| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Preclinical Pharmacology |
Parker Hughes Cancer Center [F. M. U., O. E., C-L. C.], and Departments of Oncology [F. M. U.], Pharmaceutical Sciences [C-L. C.], Chemistry [X-P. L.], and Immunology [F. M. U.], and the Drug Discovery Program [F. M. U., C-L. C.], Hughes Institute, St. Paul, Minnesota 55113; University of Minnesota Biophysical Sciences Graduate Program (O. E., F. M. U.)
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
More recently, we developed a sensitive HPLC-based quantitative detection method for measurement of plasma as well as tissue WHI-P131 levels in pharmacokinetic studies (10) . Here, we report the pharmacokinetics and toxicity of WHI-P131 in rats, mice, and cynomolgus monkeys.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Animals.
Male Lewis rats (260–310 g; Harlan Sprague Dawley, Indianapolis, IN), female CD-1 mice (7–9 weeks of age), and female BALB/c mice (6–8 weeks of age; Charles River Laboratories, Wilmington, MA) were housed in a controlled environment (12-h light/12-h dark photoperiod; 22 ± 1°C, 60 ± 10% relative humidity), which is fully accredited by the United States Department of Agriculture. All husbandry and experimental contact made with the mice maintained specific pathogen-free conditions. All rodents were kept in Micro-Isolator cages (Lab Products, Inc., Maywood, NY) containing autoclaved food, water, and bedding. Three female cynomolgus monkeys were obtained from BioMedical Resources Foundation (Houston, TX). Before entering the study, the monkeys were housed in a quarantined room in the same facility for 6 weeks. During this time, they were tested for tuberculosis three times, serologically screened for Herpes virus simiae, and screened for enteric bacterial, protozoal, and helminth pathogens. In pharmacodynamic studies, monkeys were fasted overnight before anesthesia and treatment. After induction of anesthesia (10–15 mg/kg ketamine hydrochloride), a catheter was placed percutaneously either into the right or left cephalic vein using a sterile disposable kit. This catheter was taped in place for administration of WHI-P131 or maintenance fluids (normal saline at 4 ml/kg/h via an infusion pump) and for drawing of blood samples. Animal studies were approved by the Animal Care and Use Committee, and all animal care procedures conformed to the Principles of Laboratory Animal Care (NIH publication #85–23, revised 1985).
Pharmacokinetic Studies in Rats.
Male Lewis rats were divided into two experimental groups of five and were injected either i.v. via the dorsal vein of the penis or i.p. with a single 3.3 mg/kg bolus dose of WHI-P131. The rats were anesthetized by the methoxyfluran, and blood samples (
0.2 ml) were collected from rat tail vein before and at 5, 10, and 30 min and 1, 1.5, 2, 3, 4, and 6 h after i.v. injections or at 5, 10, 15, 30, and 45 min and 1, 1.5, 2, 3, 4, 5, and 7 h after i.p. injections.
Pharmacokinetic Studies in Mice.
CD-1 mice were injected either i.v. via the tail vein or i.p. with a single 13 mg/kg bolus dose of WHI-P131. Under the anesthesia of methoxyfluran, blood samples (200 µl) were collected from ocular venous plexus by retroorbital venipuncture before and at 5, 15, and 30 min and 1, 2, 4, and 6 h after i.v. injection and at 5, 10, 15, and 30 min and 1, 2, 4, and 6 h after i.p. injection, respectively. To determine the pharmacokinetics of WHI-P131 after oral administration, 12-h fasted mice were given a single bolus dose of 13 mg/kg of WHI-P131 via gavage by using a No. 21 stainless steel ball-tipped feeding needle. Sampling time points were before and at 5, 10, 15, 30, and 45 min and 1, 2, 4, and 6 h after oral administration of WHI-P131.
For studying the linearity of pharmacokinetics of WHI-P131, the mice were given i.p. dose levels of 4, 13, 20, 40, and 80 mg/kg, and the plasma samples were obtained via orbital venipuncture at 10 min and 1 h after i.p. injection.
