Chronic lymphatic leukemia. Peroral cladribine as primary treatment

Ten patients with newly diagnosed B-chronic lymphocytic leukaemia were treated with cladribin orally for five days every four weeks with a median of four series. This is the first reported clinical study where a purine analogue is administered orally. The tumour reducing effect was fast. Eight out of 10 patients responded with a partial or clinical complete remission. Two of these were in molecular biological complete remission. With an observation time of 22 months we have seen no serious side effects so far. A randomized study (including a long term follow up) between chlorambucil, fludarabin and cladribin is needed to clarify the future role of cladribin in B-CLL treatment.     

Increased intracellular concentrations of doxorubicin in resistant lymphoma cells in vivo by concomitant therapy with verapamil and cyclosporin A

The tumor cell uptake of doxorubicin was studied in vivo in cells from 2 patients with clinically resistant leukemic lymphomas treated with continuous infusions of doxorubicin 9 mg/m2 and vincristine with oral dexamethasone. After 24 hours, intravenous or oral verapamil was added and in one treatment course intravenous cyclosporin A was given. Plasma and intracellular doxorubicin concentrations and plasma concentrations of verapamil and norverapamil were determined with HPLC. In the 1st patient the intracellular uptake rate of doxorubicin was increased from 0.007 to 0.013 nmol/mg protein/h after the start of verapamil infusion. In the first treatment course of patient number 2, the intracellular concentration of doxorubicin was increased by 280% during a 6-h infusion of verapamil. When this patient in the next treatment course was given oral verapamil, no significant effect on doxorubicin uptake was seen. However, when 100 mg of cyclosporin A was added in three intravenous injections at 8-h intervals, the doxorubicin concentration in the tumor cells increased from 0.027 to 0.086 nmol/mg protein. In conclusion, this study shows that the intracellular concentrations of doxorubicin can be increased also in vivo during patient therapy by the addition of verapamil or cyclosporin A.     

Pharmacokinetics of cladribine in plasma and its 5''-monophosphate and 5''-triphosphate in leukemic cells of patients with chronic lymphocytic leukemia

PURPOSE: To determine whether microtubule- and actin-altering drugs, which have been shown to increase aqueous humor outflow, cause cellular contraction in human trabecular meshwork (HTM) cells. METHODS: HTM cells were plated in culture dishes containing a polymerized deformable silicone substrate. After 48 hours, the dishes were placed on an inverted microscope and treated with ethacrynic acid, colchicine, vinblastine, cytochalasin B, or 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) and then recorded on videotape for 15 minutes. An increase in silicone substrate wrinkle size and/or number indicated a contraction. Sham controls were used. RESULTS: Cellular contraction was observed with ethacrynic acid, colchicine, and vinblastine in the 10(-5) to 10(-4) M dosage range. Pretreatment with H-7 blocked these effects. Cytochalasin B did not produce cellular contraction. CONCLUSIONS: Microtubule disruption causes cellular contraction in HTM cells, and this effect depends on an intact actin cytoskeleton network. Contraction of trabecular meshwork cells in response to various stimuli is an attractive hypothesis for possible homeostatic mechanisms in the outflow pathway, and this may serve as a focus for novel glaucoma drug development.     

Protein binding of 2-chloro 2'-deoxyadenosine (cladribine) in healthy subjects and in patients with leukaemia

The plasma protein binding of 2-chloro-2'-deoxyadenosine (CdA) at 37 degrees C was studied by ultrafiltration in 5 healthy volunteers, in 11 patients with haematological malignancies and in purified protein preparations. In the patients, the binding of CdA to plasma proteins was 25.0% and in healthy subjects it was 21.1%. In a solution of human serum albumin (40 g.l-1), 24.3% CdA was bound, but less than 5% was bound in a solution of alpha 1-acid-glycoprotein (0.7 g.l-1). No dependence of binding on the concentration of CdA was found within a range 25-1000 nmol.l-1. In conclusion, due to its limited binding to plasma proteins, any change in the binding of CdA is unlikely to have a major influence on its pharmacological effect.     

Increased frequency of chromosome abnormalities in fibroblasts from hairy cell leukemia patients

A hereditary component is implicated in many different cancers, including hairy cell leukemia (HCL), and may involve an instability of the genome. We have previously documented recurrent clonal and non-clonal chromosomal abnormalities in hairy cells. To ascertain whether this instability of the genome is restricted to the malignant cells or if it might also include normal cells we performed cytogenetic investigations on skin fibroblasts and hairy cells from eight HCL patients and skin fibroblasts from eight referents. The frequency of chromosome abnormalities, regardless of clonality, was significantly increased in the fibroblasts from patients compared to referents. Also, five patients compared to one referent showed clonal abnormalities in their fibroblasts. Immunohistochemical investigations excluded the possibility that the fibroblast cultures were contaminated with hairy cells. Two patients had constitutional abnormalities, inv(5)(p13.1q13.3) and t(13;14), and one additional patient, possibly mosaic, showed the same abnormality, inv(9)(p21-22q22), in both fibroblasts (17/30) and blood (5/21) cells. Aberrations in patient fibroblasts also included sporadic inv(5), del(6)q, inv(19), and del(20)q, abnormalities previously shown to occur in hairy cells. A clonal expansion with trisomy 7 occurred in vitro as documented by fluorescence in situ hybridization (FISH). The only clonal abnormality occurring in a referent was -Y/-Y,+15 in an elderly male. In conclusion, a constitutional chromosomal instability may precede chromosome abnormalities and be of importance in the development of hairy cell leukemia.     

