| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Advances in Brief |
Department of Medicine [R. H., K. L., M. E. D.], Committee on Clinical Pharmacology [R. H., M. E. D.], and Cancer Research Center [M. E. D.], University of Chicago, Chicago, Illinois 60637-1470, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202 [L. L., W. F. B.]
 |
ABSTRACT |
|---|
 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
|
Introduction |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
The conversion of CPT-11 to SN-38 has been characterized in several mammalian species (5) , but the specific enzyme(s) responsible for activation of CPT-11 in humans has not been clearly defined. Recently, Kojima et al. (6 , 7) and Kroetz et al. (8) reported the expression of a previously cloned human liver CE enzyme in human tumor cell lines. Overexpression of this enzyme resulted in increased activation of CPT-11 to SN-38 and enhanced cytotoxicity. However, conversion of CPT-11 to SN-38 by this enzyme was determined at 100 µM, a concentration significantly higher than pharmacologically relevant plasma concentrations observed after CPT-11 administration to patients. Additionally, cytotoxicity was observed in these cell lines at CPT-11 concentrations higher than typically observed clinically. IC50s ranged from approximately 2 to 20 µM after a 72-h continuous exposure. Several other recent reports have examined the conversion of CPT-11 by rabbit liver CE and compared its activity with that of the above human CE enzyme (9, 10, 11) . Although the rabbit and human enzymes were quite similar (81% sequence identity), the rabbit enzyme was found to be 100-1000-fold more efficient at converting CPT-11 to SN-38 in vitro and 12–55-fold more efficient in sensitizing transfected cells to CPT-11. Both the human and rabbit CE enzymes are being developed in enzyme/prodrug combinations with CPT-11 (6 , 7 , 9) .
Recently, Dean et al. (12)
and Takai
et al. (13)
have reported the purification and
partial characterization of two distinct human CE enzymes. These human
liver CE enzymes, designated hCE-1 and hCE-2, are both members of the
Mr 60,000 serine esterase
superfamily, but they differ substantially. Sequence homology between
the two enzymes is only 48% (Fig. 1)
. hCE-1 is a Mr 180,000 trimer with an
isoelectric point of 5.8, whereas hCE-2 is a monomer with an
isoelectric point of 4.9 (14
, 15)
. Substantial differences
in substrate specificity also exist between the two isoforms. For
example, hCE-1 hydrolyzes the methyl ester of cocaine, and hCE-2
hydrolyzes the benzoyl ester (14
, 15)
. Additionally, hCE-2
hydrolyzes aspirin (acetyl salicylic acid) and procaine, whereas hCE-1
does not (13)
. Sequence comparisons of hCE-1 and hCE-2
with the human CE enzyme cloned previously by Kroetz et al.
(8)
and used in the above studies by Kojima et
al. (6
, 7)
and Danks et al. (9
, 10)
identify it as hCE-1.
|
|
Materials and Methods |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
Fractions containing hCE-1 and hCE-2 were separately pooled and 1
mM of MgCl2, 1 mM
CaCl2, and 1 mM
MnSO4 were added to the enzyme. Each isoenzyme
sample was purified by the following procedure. The sample was loaded
onto a ConA Sepharose 4B column (2.5 x 6 cm; Pharmacia,
Piscataway, NJ), washed with 75 mM Tris-HCl plus 0.15
M NaCl, and bound protein was eluted with 0.5 M
methyl-
-mannopyranoside in 10 mM potassium phosphate (pH
7.0). The sample was concentrated to 10 ml, loaded onto a
hydroxylapatite column (2.5 x 25 cm; Bio-Rad
Laboratories, Hercules, CA), and washed with 10 mM
potassium phosphate (pH 7.0). hCE-1 was eluted with a linear gradient
of 30–250 mM potassium phosphate (pH 7.0). hCE-2 was
eluted from a separate column with 30 mM potassium
phosphate (pH 7.0). All purified enzyme samples were concentrated, and
buffer was exchanged into 50 mM sodium phosphate (pH 7.0),
sterile filtered, and stored at 4°C. Purified hCE-1 and hCE-2
exhibited single bands (>90% purity) on SDS-PAGE
(Mr 70,000 subunit size) and
nondenaturing PAGE after staining for protein. The specific activity of
hCE-1 preparations ranged from 6 to 10 units/mg (14)
and
that of hCE-2 ranged from 40 to 140 units/mg (15)
. The
wide range of specific activity for hCE-2 occurred because it is much
more labile during purification.
