Chronic Lymphocytic Leukaemia (CLL) is a disease of B-lymphocytes that
account for significant morbidity and mortality in mostly elderly patients (aged ≥ 70
years). The relative survival of patients with CLL has been shown to decrease with
patient age, and this age-related reduction in survival was found to correlate with the
levels of two inflammatory cytokine levels in the patients’ plasma. The levels of two
inflammatory cytokines, interleukin-6 and -8 (IL-6, IL-8) were found to correlate
positively with patient age, and increased levels were associated with lower overall
survival. Addition of IL-6 or IL-8 to a co-culture system of CLL cells with bone marrow
stromal cells increased the CLL-stromal cell adhesion, and co-culturing increased IL-8
secretion. In a search of a treatment regimen that may be effective and readily tolerated
by elderly patients, we examined the combination of fludarabine with valproic acid
(VPA), an epileptic that was found to inhibit histone deacetylases (HDACs). The
combination was synergistic against human leukaemic cells, including primary CLL cells.
In a phase II clinical trial where six elderly patients with relapsed, previously treated CLL
were enrolled (half of whom were clinically refractory to fludarabine), the VPAfludarabine
combination induced reduction in the peripheral and lymph node tumour
loads. Mechanistically, the fludarabine treatment induced disruption of the lysosomes,
while VPA induced increase in the level and activity of cathepsin B, a lysosomal protease.
The VPA-induced increase in cathepsin B levels was observed in in cell lines (in vitro),
primary CLL cells (ex vivo) and in patients treated with VPA (in vivo). Chemical
inhibition of cathepsin B was sufficient to dampen the VPA-fludarabine cytotoxicity, and
the addition activated cathepsin B to leukaemic cell lysates was sufficient to induce
caspase cleavage and reduction in anti-apoptotic protein levels. The VPA-fludarabine
combination also lowered phospho-Akt levels and ATM activation, which also
contributed to the VPA-fludarabine synergy, and VPA treatment lowered ATM levels
and phospho-Akt levels in vivo.
In summary, there lies a biological explanation for the poor survival observed
with elderly patients, and the VPA-fludarabine may be a useful regimen for these patients.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:MWU.1993/23317 |
| Date | 09 1900 |
| Creators | Yoon, Ju-Yoon |
| Contributors | Gibson, Spencer B (Biochemistry and Medical Genetics), Davie, James R (Biochemistry and Medical Genetics) HayGlass, Kent T (Immunology) Johnston, James B (Internal Medicine) Spaner, David (University of Toronto) |
| Publisher | Informa Healthcare, Springer, Nature |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Detected Language | English |
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