Around 20% of patients with acute lymphoblastic leukemia are Philadelphia chromosome positive (Ph-positive acute lymphoblastic leukemia) and express the Bcr/Abl tyrosine kinase. Treatment with the tyrosine kinase inhibitor Imatinib is currently standard for chronic myelogenous leukemia, which is also caused by Bcr/Abl. However, Imatinib has shown limited efficacy for treating Ph-positive acute lymphoblastic leukemia. In our study, we have investigated the effect of Imatinib therapy on murine P190 Bcr/Abl lymphoblastic leukemia cells. Three of four cultures were very sensitive to treatment with 5 Amol/L Imatinib. Significant cell death also initially occurred when the same cultures were treated in the presence of stromal support. However, after 6 days, remaining cells started to proliferate vigorously. The Bcr/Abl tyrosine kinase present in the cells that were now able to multiply in the presence of 5 Amol/L Imatinib was still inhibited by the drug. In concordance with this, the Abl ATP-binding pocket domain of Bcr/Abl in the resistant cells did not contain point mutations which would make the protein Imatinib resistant. The effect of stroma in selecting Imatinibresistant lymphoblasts did not require direct cell-cell contact. SDF-1a could substitute for the presence of stromal cells. Our results show that stroma selects Imatinib-resistant Bcr/Abl P190 lymphoblasts that are less dependent on Bcr/Abl tyrosine kinase activity. Therefore, therapy for Ph-positive acute lymphoblastic leukemia, aimed at interfering with the protective effect of stroma in combination with Imatinib, could be of benefit for the eradication of the leukemic cells. (Cancer Res 2006; 66(10): 5387-93)

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Cytosolic phospholipase A2 (cPLA2), cyclooxygenase-1 (COX-1), and cyclooxygenase-2 (COX-2) regulate the formation of physiologically active prostaglandins, the production of which is known to be elevated in several renal disorders. We studied the relevance of these enzymes in polycystic kidney disease (PKD) by using two models of the disease: a model in which decline in renal function begins in adulthood (CD1-pcy/pcy mouse) and one in which it occurs early, during growth (Han:SPRD-cy rat). Immunoblotting analyses of cytosolic and particulate kidney fractions revealed that cPLA2 levels are significantly higher (by 34-131%) in the latter stages of the disease in both models. Renal COX enzymes were found only in the particulate fractions, with COX-1 87% higher in 6-month-old CD1-pcy/pcy mice compared with normal controls, and 110% higher in male 70-day-old Han:SPRD-cy rats with cystic kidneys compared with controls. Renal COX-2 was detected only in the rats and was 58% lower in diseased kidneys of 70-day-old male Han:SPRD-cy rats, indicating that cPLA2 is coupled to COX-1 in the kidney. The altered levels of these eicosanoid-regulating enzymes has implications for the use of NSAIDS and specific COX inhibitors in individuals with this disorder.

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