Drug Resistance in Chronic Lymphocytic Leukaemia
Acta Universitatis Tamperensis No. 1602
By Ikka Kivekas
Tampere Univeristy Press
Distributed by Coronet Books
$82.50 Paper original
Background: Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the Western countries. Typically, it is a slowly progressing disease, and treatment by cytostatics is initiated after follow-up in a situation where the patient has an aggressive disease or develops general symptoms. The major obstacle in treatment is drug resistance and, moreover, multidrug resistance. Extensive research into the mechanisms or prognostic factors for chemo- or irradiation resistance has produced few clinically encouraging results.
Aims: To evaluate (I) multidrug resistance in CLL and to define the impact of (I) previous chemotherapy, (II) surface antigens, (III) the mutation status of the immunoglobulin variable region (IgHV) genes as well as (IV) programmed cell death, apoptosis, associated gene transcripts in drug and irradiation resistance in CLL.
Material and methods: Peripheral blood samples from a cohort of 36 CLL patients were collected and mononuclear cells, containing mainly CLL cells, were isolated. Nine drugs and two types of irradiation were selected according to their usefulness in CLL therapy or on the basis of their otherwise interesting mechanism of action. Doses causing 50 or 80% inhibition of living cells were measured from prednisolon (ID50) and from all other drugs and irradiations (ID80), respectively. In total, 2,376 duplicated cell cultures were performed to determinate these ID80 or ID50 values. Expressions of 34 surface antigens were analysed by means of flow cytometry. PCR assays were used to determine the mutation status of the IgHV genes. Apoptosis-associated gene mRNA expressions (anti-apoptotic: Bcl2, Mcl1, Bcl2a1, Bcl2l1; and pro-apoptotic: Bax, Myc, Dapk1) were analysed with QRT-PCR.
Results: Multidrug resistance was more common in the previously treated CLL group than the untreated group, but concordances between drug therapy and in vitro drug resistance were poor. Statistically significant correlation was confirmed between the sensitivities of the same-group drugs chlorodeoxyadenosine and fludarabine. Correlation between two P-glycoprotein-dependent drugs, vincristine and doxorubicin, was not demonstrated (I). There were no correlations between the investigated surface antigens and drug or irradiation sensitivities. The nucleoside analogues’ (chlorodeoxyadenosine and fludarabine) responses could be divided in two groups by their CD80 expression; every patient expressing the CD80 surface antigen was sensitive to nucleoside analogues, whereas all resistant cases had low or negative CD80 expression (II). IgHV mutation status divided the CLL patients in two groups, unmutated (67%) and mutated (33%), but statistically significant differences could not be confirmed in the drug or irradiation sensitivities between these groups (III). A higher amount of cell-death-inductive pro-apoptotic gene transcripts did not induce drug or irradiation sensitivity, and a higher amount of cell-death-preventive anti-apoptotic gene transcripts did not induce drug or irradiation resistance (IV).
Conclusion: Chemotherapy induces drug and irradiation resistance. Drug resistance does not always develop against the used chemotherapeutic agent, as chemotherapy may also expose to drug resistance against some other agents. CD80 could be a surrogate chemosensitivity marker for nucleoside analogues. The IgHV genes’ mutation status or apoptosis-associated genes are not determinants of drug or irradiation resistance in vitro.
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