Esterase Activity.
Enzyme activity was determined by measuring hydrolysis of 500
µM 4-methylumbelliferone acetate by purified hCE enzymes,
as described previously (15)
.
CPT-11 Hydrolysis.
Human CE enzymes, hCE-1 or hCE-2 (0.1 unit), were incubated with
increasing concentrations of CPT-11 at 37°C in 50 mM
sodium phosphate buffer (pH 7.4). At selected incubation times, the
reaction was stopped by mixing 0.5 ml of reaction solution with 2.0 ml
of ice-cold methanol and placing the solution on ice. Two hundred µl
of internal standard (camptothecin 1 µg/ml stock in 0.1 N
HCl) was added. Samples were evaporated to dryness under nitrogen and
reconstituted in 400 µl of HPLC mobile phase. SN-38 was quantitated
by HPLC.
Km and Vmax values were calculated from nonlinear regression analysis of kinetic data to the Michaelis-Menten equation using the GraFit program (GraFit Version 4.0, 1998; R. J. Leatherbarrow, Erithacus Software Ltd., Staines, United Kingdom).
Quantitation of SN-38 Production.
CPT-11 and SN-38 concentrations were determined by HPLC as modified
from Gupta et al. (16)
. Briefly, CPT-11 and
SN-38 were separated using a Partisphere 10 µM
C18 column (4.5 x 250 mm;
Whatman, Inc., Clifton, NJ) with a mobile phase consisting
of 27% acetonitrile:73% 0.1 M potassium
dihydrogen phosphate containing 3 mM sodium
heptane sulfonate (pH 4.0). Detection was monitored using a Hitachi
F1050 fluorescence detector (Hitachi Instruments, Naperville, IL) with
ex = 375 nm and
em = 566 nm. Standard curves of
CPT-11 and SN-38 were linear (r = 0.99)
within the range of 15–2500 ng/ml and 2.0–250 ng/ml, respectively.
Colony-forming Cytotoxicity Assay.
CPT-11 at varying concentrations (0.25–1 µM) was
incubated for 1 h at 37°C in the presence of 3.6 µg/ml hCE-1
or hCE-2 or no enzyme in serum-free cell culture medium (3:1
DMEM:Hank’s F-12K, 100 µg/ml penicillin-streptomycin, and 0.4
µg/ml hydrocortisone). The medium was then filtered through a 0.22
µm disc filter into a sterile 15-ml conical tube. 0.5 ml was removed
for quantitation of SN-38. SQ20b cells plated 16–18 h earlier at a
density of 5 x 105 cells/25
cm2 were exposed to the filtrate (5 ml) for
4 h at 37°C. After the 4-h incubation, another 0.5-ml aliquot
was removed for SN-38 quantitation. The cells were washed with fresh
medium containing 20% serum, trypsinized, and replated in culture
dishes at a density of 100-1000 cells/100 mm2
dish. Cell colonies (>50 cells) were counted 10–12 days later after
staining with crystal violet. Control samples (no CPT-11 or enzyme)
were treated identically.
