Differences in rhodamine-123 efflux in B-type chronic lymphocytic leukemia suggest possible gender and stage variations in drug-resistance gene activity

Abstract

Peripheral blood samples from 61 patients (36 male, 25 female) with all stages of B-type chronic lymphocytic leukemia (CLL) were studied for MDR1 phenotype using monoclonal antibodies and rhodamine-123 dye exclusion, a functional assay of MDR1 expression. The duration of the disease varied from 1 month to 22 years at the time of initial study. Overall, 74% of the patients were positive for rhodamine-123 exclusion. When analyzed by gender, significantly more men than women were positive (89% versus 48%, p<0.001). There were more positive men than women for every stage of the disease. Female patients were found to be either MDR1 phenotype positive or negative at any stage of the disease. In contrast, all male patients with early (stages 0-II) disease were MDR1 phenotype positive. One early-stage (stage II) male patient converted from rhodamine-efflux positive to rhodamine-efflux negative as he progressed from stage-II to stage-IV disease. We suggest that some of the differences in disease biology of male versus female CLL patients (women having a more benign course) may be due to gender-dependent differences in drug-resistance gene activity, including MDR1. Our results also emphasize the need to take into account gender in evaluating the clinical course of patients with CLL.

Gender Differences in the Membrane Transport of Endogenous and Exogenous Compounds

“…In humans, hepatic Pgp (total) protein expression is 2-fold higher in men than in women (Schuetz et al, 1995), suggesting that the drug disposition of Pgp substrates could be different between genders, resulting in differences in drug efficacy and toxicity between males and females. Interestingly, there are gender-related differences in Pgp expression and functional activity in peripheral blood samples of subjects with B-type chronic lymphocytic leukemia, with significantly more men (89%) than women (48%) being MDR1 phenotype-positive (Steiner et al, 1998). These findings are consistent with the overall better prognosis for women with chronic lymphocytic leukemia than for men (Steiner et al, 1998).…”

“…Interestingly, there are gender-related differences in Pgp expression and functional activity in peripheral blood samples of subjects with B-type chronic lymphocytic leukemia, with significantly more men (89%) than women (48%) being MDR1 phenotype-positive (Steiner et al, 1998). These findings are consistent with the overall better prognosis for women with chronic lymphocytic leukemia than for men (Steiner et al, 1998).…”

Gender Differences in P-Glycoprotein Expression and Function: Effects on Drug Disposition and Outcome

“…Two prominent examples include a study by Steiner and coworkers, who demonstrated that in B-cell chronic lymphocytic leukemia 89% men were positive for functional P-gp drug efflux as measured by Rh123 dye exclusion versus 48% women at all stages of disease. This corresponded with women having a more benign clinical course [86]. Likewise expression of ABCB1 was independently associated with gender with males displaying significantly higher expression of P-gp than females in PBMC isolated from HIV patients.…”

Genotyping chronic lymphocytic leukemia in China: East meets West

“…This is interesting, since most drugs used to treat CLL are not MDR1 substrates. It is interesting that rhodamine efflux (a measure of MDR1 activity) was more common in male CLL patients, whose clinical course is more aggressive than that of female patients with CLL [9]. This suggests that alterations in drug metabolizing genes including MDR1 may influence the clinical course and response to therapy in patients with CLL, including gender effects.…”