Fludarabine, a nucleoside analogue, is commonly used in combination with other agents for the treatment of chronic lymphocytic leukaemia (CLL). In previous studies, valproic acid (VPA), an inhibitor of histone deacetylases, combined with fludarabine to synergistically increase apoptotic cell death in CLL cells. In the present study, we found that the combination of fludarabine and VPA decreases the level of the anti-apoptotic proteins Mcl-1 and XIAP in primary CLL cells. Treatment with fludarabine alone, or in combination with VPA, led to the loss of lysosome integrity, and chemical inhibition of the lysosomal protease cathepsin B, using CA074-Me, was sufficient to reduce apoptosis. VPA treatment increased cathepsin B levels and activities in primary CLL cells, thereby priming CLL cells for lysosome-mediated cell death. Six previously treated patients with relapsed CLL were treated with VPA, followed by VPA/fludarabine combination. The combined therapy resulted in reduced lymphocyte count in five out of six and reduced lymph node sizes in four out of six patients. In vivo VPA treatment increased histone-3 acetylation and cathepsin B expression levels. Thus, the synergistic apoptotic response with VPA and fludarabine in CLL is mediated by cathepsin B activation leading to a decrease in the anti-apoptotic proteins.

Cooling the living organism slows the rate of the metabolic processes. Bigelow, Lindsay, and Greenwood (1950) showed that one effect of hypothermia was that an animal would survive for a longer period when deprived of its circulation. For the first time, therefore, it became possible to shut off the circulation completely, open one of the chambers of the heart, and repair certain intracardiac abnormalities (Lewis, Varco, and Taufic, 1954;Swan, Zeavin, and Blount, 1953). Serious obstacles were soon met when attempts were made to extend the application of this principle in the treatment of more complicated defects. If the surgeon required more than eight or 10 minutes of circulatory occlusion, he found himself sailing between Scylla and Charybdis, for prolonging the period of circulatory occlusion resulted in permanent damage to the central nervous system and further lowering of the temperature inevitably caused ventricular fibrillation.A wealth of time and effort has been spent in trying to overcome fibrillation associated with hypothermia, but, although a new ray of hope appears every few months, there is still no certain method of preventing it. Thus the early promise of hypothermia was not immediately fulfilled, and attention continued to be focused on the development of extracorporeal circulation. In the past five years the pioneering work of Miller, Gibbon, and Fineberg (1953) and many others has gone forward on many fronts, resulting in the development of cardiopulmonary bypass systems which are highly efficient and which carry minimal risk to the patient when employed by expert teams.And yet the enthusiasts of hypothermia were not idle. The direct attack on ventricular fibrillation had failed for the moment, but recently an outfilanking manceuvre has made it possible to deal with this hazard. The heart was apparently the weak link in

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