|
Results |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
The Km for hCE-1 and hCE-2,
respectively, are 43 and 3.4 µM (Table 1)
. Vmax values of 78 and 18
pmol/min/unit activity were obtained for the respective isoforms from
the original fit of the data. These values were then normalized to
pmol/mg/min based upon rates determined previously of
4-methylumbelliferone acetate hydrolysis by hCE-1 and hCE-2 enzymes of
6.8 units/mg protein (14)
and 140 units/mg protein
(15)
, respectively. Vmax
values for hCE-1 and hCE-2 were calculated to be 530 and 2500
pmol/mg/min, respectively. Assuming a subunit molecular weight of
Mr 59,000 and one active site per
subunit, the turnover number of the enzymes would be 0.031 and 0.160
min-1, respectively. Hence, hCE-2 has a
12.5-fold higher affinity for CPT-11 and a 5-fold higher maximal rate
of CPT-11 hydrolysis compared with hCE-1. The differences between the
two isoforms are best exhibited by comparing catalytic efficiency
(Vmax/Km).
The catalytic efficiency of hCE-2 (47 x 10-3
min-1µM-1)
is 60-fold higher than that of hCE-1 (0.74 x 10-3
min-1µM-1).
|
. At 1 µM CPT-11, the rate of hydrolysis by hCE-1 and
hCE-2 measured after 10 min was 11 and 700 pmol/mg protein/min,
respectively. Thus, at pharmacologically relevant doses, the rate of
CPT-11 conversion by hCE-2 is significantly greater than that by hCE-1.
|
. Survival of cells exposed to CPT-11 in the absence of CE
enzyme was similar to that of cells in the control group (no CPT-11).
Incubation with hCE-1, likewise, produced no significant cytotoxicity
up to 1 µM of CPT-11. Incubation of CPT-11 in
the presence of hCE-2, however, resulted in significantly greater
cytotoxicity at all three CPT-11 concentrations examined. At 1
µM CPT-11, only 38% of cells survived after
incubation with hCE-2, whereas 88% of cells survived after incubation
with an equivalent amount of hCE-1. Ninety-five % of control cells (no
hCE exposure) survived after incubation with 1
µM CPT-11. At the lower concentrations of
CPT-11, 0.25 and 0.5 µM, 62 and 44% of cells
survived, respectively, after incubation with hCE-2.
|
and after the final 4-h
incubation on the SQ20b cells (Fig. 3C)
. SN-38 ranged from 5
to 15 nM after 1 h of incubation and 12 to
30 nM after 4 h of incubation in the
presence of hCE-2. Concentrations of SN-38 were <1
nM after exposure to hCE-1 at both time points.
The additional production of SN-38 during the 4-h incubation on the
SQ20b cells is attributed to residual CE enzyme in the filtered
incubation medium. No measurable conversion of CPT-11 to SN-38 was
evident in the absence of added hCE enzyme during preincubation or
during exposure to the SQ20b cells (data not shown). |
Discussion |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
The hydrolysis of CPT-11 to SN-38 by CEs has been studied extensively
using a variety of mammalian enzymes. In humans, the majority of
studies have focused on a single CE enzyme. Both Satoh et
al. (5)
and Rivory et al.
(17)
purified and characterized a CE enzyme from human
liver. They reported single Kms of 169
and 52.9 µM, respectively. In contrast, Slatter
et al. (18)
characterized the kinetics of
CPT-11 hydrolysis using human liver microsomes and identified the
presence of two CE isoforms. Modeling of the kinetic data for CPT-11
hydrolysis by liver microsomes fit a two-enzyme model, with a
high-affinity isoform (Km = 1.4–3.9 µM) and a low-affinity isoform
(Km = 129–164
µM). These investigators proposed that
the higher affinity enzyme was most likely responsible for CPT-11
activation. Consistent with the data reported by Slatter et
al. (18)
, we now report both a low-affinity (hCE-1)
and a high-affinity (hCE-2) isoform of human liver CE. The
Km for purified hCE-2 of 3.4
µM is almost identical to that reported by
Slatter et al. (18)
for the high-affinity
enzyme. The Km for hCE-1 of 43
µM is 
3-fold lower than that reported by
Slatter et al. (18)
for the lower affinity
isoform. This small difference may reflect the use of purified enzyme
versus liver microsomes.
