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Tumor Biology |
Department of Cancer Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605 [N. R. W., D. S. O., J. P., D. C. A.], and Laboratory of Molecular Pharmacology, National Cancer Institute/NIH, Bethesda, Maryland 20892 [Y. P.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Ala exhibited accelerated clearance as compared with wild-type survivin. Sequential ablation of survivin phosphorylation on Thr34 enhanced tumor cell apoptosis induced by anticancer agents independently of p53 and suppressed tumor growth without toxicity in a breast cancer xenograft model in vivo. These data suggest that Thr34 phosphorylation critically regulates survivin levels in tumor cells and that sequential ablation of p34cdc2 kinase activity may remove the survivin viability checkpoint and enhance apoptosis in tumor cells. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The possibility of exploiting the survivin pathway for cancer therapy has been intensely investigated. In these studies, molecular antagonists of survivin including antisense or dominant negative mutants or generation of survivin-specific cytolytic T cells caused tumor cell apoptosis, enhanced chemotherapy-induced cell death, and resulted in anticancer activity in vivo (10, 11, 12)
. One of the critical requirements for survivin function was recently identified in the phosphorylation on Thr34 by the mitotic kinase p34cdc2-cyclin B1 (13)
, and a phosphorylation-mimetic survivin mutant strongly inhibited p53-induced apoptosis (6)
. This step has also been exploited for anticancer therapy, and inducible expression (14)
or adenoviral delivery (15)
of nonphosphorylatable survivin Thr34Ala prevented phosphorylation of endogenous survivin, which resulted in caspase-9-dependent apoptosis and anticancer activity in vivo (14
, 15)
. However, the mechanism(s) by which Thr34 phosphorylation participates in survivin function has not been elucidated.
Using flavopiridol as a model of a Cdk inhibitor (16) , we found that phosphorylation on Thr34 is required to maintain survivin expression/stability in cancer cells and that ablation of p34cdc2 kinase in mitotically arrested cells results in loss of survivin levels and dramatic enhancement of chemotherapy-induced anticancer activity in vivo.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-survivin T34*) were described previously (13)
.
Northern Hybridization, Reverse Transcription-PCR, Immunoprecipitation, and Kinase Assay.
Total RNA was extracted from MCF-7 cells at various time intervals after Adriamycin treatment and hybridized with 32P-labeled survivin cDNA as described previously (18)
. Radioactive bands were detected by autoradiography. Alternatively, total RNA was reverse-transcribed with Superscript II and amplified with survivin-specific primers, and products were visualized by ethidium bromide-stained agarose gels. Amplification of glyceraldehyde-3-phosphate dehydrogenase served as an internal control. Survivin or p34cdc2 was immunoprecipitated from detergent-solubilized HeLa or MCF-7 cell extracts as described previously (13)
. For kinase assays, baculovirus-expressed p34cdc2-cyclin B1 was incubated with vehicle or flavopiridol (100 nM) and mixed with histone H1 (1 µg), wild-type survivin or survivin(T34A) (6 µg) in the presence of 10 µCi of [
-32P]ATP (Amersham). After a 30–45-min reaction at 30°C, radioactive bands were separated by SDS-gel electrophoresis and visualized by autoradiography, as described previously (13)
. In other experiments, endogenous survivin was immunoprecipitated from flavopiridol-treated HeLa cells (0–500 nM), and immune complexes were analyzed by Western blotting with antibodies to p34cdc2 (1 µg/ml), survivin (2 µg/ml), or survivin T34* (5 µg/ml). For cycloheximide block experiments, subconfluent cultures of MCF-7 cells were transfected with GFP-survivin or GFP-survivin(T34A) by LipofectAMINE, as described. After a 16-h interval, cells were incubated with cycloheximide (20 µM) to prevent further expression of transfected plasmids plus the broad-spectrum caspase inhibitor Z-VAD-fmk (20 µM) to prevent loss of cell viability associated with survivin(T34A) expression. Aliquots of the various cultures were harvested 0–120 h after cycloheximide block and analyzed for expression of GFP-containing fusion proteins by Western blotting with an antibody to GFP.
Survivin Promoter-Luciferase Reporter Expression.
MCF-7 cells (1–2 x 105 cells/well) were transfected with a minimal survivin promoter upstream of a luciferase reporter gene (pLuc-cyc1.2) by LipofectAMINE as described previously (18)
. Cells were treated with Taxol or Adriamycin or exposed to UVB irradiation as described, and luciferase activity was determined after 0–24 h of incubation at 37°C on a Lumat luminometer (LB9510), with normalization to ß-galactosidase activity.
