Although the Abelson (Abl) tyrosine kinase inhibitor imatinib mesylate has improved the treatment of breakpoint cluster region-Abl (Bcr-Abl)-positive leukemia, resistance is often reported in patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib resistance, these inhibitors are less specific than imatinib.We have identified a specific dual Abl-Lyn inhibitor, NS-187 (elsewhere described as CNS-9), which is 25 to 55 times more potent than imatinib in vitro. NS-187 is also at least 10 times as effective as

Background: Primary lymphomatous effusion is a rare lymphoma that arises in the body cavity and has a peculiar proliferative form, lacking a tumor. This primary lymphomatous effusion includes human herpes virus 8 (HHV8)-related primary effusion lymphoma (PEL) and HHV8-unrelated PEL-like lymphoma. We attempted to clarify the nature of the primary lymphomatous effusion. Methods: Using ‘PEL’ and ‘body cavity-based lymphoma’ (BCBL) as key words, reports written in English were collected from PubMed. Primary lymphomatous effusion was defined as BCBL with primary effusion and without tumor at onset. Adding our 2 PEL-like lymphoma cases, each case was studied as to the patients’ and lymphomas’ characteristics, therapy and survival time. Moreover, each item was compared among four groups according to the presence of HHV8 and HIV. Results: In 214 cases investigated, there was no difference in proliferation, but an apparent difference in age, gender, phenotype, effectiveness and prognosis among the four groups. Conclusions: Both PEL and PEL-like lymphoma are thought to be characterized by a peculiar proliferation, regardless of the presence of HHV8. Dividing PEL or PEL-like lymphoma into two subgroups on the basis of HIV presentation might also be appropriate.

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IntroductionImatinib mesylate (Gleevec; imatinib [Glivec]; formerly STI571), a specific inhibitor of ABL tyrosine kinase, is efficacious in treating Philadelphia chromosome-positive (Ph ϩ ) leukemias such as chronic myeloid leukemia (CML) and Ph ϩ acute lymphoblastic leukemia (ALL). 1,2 Within a few years of its introduction to the clinic, imatinib mesylate had dramatically altered the first-line therapy for CML, because it was found that most patients with newly diagnosed CML in the chronic phase (CP) achieved durable responses when treated with imatinib mesylate. 3 However, a small percentage of these patients, as well as most patients with advanced-phase CML and Ph ϩ ALL, relapse on imatinib mesylate therapy. 2,4 Several mechanisms of refractoriness and relapse have been reported, including point mutations within the ABL kinase domain, amplification of the bcr-abl gene, overexpression of bcr-abl mRNA, [5][6][7][8] increased drug efflux via a process mediated by P-glycoprotein (P-gp), 9 and activation of the Src-family protein Lyn. [10][11][12] There has recently been an increase in the numbers of reported cases of isolated central nervous system (CNS) relapse in which mainly patients with CML-blast crisis (BC) and Ph ϩ ALL who continued to have complete cytogenetic responses (CCgR) developed an extramedullary BC in the CNS. [13][14][15][16][17][18][19][20][21][22] Leis et al 23 reported that isolated CNS relapse occurred in 5 (20.8%) of 24 patients whose protocols included imatinib mesylate treatment, whereas Pfeifer et al 24 reported that CNS leukemia developed in 13 (12.1%) of 107 patients with Ph ϩ ALL. Isolated CNS relapse may be due to a limited penetration of imatinib mesylate into the cerebrospinal fluid (CSF), because it has been shown that concentrations of imatinib mesylate in the CSF are 1 to 2 orders of magnitude lower than the corresponding plasma levels. [24][25][26][27] Brain endothelial cells are characterized by their barrier properties, including tight junctions and various selective transporters. One of the transporters in the BBB, P-gp, which is expressed at the luminal side of the endothelial cells of the capillaries in the brain, plays an important role in drug efflux from the brain. Preclinical in vitro and in vivo studies have shown that imatinib mesylate is a substrate for P-gp, so that P-gp limits the distribution of imatinib mesylate to the brain. 28,29 The CNS can thereby become a sanctuary site of relapse in patients who are on prolonged imatinib mesylate therapy.To overcome resistance to imatinib mesylate, we recently developed a specific dual BCR-ABL/Lyn inhibitor, , which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent than The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. Materials and methods Reagents ...