Our studies with purified enzymes also show that hCE-2 has a
5-fold higher Vmax than hCE-1. Thus,
not only does hCE-2 activate CPT-11 at lower concentrations, it does so
at a faster rate. This is illustrated by direct comparison of the
hydrolysis of therapeutic concentrations of CPT-11 by the two
human enzymes (Fig. 2)
. Considering the lower
Km of 3 µM for
hCE-2 (which is more consistent with plasma levels measured in patients
receiving CPT-11) and the higher hydrolytic rate, hCE-2 (and not hCE-1)
is most likely responsible for activation of CPT-11 to SN-38 in the
human liver. However, final confirmation of the roles of hCE-1 and
hCE-2 in CPT-11 activation will depend upon relative expression of the
two isoforms in the liver, and perhaps, other tissues, particularly
tumor tissues.
In our cytotoxicity experiments, SQ20b cells, which are not sensitive to 1 µM CPT-11, show increased sensitivity to CPT-11 after incubation with hCE-2. A similar increase in sensitivity to CPT-11 was not observed after incubation with an equivalent amount of hCE-1. When 20-fold higher concentrations of hCE-1 protein were added, the cytotoxic effect was similar to, but still less than, that observed with hCE-2 (data not shown).
Enzyme prodrug combinations with CPT-11 are currently being
developed using both hCE-1 and a purified rabbit CE enzyme in several
laboratories (6
, 7
, 9)
. Transfection of tumor cell lines
with either the rabbit CE enzyme or hCE-1 increases sensitivity to
CPT-11. In the case of hCE-1, increased sensitivity to CPT-11 was
observed in transfected human lung cancer cell lines. The reported
IC50 for A549 cells transfected with hCE-1 is
2 µM (6)
. However, the cells were exposed
to CPT-11 continuously for 72 h, a duration of exposure that far
exceeds that observed in a clinical setting. The half-life of CPT-11 in
humans is 8–10 h (19)
. Additionally, in vivo
cytotoxicity was not reported with systemic dosing of CPT-11 but only
after direct injection of tumors with 7 µg/ml (12
µM) CPT-11 (6)
. Ideally, an
effective enzyme/prodrug combination would be toxic to transfected
tumor cells at lower than normal plasma concentrations, minimizing
toxicities and increasing the therapeutic index.
The rabbit CE enzyme is much more efficient at converting CPT-11 to SN-38 than hCE-1 and may be a better candidate than hCE-1 for development in an enzyme prodrug combination. Rh30 cells transfected with the rabbit CE were 100-1000-fold more active in converting CPT-11 to SN-38 than those transfected with hCE-1. Transfection of rabbit CE produced an 8-fold increase in sensitivity to CPT-11, shifting the IC50 from 4.3 to 0.57 µM. Xenograft experiments also show enhanced cytotoxicity in cell lines transfected with the rabbit CE enzyme when compared with controls or those transfected with hCE-1. Nevertheless, transfection of a nonhuman protein in the clinical setting may lead to an immunological response and subsequent enzyme inactivation. Transfection of a higher affinity, higher efficiency human enzyme such as hCE-2 may overcome these limitations.
Finally, the catalytic properties of hCE-1 and hCE-2 are clearly different for a variety of substrates. hCE-2 is 20-fold more efficient than hCE-1 in hydrolyzing 4-methylumbelliferyl acetate, a compound considered to be a relatively nonspecific esterase substrate (15) . Aspirin, (acetylsalicylic acid), procaine, and oxybutynin are also specific substrates for hCE-2 (13) . Meperidine is a specific substrate for hCE-1 (20) . Identification of additional substrate specificities and elucidation of binding site structure will provide important information about the roles of these two isoforms in the metabolism of other drugs and may ultimately lead to the specific design of ester prodrugs.
