| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics |
Department of Molecular Immunology, Immunex Corp., Seattle, Washington 98101
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
, CD40 ligand, and FAS ligand, but TRAIL induced apoptosis in a majority of the cell lines (4)
. Likewise, human colon carcinoma cell lines were found to be resistant to TNF--induced apoptosis, but several of the cell lines were very sensitive to TRAIL-induced apoptosis.3 The ability of TRAIL to induce apoptosis in many transformed cells in vitro suggests that it might be a potent antitumor agent in vivo. To study this experimentally, a soluble form of TRAIL that includes a leucine zipper incorporated at its NH2 terminus to promote the formation and stabilization of TRAIL trimers was generated (5) . Analysis of the LZ-huTRAIL molecule in mice has demonstrated that it is not overtly toxic at therapeutic doses and maintains its antitumor activity in vivo (5) . Specifically, multiple treatments with LZ-huTRAIL suppress the growth of the TRAIL-sensitive human mammary adenocarcinoma cell line MDA-231 in CB.17 (SCID) mice and lengthen their mean survival times. Histological analysis of the LZ-huTRAIL-treated tumors demonstrates an increase in apoptotic necrosis and confirms the ability of LZ-huTRAIL to induce apoptosis in vivo (5) . Likewise, treatment of two human colon carcinoma xenografts with LZ-huTRAIL prevents tumor formation in a majority of treated animals and dramatically slows tumor growth in tumor-bearing animals (5) .
Analysis of TRAIL-induced apoptosis in vitro has demonstrated that there are both TRAIL-sensitive and TRAIL-resistant human melanoma and colon carcinoma cell lines (4) .3 The reason for the differential sensitivity remains unknown, but it is not regulated solely by the differential expression of the known TRAIL receptors (4) .3 Instead, it appears that an intracellular inhibitor(s) acting downstream of the TRAIL receptors renders specific transformed cell lines insensitive to TRAIL (4) . Treatment of TRAIL-resistant cell lines with metabolic inhibitors of protein synthesis can convert them to TRAIL-sensitive cell lines (4) ,3 suggesting that the antitumor activity of TRAIL may be enhanced in vivo by combining it with chemotherapeutic agents that are known disrupt a transformed cell’s metabolism or mitotic activity. In support of this, it was recently shown that the combination of doxorubicin or 5-FU with TRAIL could augment TRAIL-induced apoptosis in breast cancer cells in vitro (6) .
In this report, we have further characterized the in vivo antitumor activity of TRAIL, both alone and in combination with the chemotherapeutic agent CPT-11. We demonstrate that the sensitivity to TRAIL seen in vivo for the colon carcinoma tumors parallels the differential sensitivity to TRAIL-induced apoptosis seen in vitro for these cell lines. Moreover, by combining TRAIL with CPT-11, the antitumor activity of TRAIL is greatly enhanced and results in the complete elimination of tumors in many animals.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Purification of LZ-huTRAIL.
Expression and purification of LZ-huTRAIL was performed as described previously (5
, 7)
. Purified fractions containing recombinant proteins were pooled and dialyzed against TBS, and aliquots were stored at -70°C. Protein concentrations were determined by amino acid analysis, and endotoxin content was determined by Limulus Amoebocyte Lysate analysis. The endotoxin content of LZ-huTRAIL used in the studies was less than 9 pg/mg recombinant protein.
Cell Viability Assays.
Cells were plated at 40,000 cells/well in 96-well plates and allowed to attach overnight. Factors were added at the indicated concentration, and the cells were cultured at 37°C for 24 h. Camptothecin (Sigma Chemical Co., St. Louis, MO) was diluted in DMSO, and all cultures not receiving camptothecin received an equivalent amount of DMSO without camptothecin. Cell viability was determined by crystal violet staining and quantitated by reading the A570 nm as described previously (1)
. The percentage viability was calculated by multiplying the ratio staining of experimental versus control cultures by 100.
Treatment of Tumor-bearing Mice with LZ-huTRAIL.
