| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Advances in Brief |
Ludwig Institute for Cancer Research [M. N., W. K. C., H.-J. S. H.], Department of Medicine [W. K. C., H.-J. S. H.], Center for Molecular Genetics [W. K. C.], and Cancer Center [W. K. C.], University of California at San Diego, La Jolla, California 92093-0660; Departments of Endocrinology [G. P.] and Molecular Oncology [V. M. D.], Genentech, Inc., South San Francisco, California 94080-4990; and Department of Molecular Biology, Becton-Dickinson PharMingen, San Diego, California 92121 [J. J. W.]
 |
ABSTRACT |
|---|
 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
|
Introduction |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
Apoptosis is a genetically controlled form of cell death that appears to be involved in tumor cell killing by most chemotherapeutic agents and by irradiation through disparate modes of action and cellular targets (2) . Death ligands such as TNF2 and FasL (also called Apo1L/CD95L) interact with their cognate death domain-containing receptors, TNF receptor 1 and Fas (Apo1/CD95), respectively, thereby directly triggering suicide signal transduction pathways (3) . Death signals evoked by the interaction of death ligands and their receptors may provide a new modality in glioma treatment because of their ability to directly induce apoptosis, thus bypassing cellular drug resistance. However, the therapeutic usefulness of FasL and TNF against cancer is limited by their acute toxicity after systemic administration, especially in the liver because of high expression of cognate receptors in hepatocytes, unless selectively targeted to tumor cells (4 , 5) .
TRAIL (also called Apo2L) is a new member of the TNF family and is capable of inducing rapid apoptosis in tumor cells of diverse origins but not in most normal cells in vitro (6, 7, 8) . TRAIL can interact with two death receptors, DR4 (TRAIL-R1) (9) and DR5 (Killer/TRAIL-R2/TRICK2) (10, 11, 12) , which contain cytoplasmic death domains, thereby triggering apoptotic signals. Such signals may be blocked by expression of the antagonistic decoy receptors, DcR1 (TRID/TRAIL-R3; Refs. 10 , 11 , and 13 ), DcR2 (TRUNDD/TRAIL-R4; Refs. 14 –16), and osteoprotegerin (17) , which can compete with DR4 or DR5 for binding to TRAIL. Both DR4 and DR5 transcripts are expressed to some extent in some cancer cells, but in the brain DR5 is expressed at low levels (7 , 10 , 11 , 18) . Unlike FasL or TNF, systemic administration of soluble human TRAIL has been shown to have little toxicity in mice or nonhuman primates (19 , 20) , suggesting its potential value for cancer therapy.
Because DNA damage has been shown to up-regulate DR5 transcription in some human cancer cells (21 , 22) , the possibility arose that conventional DNA-damaging chemotherapy might enhance the cytotoxicity of TRAIL through up-regulation of its receptor DR5. This might then lead to a synergistic activation by TRAIL-triggered apoptosis pathways. Here we tested this idea and show that the DNA-damaging agents CDDP and VP16, commonly used in human glioma treatment, caused up-regulation of DR5 transcripts in most glioma cells tested. Untreated cells were relatively resistant to TRAIL, and the drug-induced DR5 expression per se did not lead to apoptosis. However, treatment with soluble human TRAIL in combination with the DNA-damaging drugs caused a dramatic and synergistic cell death through TRAIL-receptor interaction and caspase activation. This combination treatment also significantly suppressed tumor formation as well as growth of established human glioblastoma xenografts in mice without generalized toxicity. These results suggest a novel and safe therapeutic strategy for the most aggressive type of glioma, glioblastoma, which combines conventional DNA-damaging chemotherapy with the apoptotic TRAIL ligand.
|
Materials and Methods |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
Cells.
The human glioblastoma cell lines used were described previously
(23)
. The A1207 cell line was gift from Dr. S. Aaronson
(Mount Sinai Medical Center, New York, NY). All cells were cultured as
described (24)
.
Production and Purification of Human Recombinant Soluble
FLAG-TRAIL.
The plasmid encoding a soluble His-tagged FLAG-human TRAIL has been
described (9)
. TRAIL was purified from plasmid-transformed
BL21(DE3)pLysS cells by affinity chromatography on
Ni2+-NTA agarose columns according to the manufacturer’s
instructions (Qiagen, Santa Clarita, CA) and was then dialyzed against
PBS containing 10% glycerol and stored at -80°C. To generate an
endotoxin control for bacterial-derived TRAIL, lysates from mock
BL21(DE3)pLysS cells were prepared and processed by the identical
purification protocol. Soluble chimeric fusion proteins, DR5-Fc, and
its Fc control were prepared as described (10)
.
RNA Analyses.
