Quantitative PCR analysis of the expression profile of genes related to multiple drug resistance in tumors of the central nervous system.
OBJECTIVE
To evaluate and compare the profile of expression of genes related to drug resistance in brain tumors and to analyze the impact of the increased expression of these genes on overall survival.


METHODS
Eighty microdissected brain tumor samples from 79 patients were analyzed by RQ-PCR for the genes MDR1, MRP1, MRP3, LRP and BCRP. Protein expression was assessed by immunohistochemistry for MRP1 and LRP genes. Pediatric cases (0 to 20 years): 46 (17F:29M, median age 7.3 +/- 5.9 years); adult tumors: 33 (17F:16M, median age 46.6 +/- 14.5 years). Histological diagnoses: 21 astrocytomas I and II, 28 astrocytomas III and glioblastomas, 17 medulloblastomas, 8 ependymomas, and 6 oligodendrogliomas.


RESULTS
glial tumors expressed higher MDR1 (P = 0.003) and BCRP (P = 0.03) levels than embryonic tumors. Low-grade astrocytomas expressed high MDR1 (P = 0.001), MRP3 (P = 0.01) and LRP (P = 0.02) levels. The MRP1 gene was preferentially expressed by medulloblastomas (P = 0.04) and ependymomas (P = 0.04); ependymomas also presented an increase of LRP (P = 0.02). The mRNA levels of MRP1 and LRP genes were associated to protein expression. The profile of gene expression of primary pilocytic astrocytomas of the hypothalamus and of the other locations was similar. Increased expression of resistance genes, separately or jointly, was not correlated with shorter overall survival in patients with medulloblastomas/PNET and malignant gliomas.


CONCLUSIONS
Drug resistance genes do not explain the higher sensitivity of gliomas of the hypothalamus/pituitary/optic pathways to chemotherapy. The increased expression of resistance genes had no impact on the overall survival of patients with medulloblastomas/PNET and high grade gliomas. High MDR1, MRP3 and LRP levels may be implicated in the primary resistance of pilocytic astrocytomas to chemotherapy.
Valera
Elvis Terci
ET
Discipline of Pediatric Oncology, Department of Pediatrics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, 3900. Bairro Monte Alegre, Ribeirão Preto, SP CEP 14048-900, Brazil. etvalera@hcrp.fmrp.usp.br
Lucio-Eterovic
Agda Karina Brodoloni
AK
Neder
Luciano
L
Scrideli
Carlos Alberto
CA
Machado
Helio Rubens
HR
Carlotti-Junior
Carlos Gilberto
CG
Queiroz
Rosane Gomes de Paula
RG
Motta
Fabio José do Nascimento
FJ
Tone
Luiz Gonzaga
LG
D000293:Adolescent; D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D002138:Calibration; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics* / Q000502:physiology*; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D008875:Middle Aged; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods*; D016019:Survival Analysis
D017931:DNA Primers; D012334:RNA, Neoplasm