Female CB.17 (SCID) mice (Taconic Farms, Germantown, NY) were pretreated 24 h before tumor challenge with a single injection (100 µl, i.p.) of purified asialo GM-1 antibody (Wako Chemicals, Richmond, VA). Mice were injected s.c. with 3 x 105 human colon carcinoma cells, and treatment began 3, 10, or 17 days after tumor implantation, as noted. Treatments with TBS or LZ-huTRAIL were administered by i.p. injection, and CPT-11 (Pharmacia and Upjohn Co., Kalamazoo, MI) was administered i.v. as described in the text. All dilutions of LZ-huTRAIL and CPT-11 were made with TBS. For the 10- and 17-day established tumor study, changes in tumor size were calculated as follows: [(Tumor size posttreatment) - (Tumor size at day 10 or 17)/(Tumor size at day 10 or 17)] x 100%.
Statistical Analysis of Data.
Tumor growth analyses were performed by ANOVA, with Ps obtained by t test. Only tumor-bearing mice were included in the analysis. Analysis of tumor growth rates was performed using a generalized linear model, with Ps obtained via likelihood ratio 
2 tests. All statistical analyses were performed using SAS software (SAS Institute Inc., Cary, NC).
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. Beginning 3 days after tumor challenge, mice were treated with LZ-huTRAIL (500 or 1000 µg) or a control solution (TBS) for 14 days. Consistent with the in vitro findings, tumors derived from COLO 205 and HCT-15 cells were very sensitive to LZ-huTRAIL treatment (Fig. 1A)
. The growth rate for both tumors was significantly reduced in the LZ-huTRAIL-treated groups compared with that of control mice. Treatment of COLO 205 tumors with 500 or 1000 µg of LZ-huTRAIL resulted in a 74% and 93% reduction in tumor size, respectively (P = 0.004 and 0.0012, respectively, by ANOVA). Likewise, treatment of HCT-15 tumors with 500 µg of LZ-huTRAIL resulted in a >50% reduction in tumor size (P = 0.03). Moreover, a dose-dependent inhibition of COLO 205 tumor formation was also observed. Treatment of COLO 205 tumor-bearing mice with 500 µg/day LZ-huTRAIL resulted in a 90% incidence of tumor formation 6 weeks after tumor challenge, whereas treatment with 1000 µg/day LZ-huTRAIL resulted in a 30% incidence of tumor formation (P = 0.0002, using a generalized linear model). For HCT-15 tumor-bearing mice, the number of tumor-positive animals at 6 weeks was also significantly less (60%; P = 0.03) after treatment with 500 µg/day of LZ-huTRAIL. In contrast, tumors derived from the HT-29 and SW620 cell lines showed less sensitivity to LZ-huTRAIL (Fig. 1B)
. HT-29 tumor growth was reduced slightly (
25%) after LZ-huTRAIL treatment in comparison with TBS-treated animals (P = 0.007), and SW620 tumor growth was not significantly affected (P = 0.23). In addition, no difference in the frequency of HT-29 or SW620 tumor formation was observed between the treated and untreated groups. Thus, the sensitivity of these four human colon carcinomas to LZ-huTRAIL in vivo appears to closely parallel their susceptibility to LZ-huTRAIL-induced apoptosis in vitro.
|
Camptothecin is a topoisomerase I inhibitor that has antitumor activity in vitro and in vivo (8, 9, 10, 11)
. The addition of camptothecin (1 µg/ml) to colon carcinoma cell lines in vitro reduced the cell viability of all four cell lines by 40–60% within 24 h (Fig. 2)
. Incubation for 48 h resulted in a complete loss of cell viability (data not shown). Combining camptothecin with LZ-huTRAIL converted the LZ-huTRAIL-resistant cell lines, HT-29 and SW620, into LZ-huTRAIL-sensitive cell lines. Likewise, the LZ-huTRAIL-sensitive lines, COLO 205 and HCT-15, became more sensitive to LZ-huTRAIL-induced apoptosis in combination with camptothecin. These results are similar to those seen with the metabolic inhibitors actinomycin D and cyclohexamide and confirm that a chemotherapeutic agent has the potential to enhance the cytotoxic activity of LZ-huTRAIL.
|
, and CPT-11 was administered by i.v. injection six times during the LZ-huTRAIL treatment period. In these experiments, we focused on the LZ-huTRAIL-resistant HT-29 and LZ-huTRAIL-sensitive COLO 205 tumors.