Pharmacokinetic Studies in Monkeys.
For pharmacokinetic studies in monkeys, two monkeys were injected i.v. with a single bolus dose of 20 mg/kg WHI-P131. The collection time points were at 5, 15, 30, and 45 min and 1, 1.5, and 2 h after the i.v. injection. All collected blood samples were heparinized and centrifuged at 7000 x g for 10 min in a microcentrifuge to obtain plasma. The plasma samples were stored at -20°C until analysis. Aliquots of plasma were used for extraction, and HPLC analysis was used as described previously (10)
.
Protein Binding Properties of WHI-P131.
Protein binding was determined by an equilibrium dialysis technique. The experiment was performed at 37°C using a five-cell model of a Spectrum Equilibrium Dialyzer (Spectrum Medical Industries, Inc., Los Angeles, CA; Ref. 11
). The cells were separated by a semipermeable membrane (Spectrum Medical Industries, Inc.) with a molecular weight cutoff of 8000, which was rinsed in the PBS (pH 7.4) for 30 min before use. For in vivo plasma protein binding, 400 µl of plasma (pooled from six CD-1 mice at 10 min after i.v. administration of a single 40 mg/kg bolus dose of WHI-P131) were dialyzed against equal volumes of PBS. For in vitro plasma protein binding experiment, 500 µl of untreated blank mouse plasma was dialyzed against equal volumes of PBS containing 10 µM and 500 µM WHI-P131. For in vitro binding of WHI-P131 to 5% human albumin, 700 µl of 5% albumin were dialyzed against 700 µl of PBS containing final concentrations of 10, 50, 100, and 500 µM WHI-P131. The cells were incubated at 37°C for 4 h with gentle shaking (10 rpm), then aliquots of solution were taken from both chambers [protein chamber (Cp) and PBS chamber (Cb)]. The recently reported HPLC method (10)
was used to determine the concentrations of WHI-P131 both in the plasma chamber (Cp) and PBS (Cb) with the standard curve from spiked WHI-P131 in 5% albumin or plasma and PBS. A blank sample was dialyzed in each binding experiment to assess the presence of endogenous or exogenous compounds that might interfere with WHI-P131 measurements. The percentage of binding was calculated as the ratio of Cp - Cb over Cp x 100.
Determination of Plasma WHI-P131 Levels by HPLC.
WHI-P131 levels in plasma were determined by an established HPLC method (10)
. In brief, for determination of WHI-P131 levels in 100-µl plasma samples, 10 µl of the internal standard WHI-P154 (at 50 µM; Ref. 9
) were also added to the plasma. For extraction, 7 ml of chloroform were added to the plasma sample, and the mixture was vortexed. After centrifugation (300 x g, 5 min), the aqueous layer was frozen using acetone/dry ice and the organic phase was transferred into a clean test tube. The chloroform extracts were dried under a slow steady stream of nitrogen gas. The residue was reconstituted in 100 µl of methanol:water (9:1, v/v), and a 50-µl aliquot of this solution was injected for HPLC analysis. All extraction procedures were performed at room temperature.
The HPLC system (Hewlett Packard, Inc., Palo Alto, CA) consisted of a Hewlett Packard series 1100 instrument equipped with a quaternary pump, an autosampler, an auto electronic degasser, an automatic thermostatic column compartment, a diode array detector, and a computer with a Chemstation software program for data analysis. A 250 x 4-mm Lichrospher 100, RP-18 (5 µm) analytical column and a 4 x 4 mm Lichrospher 100, RP-18 (5 µM) guard column were obtained from Hewlett Packard Inc. Acetonitrile:water containing 0.1% of trifluoroacetic acid (TFA) and 0.1% triethylamine (TEA) (28:72, v/v) was used as the mobile phase (10) . The mobile phase was degassed automatically by the electronic degassing system. The column was equilibrated and eluted under isocratic conditions using a flow rate of 1.0 ml/min at ambient temperature. The wavelength of detection was set at 340 nm for WHI-P131.
