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Dive into the research topics where Francis Y. Lee is active.

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Featured researches published by Francis Y. Lee.


Drug Metabolism and Disposition | 2008

Metabolism and Disposition of Dasatinib after Oral Administration to Humans

Lisa J. Christopher; Donghui Cui; Chiyuan Wu; Roger T. Luo; James Manning; Samuel J. Bonacorsi; Michael W. Lago; Alban Allentoff; Francis Y. Lee; Betty McCann; Susan Galbraith; Donald P. Reitberg; Kan He; Anthony Barros; Anne Blackwood-Chirchir; W. Griffith Humphreys; Ramaswamy A. Iyer

SPRYCEL (dasatinib, BMS-354825; Bristol-Myers Squibb, Princeton, NJ), a multiple kinase inhibitor, is currently approved to treat chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). After a 100-mg single p.o. dose of [14C]dasatinib to healthy volunteers, the radioactivity was rapidly absorbed (Tmax ∼0.5 h). Both dasatinib and total radioactivity (TRA) plasma concentrations decreased rapidly with elimination half-life values of <4 h. Dasatinib was the major drug-related component in human plasma. At 2 h, dasatinib accounted for 25% of the TRA in plasma, suggesting that metabolites contributed significantly to the total drug-related component. There were many circulating metabolites detected that included hydroxylated metabolites (M20 and M24), an N-dealkylated metabolite (M4), an N-oxide (M5), an acid metabolite (M6), glucuronide conjugates (M8a,b), and products of further metabolism of these primary metabolites. Most of the administered radioactivity was eliminated in the feces (85%). Urine recovery accounted for <4% of the dose. Dasatinib accounted for <1 and 19% of the dose in urine and feces, respectively, suggesting that dasatinib was well absorbed after p.o. administration and extensively metabolized before being eliminated from the body. The exposures of pharmacologically active metabolites M4, M5, M6, M20, and M24 in patients, along with their cell-based IC50 for Src and Bcr-Abl kinase inhibition, suggested that these metabolites were not expected to contribute significantly toward in vivo activity.


Haematologica | 2007

Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT

Karoline V. Gleixner; Matthias Mayerhofer; Karoline Sonneck; Alexander Gruze; Puchit Samorapoompichit; Christian Baumgartner; Francis Y. Lee; Karl J. Aichberger; Paul W. Manley; Doriano Fabbro; Winfried F. Pickl; Christian Sillaber; Peter Valent

Background and Objectives In a majority of all patients with systemic mastocytosis (SM) including those with mast cell leukemia (MCL), neoplastic mast cells (MC) display the D816V-mutated variant of KIT. The respective oncoprotein, KIT D816V, exhibits constitutive tyrosine kinase (TK) activity and has been implicated in malignant cell growth. Therefore, several attempts have been made to identify KIT D816V-targeting drugs. Design and Methods We examined the effects of the novel TK-inhibitor dasatinib alone and in combination with other targeted drugs on growth of neoplastic MC. Results Confirming previous studies, dasatinib was found to inhibit the TK activity of wild type (wt) KIT and KIT-D816V as well as growth and survival of neoplastic MC and of the MCL cell line, HMC-1. The growth-inhibitory effects of dasatinib in HMC-1 cells were found to be associated with a decrease in expression of CD2 and CD63. In addition, we found that dasatinib blocks KIT D816V-induced cluster-formation and viability in Ba/F3 cells. In drug combination experiments, dasatinib was found to co-operate with PKC412, AMN107, imatinib, and 2CdA in producing growth-inhibition and apoptosis in neoplastic MC. In HMC-1.1 cells lacking KIT D816V, all drug interactions were found to be synergistic in nature. By contrast, in HMC-1.2 cells exhibiting KIT D816V, only the combinations dasatinib+PKC412 and dasatinib+2CdA were found to produce synergistic effects. Interpretation and Conclusions Combinations of targeted drugs may represent an interesting pharmacologic approach for the treatment of aggressive SM or MCL.


Journal of Bone and Joint Surgery, American Volume | 1999

Recurrent Giant-Cell Tumor Presenting as a Soft-Tissue Mass. A Report of Four Cases*

Francis Y. Lee; Mark Montgomery; Eric J. Hazan; Suzanne B. Keel; Henry J. Mankin; Susan V. Kattapuram

Giant-cell tumor of bone is a benign, locally invasive tumor that has been associated with a rate of local recurrence of 27 percent (forty-one of 151) after intralesional excision and 8 percent (ten of 122) after marginal excision1. The high rate of local recurrence and the occasional development of pulmonary metastasis are manifestations of the locally invasive nature of the tumor4-6,8,9,11,12.nnA peripheral rim of ossification has been described as an almost pathognomonic sign of a soft-tissue recurrence2,3,11. However, a soft-tissue recurrence can be difficult to detect, especially when the recurrent lesion is asymptomatic and is not associated with the characteristic ossification.nnWe report on four patients who had an isolated soft-tissue recurrence of a giant-cell tumor of bone. Although a radiodense peripheral rim of ossification is thought to be pathognomonic of a soft-tissue recurrence of giant-cell tumor, this finding was not apparent on the plain radiographs of any of these patients. In each case, a soft-tissue mass was palpable on physical examination and magnetic resonance imaging scans revealed a soft-tissue mass with a heterogeneous signal pattern. The purpose of this report is to emphasize that a soft-tissue recurrence may not be recognized if a thorough physical examination is not performed and magnetic resonance imaging studies are not carried out.nnCASE 1. A forty-two-year-old woman was seen by us because of a rapidly enlarging soft-tissue mass in the posteromedial aspect of the proximal part of the right calf. Twenty-six months previously, the patient had been managed with curettage and bone-grafting because of a giant-cell tumor of the proximal aspect of the right tibia. Six months after the initial treatment, the patient had a recurrence of the giant-cell tumor and was …