Consistent with the previous analysis (Fig. 1B)
, treatment of HT-29 tumors with LZ-huTRAIL alone slowed their growth slightly but did not result in any tumor regressions (Fig. 3A)
. Administration of CPT-11 alone resulted in a dose-dependent inhibition of HT-29 tumor growth, with six doses of CPT-11 at 25 mg/kg/dose resulting in 50% reduction in tumor size, and six doses of CPT-11 at 50 mg/kg/dose resulting in 75% reduction. For both treatments, the incidence of tumor formation was 100%. The combination of CPT-11 plus LZ-huTRAIL resulted in an additional inhibition of tumor growth, but the difference was not significantly greater than that observed with 25 or 50 mg/kg CPT-11 alone (P = 0.204 and 0.262, respectively). Thus, it appears that the treatment of HT-29 tumors with a combination of CPT-11 and LZ-huTRAIL results in an additive enhancement of antitumor activity.
|
. Control animals and those treated with LZ-huTRAIL alone were 100% positive for measurable tumors within 7 days of tumor challenge. Likewise, 90–100% of the animals treated with 50 mg/kg CPT-11 alone were tumor positive within the first 4 weeks. In contrast, LZ-huTRAIL plus CPT-11-treated animals were 70% tumor positive by the first week but had no measurable tumors at 3 weeks (4 days after treatment). However, these animals were not completely tumor free, and by 5 weeks, all of them had measurable tumors, albeit significantly smaller than those in untreated animals (Fig. 3A)
. Thus, treatment with LZ-huTRAIL and high-dose CPT-11 could induce a transient regression of LZ-huTRAIL-resistant HT-29 tumors, but tumor growth resumed with the cessation of treatment.
Results of the LZ-huTRAIL-sensitive COLO 205 tumor treated with LZ-huTRAIL and CPT-11 are shown in Fig. 4
. The administration of either LZ-huTRAIL (500 µg) or CPT-11 (50 mg/kg) alone significantly inhibited the growth of COLO 205 tumors (P = 0.003 and 0.001, respectively) and induced tumor regression in 5 of 10 mice and 6 of 9 mice, respectively (Fig. 4A)
. The combination of LZ-huTRAIL and CPT-11 was even more effective, with all of the treated animals being tumor free 6 weeks after tumor challenge. However, in the CPT-11 treatment groups, with or without LZ-huTRAIL, animal mortality was observed during the administration of the drug. Thus, CPT-11 and LZ-huTRAIL synergized to eliminate COLO 205 tumors in all of the surviving animals, but the 50 mg/kg dose of CPT-11 proved toxic for some of the treated animals.
|
10%. To determine whether a lower dose of CPT-11 could still synergize with LZ-huTRAIL, CPT-11 at 25 mg/kg was combined with 250 or 500 µg of LZ-huTRAIL (Fig. 4B)
. The administration of LZ-huTRAIL (250 or 500 µg/day) or 25 mg/kg CPT-11 alone resulted in tumor growth inhibition, but with all treatments, 
90% of mice were tumor positive 6 weeks after tumor challenge. As seen with the 50 mg/kg CPT-11 dose, the combination of LZ-huTRAIL (250 or 500 µg/day) plus 25 mg/kg CPT-11 resulted in a much greater tumor growth inhibition than that seen with either agent alone. Moreover, 5 of 10 animals treated with 250 µg/day LZ-huTRAIL and CPT-11 (P = 0.0041) were tumor free, and 18 of 19 animals treated with 500 µg/day LZ-huTRAIL plus CPT-11 (P = 0.0001) were tumor free 6 weeks after tumor challenge. These results demonstrate that multiple dosing of CPT-11 at 25 mg/kg is well tolerated (only 2% mortality) and can still synergize with LZ-huTRAIL at two different concentrations and induce tumor regression in the majority of treated animals.