Tissue Distribution Studies in Mice.
CD-1 mice were injected i.v. with a single 40 mg/kg bolus dose of WHI-P131. Mice were sacrificed by cervical dislocation at 10 min, 1 h or 4 h after the i.v. injection of WHI-P131. Selected tissues, including the brain, heart, liver, lungs, kidneys, stomach, muscle, large intestine (without contents), small intestine (without contents), spleen, adipose tissue, skin, urinary bladder, adrenal glands, pancreas, and uretus + ovary were excised. They were rinsed with PBS, blotted, weighed, and homogenized in at least 500 µl of water with a Polytron (PT-MR2000) homogenizer (Kinematical AG, Littau, Switzerland). Extraction of WHI-P131 from the tissue homogenates was done with chloroform following precipitation of tissue protein by methanol. The contents of WHI-P131 in various types of tissues were analyzed by the HPLC detection method described above.
Pharmacokinetic Analyses.
Pharmacokinetic modeling and pharmacokinetic parameter estimations were carried out using the pharmacokinetic software WinNonlin program, version 2.1 (Pharsight Incorporation, Mountain View, CA), as reported previously (11
, 12)
. In brief, an appropriate pharmacokinetic model was chosen on the basis of lowest sum of weighted squared residuals, lowest Schwartz criterion, lowest Akaike’s information criterion value, lowest SEs of the fitted parameters, and dispersion of the residuals. The half-life was estimated by linear regression analysis of the terminal phase of the plasma concentration profile. The AUC was calculated by the trapezoidal rule between the first (0 h) and last sampling time plus C/k, where C is the concentration of last sampling and k is the elimination rate constant. Systemic clearance (CLs) was determined by dividing the dose by the AUC. The apparent volume of distribution at steady state was calculated using the following equation: 
. Bioavailability (F) was estimated by the following equation: 
.
Toxicity Studies in Mice and Cynomolgus Monkeys.
The acute toxicity profile of WHI-P131 in BALB/c mice was examined using single i.p bolus injections, as reported previously for other new agents (13
, 14)
. Female BALB/c mice were used and monitored daily for lethargy, cleanliness, and morbidity. At the time of death, necropsies were performed and the toxic effects of WHI-P131 administration were assessed. For histopathological studies, tissues were fixed in 10% neutral buffered formalin, dehydrated, and embedded in paraffin by routine methods. Glass slides with affixed six micron tissue sections were prepared and stained with H&E. Female BALB/c mice were administered an i.p. bolus injection of WHI-P131 in 0.2 ml of PBS supplemented with 10% DMSO, or 0.2 ml of PBS supplemented with 10% DMSO alone (control mice). No sedation or anesthesia was used throughout the treatment period. Mice were monitored daily for mortality for determination of the day 30 LD50 values. Mice surviving until the end of the 30 days of monitoring were sacrificed, and the tissues were immediately collected from randomly selected mice, and preserved in 10% neutral buffered formalin. Standard tissues collected for histological evaluation included: bone, bone marrow, brain, cecum, heart, kidney, large intestine, liver, lung, lymph node, ovary, pancreas, skeletal muscle, skin, small intestine, spleen, stomach, thymus, thyroid gland, urinary bladder, and uterus (as available).
In one cynomolgus monkey, blood samples were collected before and after WHI-P131 administration as a single i.v. bolus dose for a complete blood cell count (with differential and platelets and determination of the serum levels for albumin, liver enzymes, bilirubin, blood urea nitrogen/creatinine, and electrolytes. In two monkeys, blood was obtained before and after infusion of a single i.v. bolus dose for use in quantitative evaluation of the plasma WHI-P131 levels. Vital signs (heart rate, systolic blood pressure, and respiratory rate), gastrointestinal symptoms, infections, and overall activity and behavior were monitored daily by staff veterinarians. Weight was monitored on an every other day schedule, and any loss or gain of weight was documented. Clinical and laboratory evaluations of drug toxicity were analyzed using a toxicity grading system adapted from the Children’s Cancer Group toxicity criteria (13 , 14) .