Northern blot analysis was performed as described with modifications
(24)
. A human DR5 cDNA fragment (583 bp) was generated by
reverse transcription-PCR from total RNA of U87MG cells using primers
5'-CTGAAAGGCATCTGCTCAGGTG-3' (sense) and 5'-CAGAGTCTGCATTACCTTCTAG-3'
(antisense). Hybridization was performed in Expresshyb buffer
(Clontech, Palo Alto, CA) at 68°C for 2 h. The RNA filter was
washed in 0.5x SSC and 0.1% SDS at 58°C for 15 min and
exposed to Kodak Biomax film at -80°C with an intensifying screen.
RNase protection assays were carried out using the RiboQuant protocol
according to the manufacturer’s instructions (PharMingen, San Diego,
CA).
Cell Death Assays.
Cytotoxicity was evaluated using the MTT survival assay as described
(25)
. Briefly, cells were plated at 1 x 104 cells/well in 96-well microtiter plates overnight.
Cells were then treated with 200 µl fresh medium containing drugs,
cultured for 24 h followed by an additional 4 h with 250
µg/ml MTT, and analyzed using a microplate reader (Molecular Devices,
Sunnyvale, CA). The effects of treatment are expressed as a percentage
of growth inhibition using untreated cells as the uninhibited control.
In vivo apoptosis assays were performed as described
(24)
.
In Vivo Treatments.
U87MG cells (2 x 106 cells) were suspended
in 0.1 ml PBS and injected s.c. into the right flank of female nude
mice, 4–5 weeks of age, of BALB/c background (Simenson’s Lab, Gilroy,
CA). For the treatment of the established xenografts, the tumors were
permitted to establish and grow for 13 days (tumor volume, 
80
mm3). For intracerebral stereotactic inoculation,
5 x 105 U87MG cells in 5 µl of PBS were
inoculated into the right corpus striatum of the mouse brain as
described (24)
. Either CDDP (3 mg/kg) or sterile normal
saline was administered i.p. daily for 3 consecutive days per one
course of treatment. Mice were also treated with either FLAG-TRAIL (250
µg) or the mock control lysate in the same volume twice a day with
i.v. and i.p. injections on the same days as the CDDP treatment. The
growth of tumors was measured as described (26)
. Systemic
toxicity of the treatments was assessed by change in body weight and by
organ inspection at autopsy. All treatment protocols were approved by
the animal care and use committee of the University of California, San
Diego.
Statistical Analysis.
The data were analyzed for significance by Student’s t
test, except for the in vivo survival assays, which used
Cox-Mantel analysis. Synergism between TRAIL and DNA-damaging agents
was assessed by the Fractional Inhibition Method as described
(27)
.
|
Results |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
4.4 kb DR5 transcripts increased significantly after
treatment with the DNA-damaging agents CDDP or VP16 for 16 h at
sublethal concentrations in most cell lines (U87MG, A1207, U178MG,
LN229, U251MG, and LN428) and to a lesser extent (T98G) or very little
(U373MG and LNZ308) in a few others (Fig. 1, A and B
; Table 1
). The induction of DR5 mRNA by these agents was dose, drug type, and time
dependent, with induction by VP16 being apparent after 2 h, by
16 h of CDDP exposure, and with the alkylating agent, BCNU, having
lesser effects (Fig. 1C)
.
|
|
. DR5 levels increased upon treatment with CDDP and VP16
in U87MG, A1207, and U178MG cells, consistent with the Northern blot
analysis. DR4 was also expressed and somewhat up-regulated in U87MG and
A1207 cells but to a much lesser extent than DR5. Expression of the two
TRAIL decoy receptors, DcR1 and DcR2, was only detectable at trace
levels in U87MG cells, and TRAIL transcripts were undetectable in all
cells.
Treatment with a Combination of Soluble Human TRAIL and
DNA-damaging Agents Causes Synergistic in Vitro
Cytotoxicity through Caspase Activation.
Having determined that DR5 expression was enhanced upon exposure to
DNA-damaging agents in a majority of human glioma cell lines tested, we
next asked whether a combination of its ligand, TRAIL, with the drugs
would enhance cytotoxicity. We measured the viability of glioma cells
upon single exposures to a wide range of concentrations of CDDP, VP16,
or BCNU. In each responder, the concentrations leading to growth
inhibition were greater than those required for DR5 induction. This
allowed the selection of doses that were sublethal but sufficient to
induce DR5 expression, and these were then tested in combination with a
low concentration (0.1 µg/ml) of TRAIL that had no effect itself on
cell viability. A combination of these low doses of CDDP or VP16 and
TRAIL induced substantial cell death in a synergistic manner in those
glioma cells whose DR5 was up-regulated with DNA-damaging treatment.