The treatment of COLO 205 tumor-bearing mice with LZ-huTRAIL and/or CPT-11 resulted in many tumor-free animals after 6 weeks. To determine whether the tumors were completely eliminated, the animals were examined 9 and 12 weeks after tumor challenge (Table 1)
. The tumor-free animals treated with only CPT-11, 250 µg/day LZ-huTRAIL, or 250 µg/day LZ-huTRAIL plus low-dose CPT-11 (25 mg/kg) all developed measurable tumors within 12 weeks. In contrast, the majority of animals treated with 500 µg/day LZ-huTRAIL, alone or in combination with CPT-11, remained tumor free at 12 weeks. These results suggest that high-dose LZ-huTRAIL (500 µg/day) treatment, alone and in combination with CPT-11, can induce the complete elimination of COLO 205 tumors.
|
. At 10 days after tumor challenge, LZ-huTRAIL (500 µg/day) was administered from day 10–23 (14 days), and six injections of CPT-11 were given at 25 or 40 mg/kg during the LZ-huTRAIL treatment period (Fig. 5A)
. The combination of LZ-huTRAIL and CPT-11, either 25 or 40 mg/kg, induced the elimination of tumors in 40% and 90% of the mice, respectively (P = 0.0033 and 0.0001, respectively). In addition, the tumors in the remaining mice regressed in size between 50–75% compared with the size of the starting tumors at day 10. In contrast, tumor growth in animals treated with only LZ-huTRAIL or CPT-11 was slowed, but no tumors were completely eliminated.
|
. LZ-huTRAIL (500 µg/day) was administered from day 17–30 (14 days), and CPT-11 was given at 40 mg/kg. Treatment with LZ-huTRAIL alone slowed the overall growth of COLO 205 tumors in comparison to the injection control group, but no reduction in tumor size compared with the size of the starting tumor mass at day 17 was observed. In contrast, treatment with CPT-11 alone induced a 30% regression in tumor size, and the combination of LZ-huTRAIL and CPT-11 induced a >50% regression in tumor size by 6 weeks in comparison to the average starting tumor size at day 17. However, the tumors began to increase in size after the sixth week, and none of the treatment groups demonstrated any complete tumor regressions. |
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The regulatory mechanism that governs sensitivity to TRAIL-induced apoptosis remains unknown. However, it has been observed that the resistance to TRAIL-induced apoptosis can be overcome in vitro by treating the cells with metabolic inhibitors (4) .3 This led us to examine a variety of chemotherapeutic agents for their ability to enhance TRAIL-induced tumor apoptosis. Although cisplatin, mitomycin, and 5-FU did show a dose-dependent cytotoxicity alone, none showed any synergy with TRAIL in vitro (data not shown). One agent, Adriamycin, did demonstrate a weak synergy with TRAIL in vitro, but no enhancement of TRAIL’s cytotoxicity was seen in vivo (data not shown). Of all of the chemotherapeutic agents we tested in the colon carcinomas, only the topoisomerase I inhibitor camptothecin was found to be a potent cytotoxic agent both alone and in combination with TRAIL.
Treating tumor-bearing mice with TRAIL plus CPT-11, a water-soluble derivative of camptothecin, resulted in a dramatic enhancement of the antitumor activity of TRAIL. Treatment of 3- or 10-day established COLO 205 tumors with TRAIL and CPT-11 resulted in both a dose-dependent reduction in tumor growth rate and the elimination of tumors in many of the treated animals. Analysis of these animals for 12 weeks confirmed that this treatment resulted in tumor-free animals. In contrast, none of the tumors allowed to establish for 17 days before treatment were eliminated, but a transient shrinkage (>50%) of tumor mass was observed. Likewise, combination treatment of TRAIL-resistant HT-29 tumors resulted in a greater tumor inhibition than observed with either agent alone. TRAIL plus high-dose CPT-11 reduced the size of HT-29 tumors >85% compared with the untreated controls and induced a transient tumor regression after treatment. However, all animals were eventually tumor positive 6 weeks after tumor challenge.
How camptothecin/CPT-11 synergizes with TRAIL at the cellular level remains unknown. Camptothecin has been shown to be an inhibitor of the nuclear enzyme topoisomerase I and is believed to block DNA transcription and replication through the inhibition of this enzyme (10 , 11) . Presumably, camptothecin/CPT-11 synergizes with TRAIL in a manner similar to that of actinomycin D and cyclohexamide by ultimately inhibiting the synthesis of an apoptosis-regulatory protein. Recently, other chemotherapeutic agents have been shown to sensitize tumor cells to TRAIL-induced apoptosis in vitro. Keane et al. (6) demonstrated that both doxorubicin (Adriamycin) and 5-FU could augment TRAIL-induced apoptosis of breast cancer cells in vitro, and this was mediated through the selective activation of caspases by these drugs. Alternatively, Wu et al. (20) demonstrated that TRAIL receptor 2 (KILLER/DR5) expression is up-regulated after doxorubicin-induced DNA damage of transformed human cells. However, it remains to be proven whether the higher level of receptor expression makes these cells more sensitive to TRAIL. Treatment of the colon carcinoma cell lines in vitro with camptothecin did not result in the up-regulation of TRAIL receptor 2 expression (data not shown). Taken together, these results demonstrate that a variety of chemotherapeutic drugs can modulate the TRAIL-induced apoptosis signaling pathway and suggest that other agents may synergize with TRAIL in vivo.