Cells and in Vitro Clonogenic Assays.
The JAK3-expressing human ALL cell line NALM-6 (15)
was maintained by serial passages in RPMI 1640 (Life Technologies, Inc., Grand Island, NY) supplemented with 10% (vol/vol) heat-inactivated FBS (Hyclone Laboratories, Logan, UT) and 1% (vol/vol) penicillin-streptomycin (Life Technologies, Inc.). Cells were cultured in tissue culture flasks at 37°C in a humidified 5% CO2 atmosphere. The antileukemic activity of plasma samples from WHI-P131-treated cynomolgus monkeys was examined using a methylcellulose colony assay system (15)
. In brief, cells (107/ml in RPMI + 10% FBS) were treated overnight at 37°C with 1:5, 1:10, or 1: 20 (v/v) PBS-diluted plasma samples from WHI-P131-treated monkeys. After treatment, cells were washed twice, plated at 104 cells/ml in RPMI + 10% FBS + 0.9% methylcellulose in Petri dishes, and cultured for 7 days at 37°C in a humidified 5% CO2 incubator. Subsequently, leukemic cell colonies were enumerated using an inverted phase-contrast microscope, and the percent inhibition of colony formation was calculated using the formula: % inhibition = (1 - mean number of colonies in test culture/mean number of colonies in control culture) x 100.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. The pharmacokinetic parameter values are presented in Table 1
. The predicted maximum plasma concentration was 21.4 ± 2.1 µM. WHI-P131 showed a moderately fast rate of elimination with a t1/2 of 80.9 ± 23.1 min. Total systemic body clearance was 623 ± 44 ml/h/kg, which is less than the renal blood flow (2208 ml/h/kg; Ref. 16
) or hepatic blood flow (3312 ml/h/kg; Ref. 16
). Fig. 1B
depicts the plasma concentration-time curve of WHI-P131 in rats (n = 5) after the i.p. injection of a 3.3-mg/kg bolus dose. The corresponding pharmacokinetic parameter values are presented in Table 1
. WHI-P131 was absorbed rapidly, and the time to reach the maximum plasma WHI-P131 concentration (tmax) was 24.7 ± 1.7 min. WHI-P131 was rapidly eliminated with an elimination half-life of 45.6 ± 5.5 min. Although the predicted maximum plasma WHI-P131 concentration was 10.5 ± 0.8 µM, which is only half of the Cmax following i.v. administration of the same bolus dose, the i.p. bioavailability was 94.6% and the systemic exposure levels (i.e., AUC) were very similar to those observed after i.v. injection (17.1 ± 2.2 µM·h versus 18.1 ± 1.2 µM·h; Table 1
).
|
|
. The obtained plasma WHI-P131 concentration-time data were fit to a two-compartment, first order pharmacokinetic model. WHI-P131 showed a moderately fast elimination (t1/2 of 103.4 min) and systemic clearance (CLs of 1482 ml/h/kg), which is less than renal blood flow (4000 ml/h/kg) or hepatic blood flow (5400 ml/h/kg).
|
). The pharmacokinetic parameter values are shown in Table 1
. The estimated Cmax of WHI-P131 was 57.7 µM, and the i.p. bioavailability was estimated to be 94.9%. Similar to rats, WHI-P131 demonstrated a rapid absorption and a time to reach maximum plasma concentration of 10.0 min. WHI-P131 showed a moderately fast rate of elimination after i.p. administration with an half-life of 123.6 min.
We also examined the pharmacokinetics of WHI-P131 in mice after oral administration of a 13 mg/kg bolus dose. A two-compartment model was used to analyze the plasma WHI-P131 concentration changes over time (Fig. 2C)
. The calculated pharmacokinetic parameter values are presented in Table 1
. The estimated oral bioavailability of WHI-P131 was 29.6% with a predicted maximum concentration of 7.7 µM. WHI-P131 showed a very rapid absorption, and the time to reach maximum plasma WHI-P131 concentration was only 5.8 min. The elimination of p.o. administered WHI-P131 was prolonged with a t1/2 of 297.6 min.
