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Multidrug resistance gene expression in pediatric primitive neuroectodermal tumors of the central nervous system
D M Tishler1, K I Weinberg, L S Sender
1Division of Hematology, Childrens Hospital of Los Angeles, California.
Abstract:
Pediatric primitive neuroectodermal tumor (PNET) is a malignancy of the central nervous system currently treated with surgery, radiation therapy, and chemotherapy. Despite aggressive management, tumors recur in almost one-half of all patients. Drug resistance of tumor cells may, in part, explain the poor outcome. Resistance to chemotherapeutic agents may be related to expression of the multidrug resistance gene (MDR1) and its protein product, P-glycoprotein. The role of MDR1 in 16 instances of PNET was investigated using Western blot analysis to detect the expression of P-glycoprotein, messenger ribonucleic acid (mRNA), polymerase chain reaction to detect MDR1 mRNA expression, and Southern blot analysis to assess gene amplification. Analysis of proteins extracted from 15 tumors revealed that two of the 15 patients expressed detectable levels of P-glycoprotein. Polymerase chain reaction of ribonucleic acid from 12 PNET's revealed that six of the 12 patients (four of 10 de novo tumors and both recurrent tumors) expressed MDR1 mRNA. Southern blot analysis of deoxyribonucleic acid from 16 PNET's revealed no evidence of MDR1 amplification in any tumor. This is the first report of MDR1 expression in pediatric brain tumors. These data suggest a possible role for MDR1 in de novo and acquired drug resistance in PNET's.
Insights
Pediatric primitive neuroectodermal tumors (PNETs) often recur due to drug resistance. This study found multidrug resistance gene (MDR1) expression in some PNETs, suggesting its role in treatment failure.
Area of Science:
- Oncology
- Molecular Biology
- Neuroscience
Background:
- Pediatric primitive neuroectodermal tumors (PNETs) are aggressive central nervous system malignancies.
- Current treatments (surgery, radiation, chemotherapy) have limited success, with nearly 50% of patients experiencing tumor recurrence.
- Drug resistance in PNET cells is a significant factor contributing to poor patient outcomes.
Purpose of the Study:
- To investigate the role of the multidrug resistance gene (MDR1) and its protein product, P-glycoprotein, in pediatric PNETs.
- To determine if MDR1 expression or amplification is associated with de novo or acquired drug resistance in PNET.
- To establish the prevalence of MDR1 expression in a cohort of pediatric PNETs.
Main Methods:
- Western blot analysis was used to detect P-glycoprotein expression in tumor protein extracts.
- Polymerase chain reaction (PCR) was employed to detect messenger ribonucleic acid (mRNA) expression of MDR1.
- Southern blot analysis was performed to assess for MDR1 gene amplification in tumor DNA.
Main Results:
- P-glycoprotein was detected in 2 out of 15 (13.3%) PNET tumor samples.
- MDR1 mRNA expression was found in 6 out of 12 (50%) PNET samples, including both de novo and recurrent tumors.
- Southern blot analysis revealed no evidence of MDR1 gene amplification in any of the 16 PNET samples.
Conclusions:
- This study provides the first evidence of MDR1 expression in pediatric brain tumors.
- The presence of MDR1 mRNA suggests a potential role for this gene in both initial and acquired drug resistance in PNET.
- These findings may open new avenues for therapeutic strategies targeting drug resistance in pediatric PNETs.