Although TRAIL is a potent inducer of apoptosis in vitro, the administration of multiple doses of LZ-huTRAIL to mice was very well tolerated, both alone or in combination with CPT-11. This is not unexpected because transcripts for TRAIL and TRAIL receptors are abundantly expressed in many tissues (1 , 2 , 7 , 21, 22, 23) , suggesting that TRAIL-induced apoptosis is tightly regulated in normal cells and/or that TRAIL may have additional activities other than cell killing in vivo. These findings are consistent with previous in vivo studies that demonstrate no systemic toxicities in mice after repeated doses of either murine or human LZ-TRAIL (5) . This apparent lack of toxicity associated with the administration of TRAIL is in direct contrast to other members of the TNF ligand superfamily whose utilization in vivo is limited by their toxicities (24, 25, 26) .
Combining TRAIL with CPT-11 may have great clinical potential. CPT-11 is currently being tested clinically and has been shown to be consistently effective in metastatic colorectal cancers (27, 28, 29) . However, myelosuppression and gastrointestinal damage are the two primary dose-limiting toxicities associated with CPT-11 (28 , 29) . An exciting outcome from our study is the observation that suboptimal doses of both TRAIL and CPT-11 can synergize to induce a strong antitumor activity. This suggests that a potent antitumor response may still be achieved by combining TRAIL with a better-tolerated dose of a chemotherapeutic agent. Thus, TRAIL may prove to be a potent antitumor agent alone and may enhance the antitumor potential of traditional chemotherapeutic drugs.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 To whom requests for reprints should be addressed, at Department of Molecular Immunology, Immunex Corp., 51 University Street, Seattle, WA 98101. Phone: (206) 587-0430, ext. 4661; Fax: (206) 233-9733; E-mail: gliniak{at}immunex.com 
2 The abbreviations used are: TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TNF, tumor necrosis factor; SCID, severe combined immunodeficient; LZ-huTRAIL, leucine zipper human TRAIL; FBS, fetal bovine serum; TBS, Tris-buffered saline; 5-FU, 5-fluorouracil.
3 B. Gliniak, T. Le, and T. Griffith. TRAIL receptor expression by human colon carcinoma cells is not predictive of sensitivity to TRAIL-induced apoptosis, submitted for publication.
Received 4/15/99. Accepted 10/19/99.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
B and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity, 7: 813-820, 1997.[Medline]
This article has been cited by other articles:
|
|
 |
|
  A. Labrinidis, P. Diamond, S. Martin, S. Hay, V. Liapis, I. Zinonos, N. A. Sims, G. J. Atkins, C. Vincent, V. Ponomarev, et al. Apo2L/TRAIL Inhibits Tumor Growth and Bone Destruction in a Murine Model of Multiple Myeloma Clin. Cancer Res., March 15, 2009; 15(6): 1998 - 2009. [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]
|
|
|
|
 |
|
 A. Ashkenazi, P. Holland, and S. G. Eckhardt Ligand-Based Targeting of Apoptosis in Cancer: The Potential of Recombinant Human Apoptosis Ligand 2/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (rhApo2L/TRAIL) J. Clin. Oncol., July 20, 2008; 26(21): 3621 - 3630. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Cao, P. Du, S.-H. Jiang, G.-H. Jin, Q.-L. Huang, and Z.-C. Hua Enhancement of antitumor properties of TRAIL by targeted delivery to the tumor neovasculature Mol. Cancer Ther., April 1, 2008; 7(4): 851 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Li, H. Wang, Z. Wang, S. Makhija, D. Buchsbaum, A. LoBuglio, R. Kimberly, and T. Zhou Inducible Resistance of Tumor Cells to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 2-Mediated Apoptosis by Generation of a Blockade at the Death Domain Function. Cancer Res., September 1, 2006; 66(17): 8520 - 8528. [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]