After i.p. injection of dose levels of 4, 13, 20, 40, and 80 mg/kg WHI-P131, the measured plasma WHI-P131 concentrations were 12.2 ± 0.9, 57.1 ± 3.0, 90.5 ± 9.3, 202.6 ± 9.5, and 356.4 ± 26.9 µM at 10 min after administration and were 0.8 ± 0.1, 3.3 ± 0.5, 24.7 ± 4.0, 65.8 ± 7.4, and 164.8 ± 12.9 µM at 1 h after administration, respectively. As shown in Fig. 3
, there was a linear relationship between the measured plasma WHI-P131 concentration and the dose level.
|
To determine the in vivo tissue distribution profile of WHI-P131, multiple tissues were collected from CD-1 mice sacrificed at 10 min, 1 h, or 4 h after i.v. administration of a 40-mg/kg bolus dose of WHI-P131. WHI-P131 was extracted from homogenized tissue specimens with chloroform after methanol precipitation of tissue proteins. The WHI-P131 contents of various tissue extracts were then determined by HPLC. The tissue distribution profile of WHI-P131 is shown in Table 2
. At 10 min after the i.v. injection of WHI-P131, tissue extracts from heart, liver, lung, kidney, stomach, spleen, adrenal gland, large intestine, and pancreas contained large amounts (>20 µg/g tissue) of WHI-P131, whereas the tissue extracts from muscle, small intestine, skin, urinary bladder, and uterus + ovaries contained moderate amounts (8–20 µg/g tissue) of WHI-P131. In contrast, only trace amounts (<5 µg/g tissue) of WHI-P131 were detected in the brain and adipose tissue. At 1 h after i.v. administration, the WHI-P131 content was substantially reduced in all tissues, except for the stomach, small intestine, large intestine, and liver. At 4 h after i.v. administration, >90% of WHI-P131 was eliminated from all tissues, except for the large intestine, which still contained moderate amounts of the drug (Table 2)
. Thus, WHI-P131 shows an extensive distribution into multiple tissues followed by a rapid elimination from most tissues. The paucity of WHI-P131 in the brain tissue extracts suggests that WHI-P131 may not be able to easily cross the blood brain barrier. Also shown in Table 2
are the TPR for WHI-P131 at different time points after administration. At 10 min, the TPR values were <1 for all tissues examined. At 1 h after the i.v. injection, the TPR was >1 for the liver, kidney, stomach, as well as the small and large intestines, with the highest TPR of 3.3 ± 1.9 for the stomach. At 4 h after the i.v injection, the TPR values were higher than those at 1 h. The 4-h TPR values were >9 for the stomach, as well as the small and large intestines, indicating that WHI-P131 is capable of binding to and accumulating in these tissues. The heart, liver, lungs, kidneys, spleen, skin, urinary bladder, and pancreas had TPR values of 1–7, suggesting that these organs may also bind and accumulate WHI-P131. The 4-h TPR values were <1 for the muscle, adrenal gland, uterus, and ovary, although moderate to high amounts of WHI-P131 were detected in these tissues at 10 min after injection of WHI-P131, indicating that WHI-P131 enters but does not accumulate in these tissues.
|
. The in vitro binding to human serum albumin that was used as a control was 79.2 ± 2.0%. The wide tissue distribution profile of WHI-P131 in mice may be partially due to its moderate plasma protein binding capacity, which may facilitate the escape of most of the drug from vascular compartments to extravascular tissues and contribute to its rapid elimination.
|
. Comprehensive laboratory checkups in the third monkey at 1, 4, 7, 12, 15, and 28 days after administration of the drug did not reveal any evidence of hematological, renal, hepatic, or pancreatic toxicity (Table 4)
.