In conclusion, we have shown that the hCE enzyme hCE-2 clearly plays a role in the conversion of CPT-11 to SN-38 in the human liver. On the basis of enzyme kinetic profiles, hCE-2 exhibits the highest catalytic efficiency for CPT-11 activation. Additional experiments are being conducted to further define the roles of hCE-2 and hCE-1 in the activation of CPT-11 and other chemotherapeutic ester prodrugs. The expression of hCE-1 and hCE-2 in normal human tissues and tumors is also being investigated.
|
FOOTNOTES |
|---|
1 Supported in part by Oral Cancer Center Grant
P50 DE/CA 11921 (to M. E. D.) and National Institute on Drug Abuse
Grant DA06836 (to W. F. B.). 
2 To whom requests for reprints should be
addressed, at University of Chicago Medical Center, Section of
Hematology/Oncology, 5841 South Maryland Avenue, Box MC2115, Chicago,
IL 60637-1470. Phone: (773) 702-4441; Fax: (773) 702-3163; E-mail: edolan{at}medicine.bsd.uchicago.edu
3 The abbreviations used are: CE,
carboxylesterase; hCE, human CE; CPT-11,
7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin
(irinotecan); SN-38, 7-ethyl-10-hydroxy-camptothecin; HPLC,
high-performance liquid chromatography.
Received 11/11/99. Accepted 1/19/00.
|
REFERENCES |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  C. Xu, X. Wang, and J. L. Staudinger Regulation of Tissue-Specific Carboxylesterase Expression by Pregnane X Receptor and Constitutive Androstane Receptor Drug Metab. Dispos., July 1, 2009; 37(7): 1539 - 1547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Takahashi, M. Katoh, T. Saitoh, M. Nakajima, and T. Yokoi Different Inhibitory Effects in Rat and Human Carboxylesterases Drug Metab. Dispos., May 1, 2009; 37(5): 956 - 961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Methling, P. Reszka, M. Lalk, O. Vrana, E. Scheuch, W. Siegmund, B. Terhaag, and P. J. Bednarski Investigation of the in Vitro Metabolism of the Analgesic Flupirtine Drug Metab. Dispos., March 1, 2009; 37(3): 479 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Meyer-Losic, C. Nicolazzi, J. Quinonero, F. Ribes, M. Michel, V. Dubois, C. de Coupade, M. Boukaissi, A.-S. Chene, I. Tranchant, et al. DTS-108, A Novel Peptidic Prodrug of SN38: In vivo Efficacy and Toxicokinetic Studies Clin. Cancer Res., April 1, 2008; 14(7): 2145 - 2153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Schiel, S.-l. Green, W. I. Davis, P. C. Sanghani, W. F. Bosron, and S. P. Sanghani Expression and Characterization of a Human Carboxylesterase 2 Splice Variant J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 94 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-R. Kim, K. Sai, T. Tanaka-Kagawa, H. Jinno, S. Ozawa, N. Kaniwa, Y. Saito, A. Akasawa, K. Matsumoto, H. Saito, et al. Haplotypes and a Novel Defective Allele of CES2 Found in a Japanese Population Drug Metab. Dispos., October 1, 2007; 35(10): 1865 - 1872. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yokoo, A. Hamada, H. Watanabe, T. Matsuzaki, T. Imai, H. Fujimoto, K. Masa, T. Imai, and H. Saito Involvement of Up-Regulation of Hepatic Breast Cancer Resistance Protein in Decreased Plasma Concentration of 7-Ethyl-10-hydroxycamptothecin (SN-38) by Coadministration of S-1 in Rats Drug Metab. Dispos., September 1, 2007; 35(9): 1511 - 1517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. N. V. S. Mamidi, G. Mannens, P. Annaert, J. Hendrickx, I. Goris, M. Bockx, C. G. M. Janssen, M. Kao, M. F. Kelley, and W. Meuldermans Metabolism and Excretion of RWJ-333369 [1,2-Ethanediol, 1-(2-Chlorophenyl)-, 2-carbamate, (S)-] in Mice, Rats, Rabbits, and Dogs Drug Metab. Dispos., April 1, 2007; 35(4): 566 - 575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Shi, J. Yang, D. Yang, E. L. LeCluyse, C. Black, L. You, F. Akhlaghi, and B. Yan Anti-Influenza Prodrug Oseltamivir Is Activated by Carboxylesterase Human Carboxylesterase 1, and the Activation Is Inhibited by Antiplatelet Agent Clopidogrel J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1477 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Higa Searching for the Holy Grail of oncology Am. J. Health Syst. Pharm., November 15, 2006; 63(22): 2260 - 2262. [Full Text] [PDF]
|
|
|
|
|
|
T. Imai, M. Taketani, M. Shii, M. Hosokawa, and K. Chiba Substrate Specificity of Carboxylesterase Isozymes and Their Contribution to Hydrolase Activity in Human Liver and Small Intestine Drug Metab. Dispos., October 1, 2006; 34(10): 1734 - 1741. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. de Jong, D. F. S. Kehrer, R. H. J. Mathijssen, G.-J. Creemers, P. de Bruijn, R. H. N. van Schaik, A. S. Th. Planting, A. van der Gaast, F. A. L. M. Eskens, J. Th. P. Janssen, et al. Prophylaxis of Irinotecan-Induced Diarrhea with Neomycin and Potential Role for UGT1A1*28 Genotype Screening: A Double-Blind, Randomized, Placebo-Controlled Study Oncologist, September 1, 2006; 11(8): 944 - 954. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Landowski, P. L. Lorenzi, X. Song, and G. L. Amidon Nucleoside Ester Prodrug Substrate Specificity of Liver Carboxylesterase J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 572 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kubo, S.-R. Kim, K. Sai, Y. Saito, T. Nakajima, K. Matsumoto, H. Saito, K. Shirao, N. Yamamoto, H. Minami, et al. FUNCTIONAL CHARACTERIZATION OF THREE NATURALLY OCCURRING SINGLE NUCLEOTIDE POLYMORPHISMS IN THE CES2 GENE ENCODING CARBOXYLESTERASE 2 (HCE-2) Drug Metab. Dispos., October 1, 2005; 33(10): 1482 - 1487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Cecchin, G. Corona, S. Masier, P. Biason, G. Cattarossi, S. Frustaci, A. Buonadonna, A. Colussi, and G. Toffoli Carboxylesterase Isoform 2 mRNA Expression in Peripheral Blood Mononuclear Cells Is a Predictive Marker of the Irinotecan to SN38 Activation Step in Colorectal Cancer Patients Clin. Cancer Res., October 1, 2005; 11(19): 6901 - 6907. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. P. Yong, J. Ramirez, F. Innocenti, and M. J. Ratain Effects of Ketoconazole on Glucuronidation by UDP-Glucuronosyltransferase Enzymes Clin. Cancer Res., September 15, 2005; 11(18): 6699 - 6704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Imai, M. Imoto, H. Sakamoto, and M. Hashimoto IDENTIFICATION OF ESTERASES EXPRESSED IN CACO-2 CELLS AND EFFECTS OF THEIR HYDROLYZING ACTIVITY IN PREDICTING HUMAN INTESTINAL ABSORPTION Drug Metab. Dispos., August 1, 2005; 33(8): 1185 - 1190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Quinney, S. P. Sanghani, W. I. Davis, T. D. Hurley, Z. Sun, D. J. Murry, and W. F. Bosron Hydrolysis of Capecitabine to 5'-Deoxy-5-fluorocytidine by Human Carboxylesterases and Inhibition by Loperamide J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1011 - 1016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tabata, M. Katoh, S. Tokudome, M. Nakajima, and T. Yokoi IDENTIFICATION OF THE CYTOSOLIC CARBOXYLESTERASE CATALYZING THE 5'-DEOXY-5-FLUOROCYTIDINE FORMATION FROM CAPECITABINE IN HUMAN LIVER Drug Metab. Dispos., October 1, 2004; 32(10): 1103 - 1110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Sun, D. J. Murry, S. P. Sanghani, W. I. Davis, N. Y. Kedishvili, Q. Zou, T. D. Hurley, and W. F. Bosron Methylphenidate Is Stereoselectively Hydrolyzed by Human Carboxylesterase CES1A1 J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 469 - 476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. P. Yoon, J. L. Hyatt, C. L. Morton, R. E. Lee, P. M. Potter, and M. K. Danks Characterization of inhibitors of specific carboxylesterases: Development of carboxylesterase inhibitors for translational application Mol. Cancer Ther., August 1, 2004; 3(8): 903 - 909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Sanghani, S. K. Quinney, T. B. Fredenburg, W. I. Davis, D. J. Murry, and W. F. Bosron HYDROLYSIS OF IRINOTECAN AND ITS OXIDATIVE METABOLITES, 7-ETHYL-10-[4-N-(5-AMINOPENTANOIC ACID)-1-PIPERIDINO] CARBONYLOXYCAMPTOTHECIN AND 7-ETHYL-10-[4-(1-PIPERIDINO)-1-AMINO]-CARBONYLOXYCAMPTOTHECIN, BY HUMAN CARBOXYLESTERASES CES1A1, CES2, AND A NEWLY EXPRESSED CARBOXYLESTERASE ISOENZYME, CES3 Drug Metab. Dispos., May 1, 2004; 32(5): 505 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. L. McLeod and J. W. Watters Irinotecan Pharmacogenetics: Is It Time to Intervene? J. Clin. Oncol., April 15, 2004; 22(8): 1356 - 1359. [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Prados, W.K.A. Yung, K. A. Jaeckle, H. I. Robins, M. P. Mehta, H. A. Fine, P. Y. Wen, T. F. Cloughesy, S. M. Chang, M. K. Nicholas, et al. Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: A North American Brain Tumor Consortium study Neuro-oncol, January 1, 2004; 6(1): 44 - 54. [Abstract] [PDF]
|
|
|
|
|
|
K. J. P. Yoon, E. J. Krull, C. L. Morton, W. G. Bornmann, R. E. Lee, P. M. Potter, and M. K. Danks Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies Mol. Cancer Ther., November 1, 2003; 2(11): 1171 - 1181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Sanghani, S. K. Quinney, T. B. Fredenburg, Z. Sun, W. I. Davis, D. J. Murry, O. W. Cummings, D. E. Seitz, and W. F. Bosron Carboxylesterases Expressed in Human Colon Tumor Tissue and Their Role in CPT-11 Hydrolysis Clin. Cancer Res., October 15, 2003; 9(13): 4983 - 4991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Oosterhoff, M. A. Witlox, V. W. van Beusechem, H. J. Haisma, G. R. Schaap, J. Bras, F. A. Kruyt, B. Molenaar, E. Boven, P. I. J. M. Wuisman, et al. Gene-directed Enzyme Prodrug Therapy for Osteosarcoma: Sensitization to CPT-11 in Vitro and in Vivo by Adenoviral Delivery of a Gene Encoding Secreted Carboxylesterase-2 Mol. Cancer Ther., August 1, 2003; 2(8): 765 - 771. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Kim, X.-y. Chu, S. Kim, C. J. Provoda, K.