Hyperplastic neuroretinopathy and disorder of pigment epithelial cells precede accelerated retinal degeneration in the SJL/N mouse

We have found a complex eye disease in the SJL/N mouse. This animal is closely related to the SJL/J mouse, which is homozygous for retinal degeneration (rd) and which also suffers from extraocular reticulum cell sarcomas at around 200 days of age. In the SJL/N animal, a high incidence of subretinal tumor is present at 9 days after birth. Furthermore, we have observed an extensive neuroretinal hyperplasia, a phenomenon that is termed "hyperplastic neuroretinopathy", and that is probably the consequence of elevated levels of cytokines in the animals. In addition to these anomalies, the SJL/N mouse shows progressive dystrophy of the retinal pigment epithelium (RPE) from day 4 onwards, and accelerated photoreceptor cell degeneration is completed by day 16. The early RPE dystrophy appears to be a secondary autoimmune disease, since cells in this structure and in the choroid develop MHC class II antigens, whereas we suspect that the accelerated photoreceptor cell loss is induced by a soluble toxic agent. The F1 progeny derived from cross-breeding the SJL/N and Balb/c +/+ strains also shows a high incidence of subretinal tumor and hyperplastic neuroretinopathy, but neither the RPE dystrophy nor retinal degeneration.     

A comparison of structural and mechanical properties in cancellous bone from the femoral head and acetabulum

Mechanical interlock obtained by penetration of bone cement into cancellous bone is critical to the success of cemented total hip replacement (THR). Although acetabular component loosening is an important mode of THR failure, the properties of acetabular cancellous bone relevant to cement penetration are not well characterized. Bone biopsies (9 mm diameter, 10 mm long) were taken from the articular surfaces of the acetabulum and femoral head during total hip replacement. After mechanical and chemical defatting the two groups of bone specimens were characterized using flow measurement, mechanical testing and finally serial sectioning and three-dimensional computer reconstruction. The mean permeabilities of the acetabular group (1.064 x 10(-10) m2) and femoral group (1.155 x 10(-10) m2) were calculated from the flow measurements, which used saline solution and a static pressure of 9.8 kPa. The mean Young's modulus, measured non-destructively, was 47.4 MPa for the femoral group and 116.4 MPa for the acetabular group. Three-dimensional computer reconstruction of the specimens showed no significant differences in connectivity and porosity between the groups. Results obtained using femoral head cancellous bone to investigate bone cement penetration and fixation are directly relevant to fixation in the acetabulum.     

Learning the Value of a New Currency From Prices.

In European countries, field studies investigate how citizens acquire knowledge of the new currency, the euro. In 3 laboratory experiments, the authors recruited 168 undergraduates to examine whether such accurate knowledge is acquired from learning prices in the new currency. The results show fast learning of prices of duration of cellular phone calls (quantity) when the prices were proportional to quantity. Inferences of call duration from given prices were likewise found to be accurate. Lower accuracy was however observed for one-to-many mappings of quantity on price and the inverse one-to-many mappings of price on quantity. Price variation may be an important reason for the difficulty in learning the value of the new currency observed in field studies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Learning the value of money from stochastically varying prices.

In 3 experiments, the authors investigated learning of the value of money from product prices in an unfamiliar currency when the prices are proportional to quantity. In support of the second stage of a hypothesized 2-stage process of learning, Experiment 1, in which 32 undergraduates participated, shows that response times for inferences of quantity are longer when participants are presented with quantity-price pairs than when they are presented with price-quantity pairs. Experiments 2 and 3, in which 54 and 34 undergraduates participated, respectively, show that (a) stochastic price variation causes systematic errors in the learning of unit prices from quantity-price pairs as a result of judgmental regression effects and (b) in support of the 2-stage learning hypothesis, inferences of quantity are the inverse of the learned unit prices. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Simvastatin impairs mitogen-induced proliferation of malignant B-lymphocytes from humans—in vitro and in vivo studies

Chronic lymphocytic leukemia (CLL) cells express lower low density lipoprotein (LDL) receptor activity and higher 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity than normal mononuclear blood cells indicating that CLL cells may depend on cholesterol synthesis for their proliferation. We studied the effects of competitive inhibitors of HMG-CoA reductase on malignant lymphocyte proliferation in vitro and in vivo. Tumor B-cells from 13 patients with CLL, hairy cell leukemia, or immunoblastic B-cell lymphoma were cultured for 4 d in the presence of B-cell mitogens and cholesterol synthesis inhibitors. Simvastatin and lovastatin suppressed, in a concentration-dependent manner, the mitogen-induced cellular thymidin uptake in medium with 10% human AB-serum or lipoprotein-deficient serum. Pravastatin was active only in medium with lipoprotein-deficient serum. Ten previously untrated patients with CLL received simvastatin orally, 40 mg daily for 12 wk. Mean reductions in total plasma and LDL cholesterol were 30% (range 9–46%) and 37% (range 16–63%), respectively. Cells from four patients showed moderate to minor increases in the degradation rate of ¹²⁵I-LDL suggesting that the need for exogenous cholesterol had increased, three patients showed an increase in HMG-CoA reductase activity, and the cells from one patient showed both. There was no significant change in the clinical disease status during medication. However, four of the ten patients developed a therapy-demanding progressive disease during the subsequent year. Further clinical studies with cholesterol synthesis inhibitors in leukemia are warranted.