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Analysis of multidrug resistance (MDR-1) gene expression in chronic lymphocytic leukaemia (CLL)
1Division of Hematology, Royal Victoria Hospital, Montreal, Quebec, Canada.
Abstract:
Multidrug resistance (MDR) in cultured human cells is caused by the overexpression of the MDR-1 gene. This gene codes for P-glycoprotein, a proposed ATP-dependent drug efflux pump, which reduces the net intracellular accumulation of a large group of chemotherapeutic agents in resistant cells. We have measured the level of expression of the human MDR-1 gene in a series of patients with chronic lymphocytic leukaemia (CLL). Forty-eight patients included in the study were at different stages of disease and were either untreated or had been treated with alkylating agents or alkylating agents in combination with drugs of the MDR spectrum, and were tested over a period of 3 years. The level of MDR-1 expression was monitored by Northern blotting analysis using a specific cDNA hybridization probe and also after polymerase chain reaction (PCR) amplification of MDR-1 complementary DNA (cDNA). Four of 28 previously untreated patients showed intrinsically high levels of MDR-1 mRNA while 5/19 treated patients had elevated MDR-1 expression. Elevated MDR-1 expression in treated patients was unrelated to the type of chemotherapy and was independent of previous exposure to drugs of the MDR spectrum. Intrinsic MDR-1 gene expression in positive patients did not appear to influence their response to chemotherapy with non-MDR drugs such as alkylating agents.
Insights
Multidrug resistance (MDR) in chronic lymphocytic leukemia (CLL) involves MDR-1 gene overexpression. Intrinsic MDR-1 expression in some untreated CLL patients did not impact alkylating agent chemotherapy response.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Multidrug resistance (MDR) in cancer is often mediated by the MDR-1 gene, which encodes P-glycoprotein, an efflux pump reducing drug accumulation.
- P-glycoprotein actively transports chemotherapeutic agents out of cells, contributing to treatment failure.
Purpose of the Study:
- To investigate the expression levels of the MDR-1 gene in patients with chronic lymphocytic leukemia (CLL).
- To determine if MDR-1 expression correlates with disease stage, treatment history, or response to chemotherapy in CLL patients.
Main Methods:
- MDR-1 gene expression was quantified in 48 CLL patients using Northern blotting and polymerase chain reaction (PCR) analysis of complementary DNA (cDNA).
- Patients included untreated individuals and those treated with alkylating agents or MDR-spectrum drugs over a 3-year period.
Main Results:
- Four of 28 (14.8%) previously untreated CLL patients exhibited intrinsically high MDR-1 mRNA levels.
- Five of 19 (26.3%) treated patients showed elevated MDR-1 expression, independent of chemotherapy type or MDR drug exposure.
- Intrinsic MDR-1 expression did not affect the response to non-MDR drugs like alkylating agents.
Conclusions:
- A subset of CLL patients, both untreated and treated, display elevated MDR-1 gene expression.
- The role of intrinsic MDR-1 expression in CLL treatment response requires further investigation, particularly concerning non-MDR agents.