|
|
|
|
|
|
F. Dong, L. Wang, J. J. Davis, W. Hu, L. Zhang, W. Guo, F. Teraishi, L. Ji, and B. Fang Eliminating Established Tumor in nu/nu Nude Mice by a Tumor Necrosis Factor-{alpha}-Related Apoptosis-Inducing Ligand-Armed Oncolytic Adenovirus Clin. Cancer Res., September 1, 2006; 12(17): 5224 - 5230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Frese, M. Frese-Schaper, A.-C. Andres, D. Miescher, B. Zumkehr, and R. A. Schmid Cardiac Glycosides Initiate Apo2L/TRAIL-Induced Apoptosis in Non-Small Cell Lung Cancer Cells by Up-regulation of Death Receptors 4 and 5 Cancer Res., June 1, 2006; 66(11): 5867 - 5874. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Thai, A. Labrinidis, S. Hay, V. Liapis, S. Bouralexis, K. Welldon, B. J. Coventry, D. M. Findlay, and A. Evdokiou Apo2l/Tumor necrosis factor-related apoptosis-inducing ligand prevents breast cancer-induced bone destruction in a mouse model. Cancer Res., May 15, 2006; 66(10): 5363 - 5370. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Sohn, G. Totzke, F. Essmann, K. Schulze-Osthoff, B. Levkau, and R. U. Janicke The proteasome is required for rapid initiation of death receptor-induced apoptosis. Mol. Cell. Biol., March 1, 2006; 26(5): 1967 - 1978. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. D. Zhang, J. J. Wu, S. Gillespie, J. Borrow, and P. Hersey Human Melanoma Cells Selected for Resistance to Apoptosis by Prolonged Exposure to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Are More Vulnerable to Necrotic Cell Death Induced by Cisplatin Clin. Cancer Res., February 15, 2006; 12(4): 1355 - 1364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Clancy, K. Mruk, K. Archer, M. Woelfel, J. Mongkolsapaya, G. Screaton, M. J. Lenardo, and F. K.-M. Chan Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis PNAS, December 13, 2005; 102(50): 18099 - 18104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Galligan, D. B. Longley, M. McEwan, T. R. Wilson, K. McLaughlin, and P. G. Johnston Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP Mol. Cancer Ther., December 1, 2005; 4(12): 2026 - 2036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Voelkel-Johnson, Y. A. Hannun, and A. El-Zawahry Resistance to TRAIL is associated with defects in ceramide signaling that can be overcome by exogenous C6-ceramide without requiring down-regulation of cellular FLICE inhibitory protein Mol. Cancer Ther., September 1, 2005; 4(9): 1320 - 1327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Cohen, R. B. Cohen, and N. J. Meropol Targeting Signal Transduction Pathways in Colorectal Cancer--More Than Skin Deep J. Clin. Oncol., August 10, 2005; 23(23): 5374 - 5385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Minderman, J. M. Conroy, K. L. O'Loughlin, D. McQuaid, P. Quinn, S. Li, L. Pendyala, N. J. Nowak, and M. R. Baer In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells Mol. Cancer Ther., June 1, 2005; 4(6): 885 - 900. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Shao, D.-F. Lee, Y. Wen, Y. Ding, W. Xia, B. Ping, H. Yagita, B. Spohn, and M.-C. Hung E1A Sensitizes Cancer Cells to TRAIL-Induced Apoptosis through Enhancement of Caspase Activation Mol. Cancer Res., April 1, 2005; 3(4): 219 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Matsuda, A. Almasan, M. Tomita, J.-n. Uchihara, M. Masuda, K. Ohshiro, N. Takasu, H. Yagita, T. Ohta, and N. Mori Resistance to Apo2 Ligand (Apo2L)/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Mediated Apoptosis and Constitutive Expression of Apo2L/TRAIL in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines J. Virol., February 1, 2005; 79(3): 1367 - 1378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Malathi, J. M. Paranjape, R. Ganapathi, and R. H. Silverman HPC1/RNASEL Mediates Apoptosis of Prostate Cancer Cells Treated with 2',5'-Oligoadenylates, Topoisomerase I Inhibitors, and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Cancer Res., December 15, 2004; 64(24): 9144 - 9151. [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]