Evident changes in morphology were typical of apoptotic cell death
(Fig. 2, A–L)
, and this was confirmed by DNA fragmentation detected by TUNEL
assays (data not shown). The combination treatment-induced apoptosis
was mediated through caspase activation because cleavage of PARP, a
substrate of effector caspases, was elicited by the combination of
TRAIL with CDDP or VP16 but not by any of the single treatments (data
not shown). The synergistic cytotoxicity and the PARP cleavage were
inhibited by the caspase inhibitors Z-Asp-CH2-DCB (Bachem,
Torrance, CA; Fig. 2, F and L
) and CrmA
(data not shown). In contrast, combination treatment, even at high
doses of CDDP or VP16, did not result in enhancement of TRAIL
cytotoxicity in U373MG and LNZ308 cells, DR5 expression of which was
not affected by DNA damage treatment, and caused moderate killing of
T98G cells, whose DR5 induction had been shown to be moderate. The
doses that were effective in the combination treatment were >100-fold
lower for TRAIL and mostly less than half for CDDP or VP16 than those
required to kill the cells when administered alone (Fig. 3, A and B
; Table 1
).
|
|
and 3, A and B).
In contrast to
CDDP and VP16, the combination of TRAIL and BCNU resulted in a less
effective, synergistic cytotoxicity only in A1207 cells, and there was
no synergy with U87MG and U178MG cells (Fig. 3C)
, concordant
with the poor induction of DR5 caused by BCNU. BCNU has also been shown
to inhibit caspase activation (28)
, which may also explain
the lack of synergism between TRAIL and BCNU.
Treatment of Animals with a Combination of TRAIL and CDDP
Suppresses Tumor Formation in Vivo.
We next determined whether the synergistic cytotoxicity induced by the
combination of TRAIL with DNA-damaging agents in vitro could
be demonstrated in vivo. We first tested the effect of
combination treatment on tumor formation in nude mice. Mice were
inoculated s.c. with U87MG cells and also treated with TRAIL (500
µg/day) and CDDP (3 mg/kg). After the third course of treatment as
described in "Materials and Methods," mice treated with the
combination of TRAIL and CDDP had not developed tumors. In contrast,
tumors in the other groups had already begun to grow, although
treatment with TRAIL or CDDP alone showed some initial suppression of
tumor growth (Fig. 4A)
. Tumor formation was significantly suppressed in the combination group
(P = 0.007 against CDDP alone group). Two
(50%) of the four mice in the combination treatment group had no
tumors >3 months after tumor cell inoculation (Fig. 4C)
.
There was no significant body weight loss or any obvious neurological
sequelae in mice of any of the treatment groups and also in treated
mice without tumors. Histological analysis of the livers, kidneys, and
brains of mice obtained at the end of the first course of treatment
showed no appreciable changes, except for minor and nonspecific single
cell necrosis in the livers in all groups. After the third course of
treatment, only minor infiltration of monocytes and granulocytes was
observed in the liver obtained from one animal in the combination
treatment group, but there were no obvious necroses in the livers from
any of the treated animals (data not shown). We further examined
effects of the treatments on normal human astrocytes. Neither the
treatment with TRAIL alone (10 µg/ml) nor combination of TRAIL (0.1
µg/ml) and CDDP (10 µg/ml) or VP16 (16 µg/ml) caused cytotoxicity
in these cells in vitro (data not shown).
|
). The suppression of tumor growth
was dose dependent for both TRAIL and CDDP (data not shown). Long-term
treatment resulted in durable remission for some tumors of the
combination group. Among 17 tumors treated with the combination of
TRAIL and CDDP, 5 tumors (29%) achieved complete remission, and 1
tumor was not growing >3 months after tumor inoculation (Fig. 4C)
. This frequency of regression caused by the combination
treatment is significantly higher than that for hundreds of established
U87MG xenografts we have observed over many years (<2%). Cultured
tumor cells derived from the xenografts that eventually developed
despite the combination treatment were equally sensitive to the
combination treatment as the original cells were in vitro
(data not shown), suggesting an inadequate drug concentration in tumors
that did not regress. The combination treatment significantly induced
apoptosis in tumor cells in the established xenografts after the first
course of treatment, as demonstrated by TUNEL assays
(P = 0.003 versus vehicle control;
Fig. 4D
). Similar suppression of tumor growth was observed
in three other independent experiments (data not shown).
We also examined the potency of the combination treatment for brain
tumors using intracerebral xenograft models. Mice stereotactically
inoculated in the brain with U87MG cells were treated with three
courses of TRAIL and CDDP beginning from day 7 after inoculation. The
combination treatment with TRAIL and CDDP significantly extended the
survival of mice bearing intracerebral xenografts when compared with
either vehicle, TRAIL, or CDDP treatment alone (P < 0.01; Fig. 4E
).