|
. The pharmacokinetic parameter values of WHI-P131 in monkeys are presented in Table 1
. WHI-P131 showed a fast rate of elimination with a plasma elimination half-life of 45.0 min and a systemic clearance of 476 ml/h/kg, which is less than either renal blood flow (1656 ml/h/kg) or hepatic blood flow (2616 ml/h/kg; Ref. 21).
|
, 1:5 diluted plasma samples obtained at 30 min after treatment with 20 mg/kg or 100 mg/kg WHI-P131(but not 1:5 diluted pretreatment plasma samples from the same monkeys) abrogated the in vitro colony formation by NALM-6 cells.
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
WHI-P131 showed a rapid absorption after i.p., as well as after p.o., administration. The time to reach the maximum plasma concentration was 10 min in mice after i.p. or p.o. administration and 
30 min in rats after i.p. administration. Whereas the bioavailability of WHI-P131 was excellent (>94%) after i.p. administration, it was quite low (29.6%) after p.o. administration. This finding is reminiscent of ICI D1694, another quinazoline derivative with thymidylate synthase inhibitory activity, which showed excellent bioavailability after i.p. administration, but only 10–20% bioavailability after p.o. administration (17)
.
Overall, WHI-P131 is rapidly eliminated after i.v. administration with an mean elimination half-life ranging from 45 min in cynomolgus monkeys to 103.4 min in CD-1 mice. Furthermore, the steady-state volume of distribution of WHI-P131 was large in rats, mice, as well as monkeys, which indicated that WHI-P131 is distributed rapidly and extensively into extravascular compartments after i.v. administration. The suspected wide tissue distribution profile was confirmed experimentally by detecting WHI-P131 in multiple tissues within 10 min after i.v. administration. We postulate that the wide tissue distribution profile of WHI-P131 is, at least in part, because of its moderate plasma protein binding capacity, which may facilitate the escape of most of the drug from vascular compartments to extravascular tissues.
We applied the allometric scaling method (18, 19, 20) to the pharmacokinetic results in rats, mice, and monkeys. The pharmacokinetic parameter values (CL, Vss, and t1/2) after i.v. administration of WHI-P131 were significantly correlated with body weight. The allometric equations were: CL (ml/h)=597.72X0.79 (r2=0.99) for clearance; Vss (ml)=421.22X0.84 (r2=0.98) for volume of distribution at steady state; and t1/2 (min)=:60.09X-0.16 (r2=:0.98) for terminal elimination half-life (data not shown). Using these allometric equations, the predicted human pharmacokinetic parameters for a human subject of 70 kg of body weight are 17,144 (ml/h; i.e., 245 ml/h/kg) for clearance, 14,941 ml (i.e., 213 ml/kg) for Vss, and 30 min for elimination half-life.
To our knowledge, this is the first preclinical toxicity and pharmacokinetic study of a JAK3 inhibitor. WHI-P131 was very well tolerated by mice and monkeys and plasma concentrations of WHI-P131 that are cytotoxic to human ALL cells in vitro could be achieved at nontoxic dose levels. The antileukemic activity and lack of significant systemic toxicity of WHI-P131 suggest that this JAK3 inhibitor may be useful in the treatment of relapsed or therapy-refractory ALL. A clinical Phase I study of WHI-P131 will be initiated at a dose level of 1.0 mg/kg, which is 20–100-fold lower than the well-tolerated dose levels of 20–100 mg/kg in cynomolgus monkeys. Because no specific toxicity was identified in mice or monkeys at the dose levels applied in the present study, all organ systems will be carefully monitored and a conservative dose escalation schedule will be used in our Phase I clinical trial.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 Supported in part by a special grant from the Parker Hughes Trust. F. M. U. was a Stohlman Scholar of the Leukemia Society of America. 
2 To whom requests for reprints should be addressed, at Hughes Institute, 2665 Long Lake Road, Suite 330, St Paul, MN 55113. Phone: (651) 697-9228; Fax: (651) 697-1042.