|
|
|
|
|
|
K. Izeradjene, L. Douglas, A. Delaney, and J. A. Houghton Influence of Casein Kinase II in Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Human Rhabdomyosarcoma Cells Clin. Cancer Res., October 1, 2004; 10(19): 6650 - 6660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jin, R. Yang, S. Fong, K. Totpal, D. Lawrence, Z. Zheng, J. Ross, H. Koeppen, R. Schwall, and A. Ashkenazi Apo2 Ligand/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Cooperates with Chemotherapy to Inhibit Orthotopic Lung Tumor Growth and Improve Survival Cancer Res., July 15, 2004; 64(14): 4900 - 4905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Deeb, H. Jiang, X. Gao, M. S. Hafner, H. Wong, G. Divine, R. A. Chapman, S. A. Dulchavsky, and S. C. Gautam Curcumin sensitizes prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L by inhibiting nuclear factor-{kappa}B through suppression of I{kappa}B{alpha} phosphorylation Mol. Cancer Ther., July 1, 2004; 3(7): 803 - 812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shah, C.-H. Tung, K. Yang, R. Weissleder, and X. O. Breakefield Inducible Release of TRAIL Fusion Proteins from a Proapoptotic Form for Tumor Therapy Cancer Res., May 1, 2004; 64(9): 3236 - 3242. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Chawla-Sarkar, J. A. Bauer, J. A. Lupica, B. H. Morrison, Z. Tang, R. K. Oates, A. Almasan, J. A. DiDonato, E. C. Borden, and D. J. Lindner Suppression of NF-{kappa}B Survival Signaling by Nitrosylcobalamin Sensitizes Neoplasms to the Anti-tumor Effects of Apo2L/TRAIL J. Biol. Chem., October 10, 2003; 278(41): 39461 - 39469. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 J.-P. Herbeuval, C. Lambert, O. Sabido, M. Cottier, P. Fournel, M. Dy, and C. Genin Macrophages From Cancer Patients: Analysis of TRAIL, TRAIL Receptors, and Colon Tumor Cell Apoptosis J Natl Cancer Inst, April 16, 2003; 95(8): 611 - 621. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Hietakangas, M. Poukkula, K. M. Heiskanen, J. T. Karvinen, L. Sistonen, and J. E. Eriksson Erythroid Differentiation Sensitizes K562 Leukemia Cells to TRAIL-Induced Apoptosis by Downregulation of c-FLIP Mol. Cell. Biol., February 15, 2003; 23(4): 1278 - 1291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Leverkus, M. R. Sprick, T. Wachter, T. Mengling, B. Baumann, E. Serfling, E.-B. Brocker, M. Goebeler, M. Neumann, and H. Walczak Proteasome Inhibition Results in TRAIL Sensitization of Primary Keratinocytes by Removing the Resistance-Mediating Block of Effector Caspase Maturation Mol. Cell. Biol., February 1, 2003; 23(3): 777 - 790. [Abstract] [Full Text]
|
|
|
|
|
|
J. Strater, U. Hinz, H. Walczak, G. Mechtersheimer, K. Koretz, C. Herfarth, P. Moller, and T. Lehnert Expression of TRAIL and TRAIL Receptors in Colon Carcinoma: TRAIL-R1 Is an Independent Prognostic Parameter Clin. Cancer Res., December 1, 2002; 8(12): 3734 - 3740. [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]
|
|
|
|
 |
|
 G. Dorothee, I. Vergnon, J. Menez, H. Echchakir, D. Grunenwald, M. Kubin, S. Chouaib, and F. Mami-Chouaib Tumor-Infiltrating CD4+ T Lymphocytes Express APO2 Ligand (APO2L)/TRAIL upon Specific Stimulation with Autologous Lung Carcinoma Cells: Role of IFN-{alpha} on APO2L/TRAIL Expression and -Mediated Cytotoxicity J. Immunol., July 15, 2002; 169(2): 809 - 817. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Chawla-Sarkar, D. W. Leaman, B. S. Jacobs, and E. C. Borden IFN-{beta} Pretreatment Sensitizes Human Melanoma Cells to TRAIL/Apo2 Ligand-Induced Apoptosis J. Immunol., July 15, 2002; 169(2): 847 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. S. Griffith, J. M. Fialkov, D. L. Scott, T. Azuhata, R. D. Williams, N. R. Wall, D. C. Altieri, and A. D. Sandler Induction and Regulation of Tumor Necrosis Factor-related Apoptosis-inducing Ligand/Apo-2 Ligand-mediated Apoptosis in Renal Cell Carcinoma Cancer Res., June 1, 2002; 62(11): 3093 - 3099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Frese, T. Brunner, M. Gugger, A. Uduehi, and R. A. Schmid Enhancement of Apo2L/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis in non-small cell lung cancer cell lines by chemotherapeutic agents without correlation to the expression level of cellular protease caspase-8 inhibitory protein J. Thorac. Cardiovasc. Surg., January 1, 2002; 123(1): 168 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Jazirehi, C.-P. Ng, X.-H. Gan, G. Schiller, and B. Bonavida Adriamycin Sensitizes the Adriamycin-resistant 8226/Dox40 Human Multiple Myeloma Cells to Apo2L/Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated (TRAIL) Apoptosis Clin. Cancer Res., December 1, 2001; 7(12): 3874 - 3883. [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]
|
|
|
|
|
|
X. D. Zhang, X. Y. Zhang, C. P. Gray, T. Nguyen, and P. Hersey Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis of Human Melanoma Is Regulated by Smac/DIABLO Release from Mitochondria Cancer Res., October 1, 2001; 61(19): 7339 - 7348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Di Pietro, P. Secchiero, R. Rana, D. Gibellini, G. Visani, K. Bemis, L. Zamai, S. Miscia, and G. Zauli Ionizing radiation sensitizes erythroleukemic cells but not normal erythroblasts to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity by selective up-regulation of TRAIL-R1 Blood, May 1, 2001; 97(9): 2596 - 2603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kagawa, C. He, J. Gu, P. Koch, S.-J. Rha, J. A. Roth, S. A. Curley, L. C. Stephens, and B. Fang Antitumor Activity and Bystander Effects of the Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Gene Cancer Res., April 1, 2001; 61(8): 3330 - 3338. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. J. Smyth, E. Cretney, K. Takeda, R. H. Wiltrout, L. M. Sedger, N. Kayagaki, H. Yagita, and K. Okumura Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Contributes to Interferon {{gamma}}-dependent Natural Killer Cell Protection from Tumor Metastasis J. Exp. Med., March 12, 2001; 193(6): 661 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R. Nimmanapalli, C. L. Perkins, M. Orlando, E. O’Bryan, D. Nguyen, and K. N. Bhalla Pretreatment with Paclitaxel Enhances Apo-2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis of Prostate Cancer Cells by Inducing Death Receptors 4 and 5 Protein Levels Cancer Res., January 1, 2001; 61(2): 759 - 763. [Abstract] [Full Text]
|
|
|
|
|
|
S.-Y. Sun, P. Yue, W. K. Hong, and R. Lotan Augmentation of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced Apoptosis by the Synthetic Retinoid 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene Carboxylic Acid (CD437) through Up-Regulation of TRAIL Receptors in Human Lung Cancer Cells Cancer Res., December 1, 2000; 60(24): 7149 - 7155. [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]
|
|
|
|
|
|
T. S. Griffith, R. D. Anderson, B. L. Davidson, R. D. Williams, and T. L. Ratliff Adenoviral-Mediated Transfer of the TNF-Related Apoptosis-Inducing Ligand/Apo-2 Ligand Gene Induces Tumor Cell Apoptosis J. Immunol., September 1, 2000; 165(5): 2886 - 2894. [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 |
) or 500 µg of LZ-huTRAIL (
), and COLO 205 tumor-bearing mice were treated with TBS (
), 500 µg of LZ-huTRAIL (
), or 1000 µg of LZ-huTRAIL (
) by i.p. injection. B, HT-29 tumor-bearing mice were treated with TBS (
). Tumor size was determined weekly, and the mean tumor size of only tumor-bearing mice is shown. The number of tumor-bearing animals/number of total animals per treatment group is shown at the end of 6 weeks. B, the percentage of tumor-bearing animals treated with TBS (