|
Discussion |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
The drug-induced DR5 up-regulation and subsequent enhancement of TRAIL-mediated cytotoxicity in glioma cells may correlate with their p53 status, because DR5 was up-regulated upon DNA-damaging treatments in all p53 wild-type glioma cells (U87MG, A1207, and U178MG), whereas it was not in p53-mutated U373MG and LNZ308 cells (29) . In addition, adenovirus-mediated wild-type p53 expression has been shown to increase DR5 transcripts in human cancer cell lines with mutated p53 (22) . However, we have been unable to show the direct involvement of wild-type p53 in this phenotype thus far using several approaches, including disruption of p53 function by introducing p53DD, a dominant-negative p53 (30) , in p53-positive glioma cells, introducing wild-type p53 in p53-mutated glioma cells, and using syngeneic mouse cells with or without intact p53 alleles (data not shown). DR5 was also up-regulated in other p53-mutated glioma cell lines, U251MG, LN229, and LN428 (29) , consistent with the suggestion that there are p53-independent pathways leading to its up-regulation (21) . This raises the possibility that our combination treatment approach could target both p53-wild type and -mutated glioma cells. Regulation of DR5 expression may also depend on the type of DNA damage, because the primary DNA lesions induced by the drugs used here are distinct, and the level of DR5 up-regulation varied among them. Perhaps certain DNA lesions preferentially initiate downstream pathways that activate the transcriptional machinery for DR5 expression. Identification and activation of the factor(s) responsible for direct DR5 transactivation would provide an alternative approach to augment TRAIL-mediated treatment of tumor cells.
Systemic administration of soluble TRAIL did not cause apparent neurological disorders or histopathological changes. Normal human astrocytes in culture were also resistant to the soluble TRAIL or the combination of TRAIL and DNA-damaging agents, consistent with the report by Ashkenazi et al. (20) . The trace level expression of DR5 transcripts in normal brain tissue may also account for the absence of TRAIL-related toxicity in the brain (10 , 11) . Thus, the differences in DR5 expression between normal brain and glioma cells may provide a therapeutic window through which glioma cells could be selectively killed by TRAIL. Although further pharmacokinetic studies of soluble TRAIL in the central nervous system remain to be done, our results suggest a novel therapeutic strategy in which death ligands are combined with conventional DNA-damaging chemotherapy.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 To whom requests for reprints should be
addressed, at Ludwig Institute for Cancer Research, 9500 Gilman Drive,
CMME-3080, University of California at San Diego, La Jolla, CA
92093-0660. Phone: (858) 534-7808; Fax: (858) 534-7816; E-mail: mnagane{at}ucsd.edu 
2 The abbreviations used are: TNF, tumor necrosis
factor; FasL, Fas ligand; TRAIL, TNF-related apoptosis-inducing ligand;
CDDP, cis-diamminedichloroplatinum(II); BCNU,
1,3-bis(2-chloroethyl)-1-nitrosourea; MTT,
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide;
TUNEL, terminal deoxynucleotidyl transferase-mediated nick end
labeling; VP16, etoposide.
Received 12/13/99. Accepted 12/29/99.
|
REFERENCES |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
B and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity, 7: 813-820, 1997.[Medline]
. Cancer Res., 58: 1593-1598, 1998.This article has been cited by other articles:
|
|
 |
|
  M. Candolfi, K. Yagiz, D. Foulad, G. E. Alzadeh, M. Tesarfreund, A.K.M. G. Muhammad, M. Puntel, K. M. Kroeger, C. Liu, S. Lee, et al. Release of HMGB1 in Response to Proapoptotic Glioma Killing Strategies: Efficacy and Neurotoxicity Clin. Cancer Res., July 1, 2009; 15(13): 4401 - 4414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. W. Duiker, E. G.E. de Vries, D. Mahalingam, G. J. Meersma, W. Boersma-van Ek, H. Hollema, M. N. Lub-de Hooge, G. M. van Dam, R. H. Cool, W. J. Quax, et al. Enhanced Antitumor Efficacy of a DR5-Specific TRAIL Variant over Recombinant Human TRAIL in a Bioluminescent Ovarian Cancer Xenograft Model Clin. Cancer Res., March 15, 2009; 15(6): 2048 - 2057. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Lunghi, N. Giuliani, L. Mazzera, G. Lombardi, M. Ricca, A. Corradi, A. M. Cantoni, L. Salvatore, R. Riccioni, A. Costanzo, et al. Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways Blood, September 15, 2008; 112(6): 2450 - 2462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Oliver, A. F. LoBuglio, K. R. Zinn, H. Kim, L. Nan, T. Zhou, W. Wang, and D. J. Buchsbaum Treatment of Human Colon Cancer Xenografts with TRA-8 Anti-death Receptor 5 Antibody Alone or in Combination with CPT-11 Clin. Cancer Res., April 1, 2008; 14(7): 2180 - 2189. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Ziegler, A. L. Kung, and M. W. Kieran Anti-Apoptosis Mechanisms in Malignant Gliomas J. Clin. Oncol., January 20, 2008; 26(3): 493 - 500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. B. Furnari, T. Fenton, R. M. Bachoo, A. Mukasa, J. M. Stommel, A. Stegh, W. C. Hahn, K. L. Ligon, D. N. Louis, C. Brennan, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment Genes & Dev., November 1, 2007; 21(21): 2683 - 2710. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Baritaki, A. Katsman, D. Chatterjee, K. C. Yeung, D. A. Spandidos, and B. Bonavida Regulation of Tumor Cell Sensitivity to TRAIL-Induced Apoptosis by the Metastatic Suppressor Raf Kinase Inhibitor Protein via Yin Yang 1 Inhibition and Death Receptor 5 Up-Regulation J. Immunol., October 15, 2007; 179(8): 5441 - 5453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Smith, F. Jin, and I. Joshi Bortezomib Sensitizes Non Hodgkin's Lymphoma Cells to Apoptosis Induced by Antibodies to Tumor Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL) Receptors TRAIL-R1 and TRAIL-R2 Clin. Cancer Res., September 15, 2007; 13(18): 5528s - 5534s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Koschny, H. Holland, J. Sykora, T. L. Haas, M. R. Sprick, T. M. Ganten, W. Krupp, M. Bauer, P. Ahnert, J. Meixensberger, et al. Bortezomib Sensitizes Primary Human Astrocytoma Cells of WHO Grades I to IV for Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis Clin. Cancer Res., June 1, 2007; 13(11): 3403 - 3412. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liu, P. Yue, S. Chen, L. Hu, S. Lonial, F. R. Khuri, and S.-Y. Sun The Proteasome Inhibitor PS-341 (Bortezomib) Up-Regulates DR5 Expression Leading to Induction of Apoptosis and Enhancement of TRAIL-Induced Apoptosis Despite Up-Regulation of c-FLIP and Survivin Expression in Human NSCLC Cells Cancer Res., May 15, 2007; 67(10): 4981 - 4988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Baritaki, S. Huerta-Yepez, T. Sakai, D. A. Spandidos, and B. Bonavida Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: up-regulation of DR5 and inhibition of Yin Yang 1 Mol. Cancer Ther., April 1, 2007; 6(4): 1387 - 1399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. C. Lee, D. A. Hamstra, M. S. Bhojani, A. P. Khan, B. D. Ross, and A. Rehemtulla Noninvasive Molecular Imaging Sheds Light on the Synergy between 5-Fluorouracil and TRAIL/Apo2L for Cancer Therapy Clin. Cancer Res., March 15, 2007; 13(6): 1839 - 1846. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gong, D. Yang, S. Kohanim, R. Humphreys, L. Broemeling, and R. Kurzrock Novel in vivo imaging shows up-regulation of death receptors by paclitaxel and correlates with enhanced antitumor effects of receptor agonist antibodies Mol. Cancer Ther., December 1, 2006; 5(12): 2991 - 3000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. van Geelen, J. L. Westra, E. G. de Vries, W. Boersma-van Ek, N. Zwart, H. Hollema, H. M. Boezen, N. H. Mulder, J. T. Plukker, S. de Jong, et al. Prognostic Significance of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand and Its Receptors in Adjuvantly Treated Stage III Colon Cancer Patients J. Clin. Oncol., November 1, 2006; 24(31): 4998 - 5004. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Matsubara, Y. Mizutani, F. Hongo, H. Nakanishi, Y. Kimura, S. Ushijima, A. Kawauchi, T. Tamura, T. Sakata, and T. Miki Gene therapy with TRAIL against renal cell carcinoma. Mol. Cancer Ther., September 1, 2006; 5(9): 2165 - 2171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-C. Li, C.-C. Tzeng, J. H. Song, F.-J. Tsia, L.-J. Hsieh, S.-J. Liao, C.-H. Tsai, E. G. Van Meir, C. Hao, and C.-C. Lin Genomic alterations in human malignant glioma cells associate with the cell resistance to the combination treatment with tumor necrosis factor-related apoptosis-inducing ligand and chemotherapy. Clin. Cancer Res., May 1, 2006; 12(9): 2716 - 2729. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Ricci and W.-X. Zong Chemotherapeutic approaches for targeting cell death pathways. Oncologist, April 1, 2006; 11(4): 342 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Hasegawa, Y. Yamada, K. Komiyama, M. Hayashi, M. Ishibashi, T. Yoshida, T. Sakai, T. Koyano, T.-S. Kam, K. Murata, et al. Dihydroflavonol BB-1, an extract of natural plant Blumea balsamifera, abrogates TRAIL resistance in leukemia cells Blood, January 15, 2006; 107(2): 679 - 688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Eramo, R. Pallini, F. Lotti, G. Sette, M. Patti, M. Bartucci, L. Ricci-Vitiani, M. Signore, G. Stassi, L. M. Larocca, et al. Inhibition of DNA Methylation Sensitizes Glioblastoma for Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Mediated Destruction Cancer Res., December 15, 2005; 65(24): 11469 - 11477. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Kim, J. J. Song, J. Y. An, Y. T. Kwon, and Y. J. Lee Pretreatment of Acetylsalicylic Acid Promotes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis by Down-regulating BCL-2 Gene Expression J. Biol. Chem., December 9, 2005; 280(49): 41047 - 41056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhang, R. M. Cheung, R. Komaki, B. Fang, and J. Y. Chang Radiotherapy Sensitization by Tumor-Specific TRAIL Gene Targeting Improves Survival of Mice Bearing Human Non-Small Cell Lung Cancer Clin. Cancer Res., September 15, 2005; 11(18): 6657 - 6668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R.-X. Shi, C.-N. Ong, and H.-M. Shen Protein Kinase C Inhibition and X-Linked Inhibitor of Apoptosis Protein Degradation Contribute to the Sensitization Effect of Luteolin on Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Cancer Cells Cancer Res., September 1, 2005; 65(17): 7815 - 7823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Klucking, A. S. Collins, and J. A. T. Young Avian Sarcoma and Leukosis Virus Cytopathic Effect in the Absence of TVB Death Domain Signaling J. Virol., July 1, 2005; 79(13): 8243 - 8248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. C. Broaddus, T. B. Dansen, K. S. Abayasiriwardana, S. M. Wilson, A. J. Finch, L. B. Swigart, A. E. Hunt, and G. I. Evan Bid Mediates Apoptotic Synergy between Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) and DNA Damage J. Biol. Chem., April 1, 2005; 280(13): 12486 - 12493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Lu, T. Kwan, C. Yu, F. Chen, B. Freedman, J. M. Schafer, E.-J. Lee, J. L. Jameson, V. C. Jordan, and V. L. Cryns Peroxisome Proliferator-activated Receptor {gamma} Agonists Promote TRAIL-induced Apoptosis by Reducing Survivin Levels via Cyclin D3 Repression and Cell Cycle Arrest J. Biol. Chem., February 25, 2005; 280(8): 6742 - 6751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yamamoto, H. Nagano, M. Sakon, H. Wada, H. Eguchi, M. Kondo, B. Damdinsuren, H. Ota, M. Nakamura, H. Wada, et al. Partial Contribution of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)/TRAIL Receptor Pathway to Antitumor Effects of Interferon-{alpha}/5-Fluorouracil against Hepatocellular Carcinoma Clin. Cancer Res., December 1, 2004; 10(23): 7884 - 7895. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Merchant, X. Yang, F. Melchionda, M. Romero, R. Klein, C. J. Thiele, M. Tsokos, H. U. Kontny, and C. L. Mackall Interferon {gamma} Enhances the Effectiveness of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor Agonists in a Xenograft Model of Ewing's Sarcoma Cancer Res., November 15, 2004; 64(22): 8349 - 8356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Saito, J. R. Bringas, A. Panner, M. Tamas, R. O. Pieper, M. S. Berger, and K. S. Bankiewicz Convection-Enhanced Delivery of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand with Systemic Administration of Temozolomide Prolongs Survival in an Intracranial Glioblastoma Xenograft Model Cancer Res., October 1, 2004; 64(19): 6858 - 6862. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-H. Kim, K. Kim, J. G. Kwagh, D. T. Dicker, M. Herlyn, A. K. Rustgi, Y. Chen, and W. S. El-Deiry Death Induction by Recombinant Native TRAIL and Its Prevention by a Caspase 9 Inhibitor in Primary Human Esophageal Epithelial Cells J. Biol. Chem., September 17, 2004; 279(38): 40044 - 40052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Spierings, E. G. de Vries, E. Vellenga, F. A. van den Heuvel, J. J. Koornstra, J. Wesseling, H. Hollema, and S. de Jong Tissue Distribution of the Death Ligand TRAIL and Its Receptors J. Histochem. Cytochem., June 1, 2004; 52(6): 821 - 831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Guo, C. Sigua, J. Tao, P. Bali, P. George, Y. Li, S. Wittmann, L. Moscinski, P. Atadja, and K. Bhalla Cotreatment with Histone Deacetylase Inhibitor LAQ824 Enhances Apo-2L/Tumor Necrosis Factor-Related Apoptosis Inducing Ligand-Induced Death Inducing Signaling Complex Activity and Apoptosis of Human Acute Leukemia Cells Cancer Res., April 1, 2004; 64(7): 2580 - 2589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Waxman and P. S. Schwartz Harnessing Apoptosis for Improved Anticancer Gene Therapy Cancer Res., December 15, 2003; 63(24): 8563 - 8572. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Efimova, O. Martinez, A. Lokshin, T. Arima, and B. S. Prabhakar IG20, a MADD Splice Variant, Increases Cell Susceptibility to {gamma}-Irradiation and Induces Soluble Mediators That Suppress Tumor Cell Growth Cancer Res., December 15, 2003; 63(24): 8768 - 8776. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Rosato, J. A. Almenara, Y. Dai, and S. Grant Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells Mol. Cancer Ther., December 1, 2003; 2(12): 1273 - 1284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Younes and M. E. Kadin Emerging Applications of the Tumor Necrosis Factor Family of Ligands and Receptors in Cancer Therapy J. Clin. Oncol., September 15, 2003; 21(18): 3526 - 3534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Song, D. K. Song, M. Herlyn, K. C. Petruk, and C. Hao Cisplatin Down-Regulation of Cellular Fas-associated Death Domain-like Interleukin-1{beta}-converting Enzyme-like Inhibitory Proteins to Restore Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Melanoma Cells Clin. Cancer Res., September 15, 2003; 9(11): 4255 - 4266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. R. Singh, S. Shankar, X. Chen, M. Asim, and R. K. Srivastava Synergistic Interactions of Chemotherapeutic Drugs and Tumor Necrosis Factor-related Apoptosis-inducing Ligand/Apo-2 Ligand on Apoptosis and on Regression of Breast Carcinoma in Vivo Cancer Res., September 1, 2003; 63(17): 5390 - 5400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Buchsbaum, T. Zhou, W. E. Grizzle, P. G. Oliver, C. J. Hammond, S. Zhang, M. Carpenter, and A. F. LoBuglio Antitumor Efficacy of TRA-8 Anti-DR5 Monoclonal Antibody Alone or in Combination with Chemotherapy and/or Radiation Therapy in a Human Breast Cancer Model Clin. Cancer Res., September 1, 2003; 9(10): 3731 - 3741. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ray and A. Almasan Apoptosis Induction in Prostate Cancer Cells and Xenografts by Combined Treatment with Apo2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand and CPT-11 Cancer Res., August 1, 2003; 63(15): 4713 - 4723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Kim, M. Ajaz, A. Lokshin, and Y. J. Lee Role of Antiapoptotic Proteins in Tumor Necrosis Factor-related Apoptosis-inducing Ligand and Cisplatin-augmented Apoptosis Clin. Cancer Res., August 1, 2003; 9(8): 3134 - 3141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. J. Spierings, E. G. E. de Vries, W. Timens, H. J. M. Groen, H. M. Boezen, and S. de Jong Expression of TRAIL and TRAIL Death Receptors in Stage III Non-Small Cell Lung Cancer Tumors Clin. Cancer Res., August 1, 2003; 9(9): 3397 - 3405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Liu, S. Hilsenbeck, and Y. Gazitt Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL Blood, May 15, 2003; 101(10): 4078 - 4087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Guo, B. Hu, W. Gu, L. Xu, D. Wang, H.-J. S. Huang, W. K. Cavenee, and S.-Y. Cheng Platelet-Derived Growth Factor-B Enhances Glioma Angiogenesis by Stimulating Vascular Endothelial Growth Factor Expression in Tumor Endothelia and by Promoting Pericyte Recruitment Am. J. Pathol., April 1, 2003; 162(4): 1083 - 1093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Asakuma, M. Sumitomo, T. Asano, T. Asano, and M. Hayakawa Selective Akt Inactivation and Tumor Necrosis Factor-related Apoptosis-inducing Ligand Sensitization of Renal Cancer Cells by Low Concentrations of Paclitaxel Cancer Res., March 15, 2003; 63(6): 1365 - 1370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Naka, K. Sugamura, B. L. Hylander, M. B. Widmer, Y. M. Rustum, and E. A. Repasky Effects of Tumor Necrosis Factor-related Apoptosis-inducing Ligand Alone and in Combination with Chemotherapeutic Agents on Patients' Colon Tumors Grown in SCID Mice Cancer Res., October 15, 2002; 62(20): 5800 - 5806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Tang, Y. J. Sun, E. Half, M. T. Kuo, and F. Sinicrope Cyclooxygenase-2 Overexpression Inhibits Death Receptor 5 Expression and Confers Resistance to Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Colon Cancer Cells Cancer Res., September 1, 2002; 62(17): 4903 - 4908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. G. Ferreira, M. Epping, F. A. E. Kruyt, and G. Giaccone Apoptosis: Target of Cancer Therapy Clin. Cancer Res., July 1, 2002; 8(7): 2024 - 2034. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Weber, M. Lu, L. Andera, H. Lahm, N. Gellert, M. W. Fariss, V. Korinek, W. Sattler, D. S. Ucker, A. Terman, et al. Vitamin E Succinate Is a Potent Novel Antineoplastic Agent with High Selectivity and Cooperativity with Tumor Necrosis Factor-related Apoptosis-inducing Ligand (Apo2 Ligand) in Vivo Clin. Cancer Res., March 1, 2002; 8(3): 863 - 869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Choi, O. Kutsch, J. Park, T. Zhou, D.