Type B Niemann-Pick disease (NPD) is a nonneuronopathic lysosomal storage disorder which is characterized by accumulation of sphingomyelin-laden macrophages. The availability of plasma markers for storage cells may be of great value in facilitating therapeutic decisions. Given the similarity of the storage cells in NPD and Gaucher disease, we studied Gaucher plasma markers (chitotriosidase and CCL18) in two siblings homozygous for the R228C mutation in acid sphingomyelinase (ASM) and a type B course of NPD. The older sibling, first examined at the age of 9 months, showed marked hepatosplenomegaly and pulmonary involvement. The younger sibling has mild asymptomatic hepatosplenomgaly at the age of 5 months. Analysis of plasma specimens revealed markedly increased levels of chitotriosidase and CCL18 in the older sibling. In the younger child also, plasma chitotriosidase and CCL18 were clearly elevated above normal values almost immediately after birth and rapidly increased further. Histochemistry confirmed production of CCL18 by foam cells. In conclusion, plasma chitotriosidase and CCL18 may also serve as markers for the formation of pathological lipid-laden macrophages in type B NPD, in analogy to Gaucher disease. The availability of sensitive plasma surrogate markers may be of great value for monitoring the efficacy of enzyme supplementation therapy that is currently being developed.
The cytotoxic effect of 1--D-arabinofuranosyl cytosine (araC) depends on the intracellular phosphorylation into its active compound araCTP, on the degree of degradation of araCTP and on the incorporation of araCTP into DNA. Deoxycytidine triphosphate (dCTP) inhibits the phosphorylation of araC (by feedback inhibition of the enzyme deoxycytidine kinase) and the incorporation of araCTP into DNA (by competition for DNA polymerase). In a T-lymphoblastic cell line, we studied whether the cytotoxicity of araC (2 nM-50 M) could be enhanced by decreasing the concentration of dCTP, using the nucleoside-analogue cyclopentenyl cytosine (CPEC), an inhibitor of the enzyme CTP synthetase. Preincubation of the cells with CPEC (100 -1,600 nM) for 2 hr increased the concentrations of araCMP 1.6 -9.5-fold, which was significant for each concentration of CPEC used. The concentration of araCDP remained low, whereas the concentration of araCTP changed depending on the concentration of araC used. With 2-15 M of araC and a preincubation with 400 nM of CPEC, the araCTP concentration increased by 4 -15% (not significant), and the total amount of araC nucleotides increased significantly by 21-45%. When using a concentration of araC of 2 nM after a preincubation with CPEC of 100 nM, the concentration of araCMP increased by 60% (p ؍ 0.015), whereas that of araCTP decreased by 10% (p ؍ 0.008). This was compensated by an increase of 41% (p ؍ 0.005) of araCTP incorporation into DNA, which represented 43% of all araC metabolites. Moreover, by performing pulse/chase experiments with 400 nM of CPEC and 2 M of araC, the retention of cytosolic araCTP and the incorporated amount of araCTP into DNA were increased by CPEC. The modulation by CPEC of araC metabolism was accompanied by a synergistic increase of araC-induced apoptosis and by an additive effect on the araC-induced growth inhibition. © 2002 Wiley-Liss, Inc. Key words: cytarabine; deoxycytidine kinase; dCTP; CTP synthetase; cyclopentenyl cytosine 1--D arabinofuranosyl cytosine (araC) is a nucleoside analogue that constitutes the main drug of virtually all treatment protocols for AML and proved its benefit in precursor-B acute lymphocytic leukemia (ALL) and T-ALL. 1-3 One can distinguish low-dose (LD-araC) regimens, applying doses of 75-200 mg/m 2 , from high-dose (HD-araC) regimens where 1-3 g/m 2 are used. The cytotoxic effect of araC depends on several intracellular mechanisms: araC is metabolized into arabinofuranosyl cytosine triphosphate (araCTP) by 3 consecutive phosphorylating steps, catalyzed by deoxycytidine kinase (dCK), nucleoside monophosphate (NMP) kinase and nucleoside diphosphate (NDP) kinase, respectively (Fig. 1). AraCTP is incorporated into DNA as a deoxynucleotide-analogue, where it exerts its cytotoxic properties by inhibiting DNA replication. 4 -6 The phosphorylation of araC into araCTP can be counteracted by the enzyme (deoxy)cytidine deaminase, which converts araC into arabinofuranosyl uracil (araU), dCMP deaminase, converting arabinofuranosyl cytosine mon...
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