Multi-drug resistance in chronic lymphocytic leukemia

Area of Science:

• Hematology
• Oncology
• Pharmacology

Background:

• Chronic lymphocyte leukemia (CLL) is a common hematologic malignancy.
• Multi-drug resistance (MDR) is a significant challenge in CLL treatment.
• P-glycoprotein (p-gp 170) is a key transporter involved in MDR.

Purpose of the Study:

• To evaluate the prevalence and characteristics of MDR in CLL patients.
• To correlate ex vivo MDR detection methods with clinical parameters.
• To assess the efficacy of PSC-833 as an MDR modulator.

Main Methods:

• Utilized ex vivo functional assays (doxorubicin retention, MTT cytotoxicity) and monoclonal antibodies to detect MDR in 45 CLL patients.
• Correlated test results with disease stage, prior treatment, and chemotherapy resistance.
• Repeated assays as patients developed resistance to alkylating agents, fludarabine, and VAD chemotherapy.

Main Results:

• MDR was frequently detected in CLL patients (64.4% in early stage, 62.2% untreated).
• P-glycoprotein (p-gp 170) was detected by MRK-16 (48%) and functional assays (40.6%).
• Functional p-gp 170 expression correlated with advancing stage and prior treatment, and predicted resistance to VAD chemotherapy.

Conclusions:

• MDR is prevalent in CLL and its p-gp 170 expression increases with disease stage.
• Ex vivo functional assays, particularly with PSC-833, effectively detect MDR and correlate with clinical outcomes.
• PSC-833 demonstrates potent MDR modulation ex vivo, outperforming cyclosporin-A.