-W. Seol, and E. N. Benveniste Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Induces Caspase-Dependent Interleukin-8 Expression and Apoptosis in Human Astroglioma Cells Mol. Cell. Biol., February 1, 2002; 22(3): 724 - 736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Lum, A. A. Pilon, J. Sanchez-Dardon, B. N. Phenix, J. E. Kim, J. Mihowich, K. Jamison, N. Hawley-Foss, D. H. Lynch, and A. D. Badley Induction of Cell Death in Human Immunodeficiency Virus-Infected Macrophages and Resting Memory CD4 T Cells by TRAIL/Apo2L J. Virol., November 15, 2001; 75(22): 11128 - 11136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sridhar, A. A. Ali, Y. Liang, M. F. El Etreby, R. W. Lewis, and M. V. Kumar Differential Expression of Members of the Tumor Necrosis Factor {alpha}-related Apoptosis-inducing Ligand Pathway in Prostate Cancer Cells Cancer Res., October 1, 2001; 61(19): 7179 - 7183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Naumann, S. Kugler, H. Wolburg, W. Wick, G. Rascher, J. B. Schulz, E. Conseiller, M. Bahr, and M. Weller Chimeric Tumor Suppressor 1, a p53-derived Chimeric Tumor Suppressor Gene, Kills p53 Mutant and p53 Wild-type Glioma Cells in Synergy with Irradiation and CD95 Ligand Cancer Res., August 1, 2001; 61(15): 5833 - 5842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Mitsiades, S. P. Treon, N. Mitsiades, Y. Shima, P. Richardson, R. Schlossman, T. Hideshima, and K. C. Anderson TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications Blood, August 1, 2001; 98(3): 795 - 804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Demidem, D. Morvan, J. Papon, M. De Latour, and J. C. Madelmont Cystemustine Induces Redifferentiation of Primary Tumors and Confers Protection against Secondary Tumor Growth in a Melanoma Murine Model Cancer Res., March 1, 2001; 61(5): 2294 - 2300. [Abstract] [Full Text]
|
|
|
|
|
|
N. Mitsiades, V. Poulaki, C. Mitsiades, and M. Tsokos Ewing's Sarcoma Family Tumors Are Sensitive to Tumor Necrosis Factor-related Apoptosis-inducing Ligand and Express Death Receptor 4 and Death Receptor 5 Cancer Res., March 1, 2001; 61(6): 2704 - 2712. [Abstract] [Full Text]
|
|
|
|
|
|
C. Hao, F. Beguinot, G. Condorelli, A. Trencia, E. G. Van Meir, V. W. Yong, I. F. Parney, W. H. Roa, and K. C. Petruk Induction and Intracellular Regulation of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Mediated Apotosis in Human Malignant Glioma Cells Cancer Res., February 1, 2001; 61(3): 1162 - 1170. [Abstract] [Full Text]
|
|
|
|
|
|
J. Wen, N. Ramadevi, D. Nguyen, C. Perkins, E. Worthington, and K. Bhalla Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute leukemia cells Blood, December 1, 2000; 96(12): 3900 - 3906. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Mishima, A. P. Mazar, A. Gown, M. Skelly, X.-D. Ji, X.-D. Wang, T. R. Jones, W. K. Cavenee, and H.-J. S. Huang A peptide derived from the non-receptor-binding region of urokinase plasminogen activator inhibits glioblastoma growth and angiogenesis in vivo in combination with cisplatin PNAS, July 18, 2000; 97(15): 8484 - 8489. [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 |
, one course of treatment. The treatment course was
repeated at a weekly basis, except for the fourth week. 
, vehicle
control with normal saline and bacteria-derived mock lysate; 
, TRAIL
(500 µg/day); 
, CDDP (3 mg/kg); 
, combination of TRAIL and
CDDP. Data are shown as the means; bars, SE. **,
P = 0.007 (combination versus
CDDP). The experiment was repeated independently two times with similar
results. B, synergistic growth suppression of established
U87MG xenografts by combination of TRAIL and CDDP in vivo.
Nude mice (13 for TRAIL plus CDDP, 4 per other groups) received s.c.
injections of 2 x 106 U87MG cells and were
allowed to establish tumors. From postimplantation day 13, mice were
treated as described in A. The treatment was continued up to
six courses. Symbols are the same as described in A. **,
P = 0.002 (combination versus
CDDP). The experiment was repeated independently four times with
similar results. C, photograph showing representative mice
bearing U87MG xenografts after three courses of treatment
(1–4) and extensive survivors with complete regression of
xenografts (5 and 6). D, induction of
apoptosis in established U87MG xenografts by the combination treatment
with TRAIL and CDDP in vivo. Nude mice with subcutaneous
U87MG xenografts were treated with one course of combination of
vehicles or TRAIL plus CDDP as described in A. Paraffin
sections were subjected to TUNEL assay, and TUNEL-positive cells were
counted in 10 high magnification fields (x800) per tumor (means;
bars, SD). **, P = 0.003.
E, effect of the combination treatment on survival of mice
bearing intracerebral U87MG xenografts. Nude mice received
intracerebral injections of 5 x 105 U87MG
cells and were treated from postimplantation day 7 for three courses as
described in A. **, P < 0.01
(combination versus CDDP).