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MDR-1 expression in non-Hodgkin's lymphomas is unrelated to treatment intensity or response to therapy
M C Finnegan1, J Royds, J R Goepel
1Department of Clinical Oncology, Sheffield University Medical School, England, UK.
Abstract:
Over-expression of the MDR-1 gene, which codes for P-glycoprotein, is thought to be an important mechanism in the drug resistance exhibited by many tumours. A number of chemotherapeutic agents which induce MDR-1 expression are also components of combination chemotherapies that are used in the treatment of high grade non-Hodgkin's lymphomas (NHL). We have therefore examined expression of MDR-1 in a series of NHL by Northern blot analysis as well as investigated the localization of P-glycoprotein by immunohistochemistry. The series included 11 hyperplastic reactive nodes and tonsils, 17 low grade NHL and 15 high grade NHL. The levels of MDR-1 mRNA were quantified by scanning densitometry and comparison with levels of glucose-6-phosphate dehydrogenase (G6PD). The MDR-1 mRNA was observed in both non-malignant and NHL tissues. Immunohistochemical staining revealed that expression of MDR-1 mRNA in reactive nodes was related to the presence of P-glycoprotein in lymphocytes, however, P-glycoprotein was apparent in both the reactive lymphocytes and tumour cells in the NHL samples. Elevated mRNA levels (2-3 fold increase) were observed in some low grade and high grade NHL relative to those observed in reactive lymphoid tissue. There appeared to be little correlation, however, between expression of the MDR-1 gene and either treatment intensity or response to therapy. The drug resistance that is often encountered in NHL patients is therefore likely to involve mechanisms other than over-expression of P-glycoprotein.
Insights
Drug resistance in non-Hodgkin's lymphomas (NHL) may not be primarily due to P-glycoprotein. MDR-1 gene expression was found in NHL tissues, but its correlation with treatment response was minimal, suggesting other resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Over-expression of the MDR-1 gene, coding for P-glycoprotein, is a known factor in tumor drug resistance.
- MDR-1 inducers are used in treating high-grade non-Hodgkin's lymphomas (NHL).
Purpose of the Study:
- To investigate MDR-1 gene and P-glycoprotein expression in NHL.
- To determine the correlation between MDR-1 expression and drug resistance in NHL patients.
Main Methods:
- Northern blot analysis for MDR-1 mRNA expression.
- Immunohistochemistry for P-glycoprotein localization.
- Quantification of mRNA levels using scanning densitometry and G6PD comparison.
Main Results:
- MDR-1 mRNA and P-glycoprotein were present in both non-malignant and NHL tissues.
- Elevated MDR-1 mRNA levels (2-3 fold) were observed in some NHL cases compared to reactive tissues.
- Little correlation was found between MDR-1 gene expression and treatment intensity or response.
Conclusions:
- P-glycoprotein over-expression is likely not the primary driver of drug resistance in NHL.
- Alternative mechanisms are probably responsible for the drug resistance observed in NHL patients.