Delattre
Olivier
O
Klijanienko
Jerzy
J
Vielh
Philippe
P
Michon
Jean
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000648:ultrastructure; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D003199:Computer Systems; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D019450:Genes, MDR; D016259:Genes, myc; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase; D016896:Treatment Outcome; D020394:Vault Ribonucleoprotein Particles / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014750:Vincristine / Q000008:administration & dosage / Q000494:pharmacology; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016190:Carboplatin; D002945:Cisplatin; D003520:Cyclophosphamide; D004317:Doxorubicin; D005047:Etoposide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D020394:Vault Ribonucleoprotein Particles; D014750:Vincristine; D000099187:Major Vault Protein; C120809:ABCC5 protein, human; C421109:multidrug resistance-associated protein 1