-D. Lee, and G. L. Amidon Identification of a Human Valacyclovirase: BIPHENYL HYDROLASE-LIKE PROTEIN AS VALACYCLOVIR HYDROLASE J. Biol. Chem., July 3, 2003; 278(28): 25348 - 25356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Xie, D. Yang, M. Wu, B. Xue, and B. Yan Mouse Liver and Kidney Carboxylesterase (M-LK) Rapidly Hydrolyzes Antitumor Prodrug Irinotecan and the N-Terminal Three Quarter Sequence Determines Substrate Selectivity Drug Metab. Dispos., January 1, 2003; 31(1): 21 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Xu and M. A. Villalona-Calero Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity Ann. Onc., December 1, 2002; 13(12): 1841 - 1851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Xu, W. Zhang, M. K. Ma, and H. L. McLeod Human Carboxylesterase 2 Is Commonly Expressed in Tumor Tissue and Is Correlated with Activation of Irinotecan Clin. Cancer Res., August 1, 2002; 8(8): 2605 - 2611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Wu, B. Yan, R. Humerickhouse, and M. E. Dolan Irinotecan Activation by Human Carboxylesterases in Colorectal Adenocarcinoma Cells Clin. Cancer Res., August 1, 2002; 8(8): 2696 - 2700. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. F.S. Kehrer, R. H.J. Mathijssen, J. Verweij, P. de Bruijn, and A. Sparreboom Modulation of Irinotecan Metabolism by Ketoconazole J. Clin. Oncol., July 15, 2002; 20(14): 3122 - 3129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Satoh, P. Taylor, W. F. Bosron, S. P. Sanghani, M. Hosokawa, and B. N. L. Du Current Progress on Esterases: From Molecular Structure to Function Drug Metab. Dispos., May 1, 2002; 30(5): 488 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Ratain Irinotecan Dosing: Does the CPT in CPT-11 Stand for "Can't Predict Toxicity"? J. Clin. Oncol., January 1, 2002; 20(1): 7 - 8. [Full Text] [PDF]
|
|
|
|
|
|
R. H.J. Mathijssen, J. Verweij, M. J.A. de Jonge, K. Nooter, G. Stoter, and A. Sparreboom Impact of Body-Size Measures on Irinotecan Clearance: Alternative Dosing Recommendations J. Clin. Oncol., January 1, 2002; 20(1): 81 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sai, N. Kaniwa, S. Ozawa, and J.-i. Sawada A New Metabolite of Irinotecan in Which Formation Is Mediated by Human Hepatic Cytochrome P-450 3a4 Drug Metab. Dispos., November 1, 2001; 29(11): 1505 - 1513. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Wadkins, C. L. Morton, J. K. Weeks, L. Oliver, M. Wierdl, M. K. Danks, and P. M. Potter Structural Constraints Affect the Metabolism of 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) by Carboxylesterases Mol. Pharmacol., August 1, 2001; 60(2): 355 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. J. Mathijssen, R. J. van Alphen, J. Verweij, W. J. Loos, K. Nooter, G. Stoter, and A. Sparreboom Clinical Pharmacokinetics and Metabolism of Irinotecan (CPT-11) Clin. Cancer Res., August 1, 2001; 7(8): 2182 - 2194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. F. S. Kehrer, A. Sparreboom, J. Verweij, P. de Bruijn, C. A. Nierop, J. van de Schraaf, E. J. Ruijgrok, and M. J. A. de Jonge Modulation of Irinotecan-induced Diarrhea by Cotreatment with Neomycin in Cancer Patients Clin. Cancer Res., May 1, 2001; 7(5): 1136 - 1141. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. Khanna, C. L. Morton, M. K. Danks, and P. M. Potter Proficient Metabolism of Irinotecan by a Human Intestinal Carboxylesterase Cancer Res., September 1, 2000; 60(17): 4725 - 4728. [Abstract] [Full Text]
|
|
|
|
|
|
M. J. Ratain Insights into the Pharmacokinetics and Pharmacodynamics of Irinotecan Clin. Cancer Res., September 1, 2000; 6(9): 3393 - 3394. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