3 The abbreviations used are: JAK, Janus kinase; ALL, acute lymphoblastic leukemia; WHI-P131, 4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline; HPLC, high-performance liquid chromatography; AUC, area under the concentration-time curve; TPR, tissue:plasma ratio; FBS, fetal bovine serum.
Received 6/17/99; revised 8/ 3/99; accepted 8/ 3/99.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  P. S. Changelian, D. Moshinsky, C. F. Kuhn, M. E. Flanagan, M. J. Munchhof, T. M. Harris, J. L. Doty, J. Sun, C. R. Kent, K. S. Magnuson, et al. The specificity of JAK3 kinase inhibitors Blood, February 15, 2008; 111(4): 2155 - 2157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Uckun, C.-L. Chen, P. Samuel, S. Pendergrass, T. K. Venkatachalam, B. Waurzyniak, and S. Qazi In Vivo Antiretroviral Activity of Stampidine in Chronically Feline Immunodeficiency Virus-Infected Cats Antimicrob. Agents Chemother., April 1, 2003; 47(4): 1233 - 1240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-L. Chen, G. Yu, T. K. Venkatachalam, and F. M. Uckun Metabolism of Stavudine-5'-[p-Bromophenyl Methoxyalaninyl Phosphate], Stampidine, in Mice, Dogs, and Cats Drug Metab. Dispos., December 1, 2002; 30(12): 1523 - 1531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Uckun, B. A. Roers, B. Waurzyniak, X.-P. Liu, and M. Cetkovic-Cvrlje Janus kinase 3 inhibitor WHI-P131/JANEX-1 prevents graft-versus-host disease but spares the graft-versus-leukemia function of the bone marrow allografts in a murine bone marrow transplantation model Blood, May 13, 2002; 99(11): 4192 - 4199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Uckun, Y. Zheng, M. Cetkovic-Cvrlje, A. Vassilev, E. Lisowski, B. Waurzyniak, H. Chen, R. Carpenter, and C.-L. Chen In Vivo Pharmacokinetic Features, Toxicity Profile, and Chemosensitizing Activity of {alpha}-Cyano-{beta}-hydroxy-{beta}- methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13), a Novel Antileukemic Agent Targeting Bruton's Tyrosine Kinase Clin. Cancer Res., May 1, 2002; 8(5): 1224 - 1233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Uckun, J. Thoen, H. Chen, E. Sudbeck, C. Mao, R. Malaviya, X.-P. Liu, and C.-L. Chen CYP1A-Mediated Metabolism of the Janus Kinase-3 Inhibitor 4-(4'-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline: Structural Basis for Inactivation by Regioselective O-Demethylation Drug Metab. Dispos., January 1, 2002; 30(1): 74 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cetkovic-Cvrlje, B. A. Roers, B. Waurzyniak, X.-P. Liu, and F. M. Uckun Targeting Janus kinase 3 to attenuate the severity of acute graft-versus-host disease across the major histocompatibility barrier in mice Blood, September 1, 2001; 98(5): 1607 - 1613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-L. Chen, T. K. Venkatachalam, Z.-H. Zhu, and F. M. Uckun In Vivo Pharmacokinetics and Metabolism of Anti-Human Immunodeficiency Virus Agent d4T-5'-[p-Bromophenyl Methoxyalaninyl Phosphate] (SAMPIDINE) in Mice Drug Metab. Dispos., July 1, 2001; 29(7): 1035 - 1041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Narla, C.-L. Chen, Y. Dong, and F. M. Uckun In Vivo Antitumor Activity of Bis(4,7-dimethyl-1,10-phenanthroline) Sulfatooxovanadium(IV) {METVAN [VO(SO4)(Me2-Phen)2]} Clin. Cancer Res., July 1, 2001; 7(7): 2124 - 2133. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J O'Shea, R. Visconti, T. P Cheng, and M. Gadina Jaks and Stats as therapeutic targets Ann Rheum Dis, November 1, 2000; 59(90001): i115 - 118. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