Journal of Pediatric Orthopaedics | 1998

Micromechanical properties of epiphyseal trabecular bone and primary spongiosa around the physis : An in situ nanoindentation study

Francis Y. Lee; Jae Young Rho; Robert D. Harten; J. Russell Parsons; Fred F. Behrens

The elastic modulus and hardness of the mineralized bone around the growth plate was measured to determine its regional micromechanical properties. Multiple nanoindentation tests, >10 sessions, with depths ranging from 100 to 1,000 nm at loading rates of 12.5 and 750 microN/s, were performed on the trabecular bone in the epiphysis, trabecular bone at the junction of the physis and epiphysis, primary spongiosa in the metaphysis, and surrounding cortical bone of the distal femur of 300-gm Sprague-Dawley rats. The indentation load-displacement data obtained in these tests were analyzed to determine the elastic modulus and hardness of the tissues. The nanoindentation results highlighted the regional variations in the material properties of the mineralized tissues around the growth plate. The primary spongiosa had a lower elastic modulus and hardness than both epiphyseal trabecular and cortical bone (p < 0.01). A relatively well-defined thick trabecular band at the physeal-epiphyseal junction had modulus and hardness values comparable to those of cortical bone (p > 0.05). These findings support the hypothesis that the primary spongiosa has micromechanical properties that are significantly lower than the epiphyseal trabecular bone. On this basis, it is speculated that the fracture patterns commonly seen in patients with physeal injuries are influenced by the micromechanical properties of these tissues, as well as by the nature and direction of the applied force.


Journal of Pediatric Orthopaedics | 2003

In situ pinning of hip for stable slipped capital femoral epiphysis on a radiolucent operating table.

Francis Y. Lee; Cary B. Chapman

Patients with stable slipped capital femoral epiphysis (SCFE) usually can ambulate at the time of diagnosis. Satisfactory results have been reported after percutaneous in situ pinning using a fracture table. The authors describe a technique to determine the skin-pin entry point for percutaneous pinning of the hip on a regular radiolucent operating table. The pin entry point determined by this modified method was reliable in 15 SCFEs in 13 patients. Pinning on a regular radiolucent table was much easier, without the need to transfer obese patients to a fracture table. It was also useful when a bilateral pinning procedure was performed using single draping. Obtaining modified frog-leg lateral radiographs in patients with a stable SCFE was not associated with avascular necrosis or chondrolysis.


Journal of Pediatric Orthopaedics | 2001

Coronal split fracture of the proximal tibia epiphysis through a partially closed physis: a new fracture pattern.

Sanjay K. Patari; Francis Y. Lee; Fred F. Behrens

SUMMARYnA comminuted coronal split fracture of the proximal tibial epiphysis is an uncommon injury in children. The authors evaluated and treated two patients who sustained an epiphyseal fracture through a partially closed proximal tibial epiphysis. Plain radiography and computed tomography with three-dimensional reconstruction showed a comminuted coronal split fracture of the proximal tibial epiphysis. Each patient underwent definitive operative fixation of the fracture and was followed at least 1 year after clinical union. A mechanism consisting of three-point bending on the tibial plateau is proposed.


Blood | 2006

Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis

Neil P. Shah; Francis Y. Lee; Roger T. Luo; Yibin Jiang; Marjolein L. Donker; Cem Akin


Journal of Orthopaedic Research | 1998

Programmed removal of chondrocytes during endochondral fracture healing

Francis Y. Lee; Yong Won Choi; Fred F. Behrens; David O. DeFouw; Thomas A. Einhorn


Experimental Cell Research | 1994

Insulin-like Growth Factor I Regulation of Swarm Rat Chondrosarcoma Chondrocytes in Culture

Sang Cheol Seong; Takashi Matsumura; Francis Y. Lee; Mary C. Whelan; Xiao Qing Li; Stephen B. Trippel


Blood | 2007

In Vitro Cardiotoxicity Potential Comparative Assessments of Chronic Myelogenous Leukemia Tyrosine Kinase Inhibitor Therapies: Dasatinib, Imatinib and Nilotinib.

Wendy J. Freebern; Hengsheng S. Fang; Martin Slade; Susan Wells; Jennifer Canale; John Megill; Branka Grubor; Hong Shi; Anthony P. Fletcher; Louis J. Lombardo; Paul Levesque; Francis Y. Lee; Vito Sasseville

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John Wityak

Genomics Institute of the Novartis Research Foundation

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