Universidad Católica Santo Toribio de. Mogrovejo Integrantes Calderón Dávila Ana Elisa Pinglo Chapiama Wendy Narro Julca Miguel Angel. ley (Pickett) Burwell, and Mary Johnston. (Burwell) Butler; and papers, . Virginia Historical Society, P.O. Box , Richmond, VA Full Name and. DER. ADMINISTRATIVO; DER. CONSTITUCIONAL; Asistencia legal; Defensoría del Pueblo. Justia Legal Resources. Find a Lawyer.
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Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Pharmacokinetic study of LDD A phase 2 trial of the FLT3 inhibitor lestaurtinib CEP as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. From the metabolite information acquired from the pharmacokinetic experiments, the major metabolite LDD is expected to contribute to the anti-tumor effects of LDD Imprinting Control Region; IC Experiences from FLT3 inhibitor clinical trials have accumulated, and the follow-up analysis of the clinical data suggests that more effective FLT inhibitors are still required [ 28 ].
The relevant pharmacokinetic parameters are listed in Table 3. The pharmacokinetic profile of the metabolite LDD was measured and is shown in Table 3. After measuring the concentrations of ely LDD and LDD, standard methods were used to calculate the pharmacokinetic parameters using a non-compartmental analysis WinNonlin 2.
Additionally, oey non-renal clearance of LDD was the main route of elimination due to the negligible contribution of the CL R to CL, and the urinary excretion was 0. Cells were then subjected to cell cycle analyses using a flow cytometer.
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These favorable pharmacokinetic properties may contribute to the effective anti-tumor activity in vivo. Will FLT3 inhibitors fulfill their promise in acute meyloid leukemia?
Analysis of FLT3-activating mutations in patients with acute myelogenous leukemia: To address the solubility problems of these indirubin derivatives, in this study, we designed and synthesized new analogues with hydrophilic functional groups on the molecules. Based on the low F value 1. The apoptotic cell leg increased in a dose-dependent manner shown in Figure 2B.
However, differentiated cells were not observed in LDDtreated cells data not shown. The IC 50 s lfy other kinase activities were also measured Table 1. We previously reported that a series of 5-substituted indirubin derivatives are potent FLT3 inhibitors [ 21 ], which effectively inhibited the growth of acute myeloid leukemic cells. Two major types 32221 FLT3 mutations have been identified: Bioorg Med Chem 233221. PKC—a leu kinase inhibitor with a broad therapeutic potential. All mice were provided food and water ad libitum and were then maintained during this study.
Therefore, the development of new potent and selective FLT3 kinase inhibitors is needed at the present time. As mechanisms of the anti-leukemic effects, apoptotic cell death Figure 2 and cell cycle arrest Figure 3 by the LDD treatment was investigated in this study. MV cells were treated with LDD for 4 h at the indicated concentration.
Several clinical candidates targeting FLT3 have been reported including lestaurtinib [ 11 ], tandutinib [ 12 ], sorafenib [ 13 ], KW [ ldy ], and quizartinib [ 15 ]. In vitro activity of LDD against select kinases. In vivo antitumor efficacy of LDD Theoretical basis, leu design, and computerized simulation of synergism and antagonism in drug combination studies.
The IC 50 was calculated with nonlinear regression using Prism version 5. The role of FLT3 in haematopoietic malignancies. The kinase reactions were incubated for 90 min. The antibodies used were as follows: The signal was measured on an EnVision multi-label reader. The activation of FLT3 is initiated by the binding of the FLT3 ligand, which is expressed by stromal cells, to the receptor.
Cells were treated with each compound alone and a combination of two compounds.
Cell viability was assessed as described above, and the combination index CI was calculated with the CompuSyn software version 1. Blood samples were collected at the indicated time points after the injection. The ability of LDD to suppress tumor cell growth in vivo and in vitro makes it a promising candidate to treat AML patients as well as to possibly treat other types of cancers also.
Its indication is newly diagnosed AML that is FLT3 positive, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.
The sub-G1 population indicating the dead cell population increased by the LDD treatment from 4. At day 21 after drug administration, mice were sacrificed, and the tumor weights measured B.