We report the structure-activity relationship of quinoline and quinazoline derivatives, which include urea, thiourea, urethane, and acylthiourea groups, as inhibitors of the platelet-derived growth factor (PDGF) receptor autophosphorylation. Our previous studies showed that the quinoline and quinazoline derivatives including urea, thiourea, and carbamate groups were highly potent compounds as the PDGF receptor autophosphorylation inhibitor, but these compounds did not exhibit receptor selectivity between the PDGF receptor and the c-kit receptor. As a result of further synthesis and biological evaluation, we have found that the quinoline and quinazoline-acylthiourea derivatives showed not only good inhibitory activity for the PDGF receptor but also receptor selectivity between the PDGF receptor and the c-kit receptor. Furthermore N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(2-methylbenzoyl)thiourea exhibited potent oral efficacy in in vivo assay using the rat carotid balloon injury model. Therefore, the quinoline and quinazoline-acylthiourea derivatives may be expected to have potential as therapeutic agents for the treatment of restenosis.
Objective : To determine the effectiveness of acupuncture therapy on hiesho in maturate stage females. Design : Multicenter, randomized, prospective, open blind, waiting list-controlled trial. Setting : A clinical center attached to three universities and one vocational school. Participants : Twenty two females between 18-39 years of age and with a level of more than four points on the "hiesho sensation scale" proposed by Kusumi et al for hiesho.Interventions : Participants were randomly assigned to receive therapies of either acupuncture or no therapy (waiting list controls). Acupuncture therapy was provided by needle retention to SP 6 and electro-acupuncture therapy to BL 32 at a frequency of 1 Hz for 20 minutes. One session per week of this therapy was provided for a total of four sessions.Method of Measurement : The primary outcome of change in hiesho intensity was measured using the visual analogue scale (VAS). Secondary changes were measured by an eight heading score and three component summaries of the standard edition SF-36 v 2.Results : The statistical analyses used an intent-to-treat analysis that included two participants who dropped out, and the mixture of one participant targeted for exclusion who was censored from the analyses. As a result, 21 participants were classified as either in the acupuncture group (n = 12) or the control group (n = 9). Efficacy with acupuncture therapy was not found for effect size (Cohen d , point-biserial correlation r) for VAS and the scores of SF-36 between the two groups.Conclusions : Effectiveness of the acupuncture therapy was not found, which suggests that it may be due to the smaller sample size, frequency of intervention, and symptoms associated with autonomic dysfunction.
HM1.24/BST-2 (CD317) is a type II transmembrane protein that was originally identified as a cell surface antigen overexpressed on multiple myeloma (MM) cells. Our previous studies have demonstrated that HM1.24 has a potential as an attractive target molecule for antibody-based or cellular-mediated immunotherapy of MM. Subsequent studies have revealed that rat homologue of HM1.24 at the cell surface can be internalized and localized to the intracellular trans-Golgi network, suggesting that HM1.24 may play an important role in trafficking and signaling. To evaluate the potential effect of HM1.24-targeting therapy in MM, we generated internalizing fully human monoclonal antibodies specific for human HM1.24 by using KM mice. Among these monoclonal antibodies, b-76-8 had the highest affinity to HM1.24 and induced ADCC activity and complement-dependent cytotoxicity in the presence of immune effectors. Importantly, b-76-8 internalized rapidly after cell surface binding and approximately 80% of b-76-8 was delivered to the intracellular location within 30 min as determined by immunofluorescence staining of b-76-8-treated RPMI 8226 cells. We next developed the immunoconjugate of b-76-8 with the analog of the cytotoxic drug maytansine, DM1 [N2′-deacetyl-N2′-(3-mercapto-1-oxopropyl)-maytansine] and further evaluated its potential impact on MM cells. The ratio of DM1 molecules linked per antibody molecule was 1.8–3.0. Several MM cell lines as well as primary MM cells were cultured with either b-76-8, DM1, b-76-8-DM1, or control IgG-DM1, and cell viability was determined by a WST-8 assay. Treatment with b-76-8-DM1 (2–10 nM, based on the concentration of DM1) induced 50–70% of cell death in RPMI 8226, KMS12-BM, and IM-9 cells. In contrast, the relevant amount of b-76-8, DM1 (10 nM), or control IgG-DM1 (10 nM) did not inhibit growth of these MM cells. Of interest, T-cell lines such as MOLT-4 and CEM also expressed HM1.24; however, these cells showed minimal cytotoxicity (<10%) to b-76-8-DM1 (10 nM) despite having a similar sensitivity to DM1. On the other hand, primary MM cells from 5 patients were relatively resistant to DM1, but maximal cytotoxicity (10–40%) was achieved at the concentration of 250 nM by b-76-8-DM1 but not by control IgG-DM1. This dose of b-76-8-DM1 did not mediate significant cytotoxicity against normal bone marrow mononuclear cells. We finally examined the anti-tumor activity of b-76-8-DM1 in an xenograft model of human MM. SCID mice were inoculated intravenously with IM-9 cells, and groups of 8 mice were treated with control IgG, b-76-8, b-76-8 mixed with free DM1, or b-76-8-DM1 on day 5–8. Treatment with b-76-8 (160 μg/dose) alone or b-76-8 together with DM1 (1.9 nmol/dose) significantly prolonged survival of these mice (p<0.01). In contrast, administration of b-76-8-DM1 (160 μg/dose) resulted in more significant tumor regression including complete remission in 3 of 8 mice (p<0.003). These results suggest that HM1.24 might be involved in trafficking between the cell surface and intracellular sites of MM cells, and that the immunoconjugate targeting HM1.24 provides a novel therapeutic approach in patients with MM.
The receptor tyrosine kinase FGFR and its ligand fibroblast growth factor (FGF) play important roles in cell growth, migration, and survival. Dysregulation of the FGFR/FGF signaling pathway has been found in many human malignancies. K-983 was identified as a novel, potent, and orally active small molecule inhibitor of FGFR. The anti-tumor activity of K-983 was evaluated in a rat xenograft models. K-983 displayed dose dependent anti-tumor efficacy. K-983 demonstrated dose dependent inhibition of FGFR phosphorylation and prolonged survival in a mouse peritoneal dissemination model of gastric cancer. Furthermore, K-983 was examined using an orthotopic model of human scirrhous gastric cancer in nude mouse. K-983 (80 mg/kg) was orally administered once daily to the mice for 28 days. Histopathological examination revealed that K-983 inhibited tumor growth at inoculated site, invasion in gastric wall and metastasis to other organs. K-983 also significantly prolonged the survival of mice in this orthotopic tumor model. In summary, these results demonstrated the promising therapeutic potential of K-983 in anticancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4779. doi:1538-7445.AM2012-4779
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