MPM-2 Mitotic Phosphoepitope Expression.
For detection of mitotic phosphoproteins (19)
, MCF-7 cells (1–2 x 105 cells/60-mm dish) were treated with Taxol or Adriamycin or exposed to UVB irradiation as described and cultured for 0, 8, 16, 24, or 36 h at 37°C. Cells were fixed in 70% ethanol and labeled with MPM-2 antibody (6 µg/ml) followed by the addition of goat antimouse FITC (Boehringer Mannheim) for 1 h at 22°C in the presence of 5 µg/ml PI containing 50 µg/ml RNase A. Samples were analyzed on a FACScan (Becton Dickinson, Mountain View, CA) using CellQuest software.
Xenograft Breast Cancer Model.
All experiments involving animals were approved by the Institutional Animal Care and Use Committee. Breast carcinoma MCF-7 xenografts were developed in 5-week-old female CB.17 SCID/beige mice (Taconic Farms, Germantown, NY) as described previously (15)
. Each mouse received 2.5 x 106 exponentially growing MCF-7 cells (in 100 µl of sterile 1x PBS) s.c. in the right flank area. Tumors became palpable (25–75 mm3) within 5 days of tumor cell injection, after which groups of five animals were randomized and assigned to different treatment groups. Tumor size was measured in three dimensions with a caliper. Animals were sacrificed once their tumor burden reached 3000 mm3. Animals were given i.p. injections with Adriamycin alone (1.0, 2.0, or 4.0 mg/kg), flavopiridol alone (15 mg/kg), or the sequential combination of Adriamycin/flavopiridol for two consecutive days, each divided by a day with no treatment. For single-agent treatment, vehicle was given in place of Adriamycin or flavopiridol with the same schedule. Each complete cycle was separated by 2 days without treatment.
Statistical Analysis.
All in vitro experiments were repeated at least three times unless otherwise indicated. For in vivo studies, each X value (time) shows the fraction still alive. We calculated survival fractions using the product limit or Kaplan-Meier method. The survival curves were compared using the log-rank test. This test generates a P value testing the null hypothesis that the survival curves are identical in the overall populations.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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32-kDa histone H1 and wild-type survivin in a kinase assay in vitro (Fig. 1A)
. In contrast, no phosphorylation of survivin(T34A) by p34cdc2-cyclin B1 was observed in the presence or absence of flavopiridol (Fig. 1A)
. Treatment of HeLa cells with flavopiridol resulted in concentration-dependent inhibition of survivin phosphorylation on Thr34 by Western blotting of survivin immunoprecipitates with a Thr34-phosphospecific antibody (-survivin T34*; Fig. 1B
). Inhibition of survivin phosphorylation on Thr34 was also associated with progressive loss of survivin expression at increasing flavopiridol concentrations by Western blotting with an antibody to survivin (Fig. 1B)
. Consistent with these observations, exposure of HeLa cells to flavopiridol resulted in progressive decrease in endogenous survivin levels by Western blotting (Fig. 1C)
. In control experiments, flavopiridol did not affect the expression of antiapoptotic Bcl-2, whereas the flavone genistein, which does not inhibit Cdk activity (20)
, or TNF- did not affect survivin expression by Western blotting (data not shown; Fig. 1D
). To confirm that Thr34 phosphorylation influenced survivin stability, we used cycloheximide block in MCF-7 cells transfected with survivin cDNAs fused to GFP. To overcome apoptosis induced by expression of survivin(T34A) (13)
, a broad-spectrum caspase inhibitor, Z-VAD-fmk (20 µM), was also added. MCF-7 cells transfected with wild-type survivin exhibited time-dependent expression of a GFP-containing fusion protein that remained sustained for up to 96 h after transfection by Western blotting (Fig. 1E)
. In contrast, nonphosphorylatable survivin(T34A) was rapidly cleared from MCF-7 cells and nearly entirely depleted 72 h after transfection (Fig. 1E)
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. In contrast, cisplatin (3 µM) or 300 J/m2 UVB irradiation did not significantly affect survivin levels in MCF-7 cells (Fig. 2A)
. The increase in survivin expression by anticancer drugs was not accompanied by changes in survivin mRNA levels at various time intervals after Adriamycin treatment by Northern hybridization (Fig. 2B)
. Similar results were obtained by reverse transcription-PCR amplification of survivin transcript(s) in Adriamycin-treated MCF-7 cells (data not shown). When directly analyzed for potential changes in survivin gene expression, treatment of MCF-7 cells with the various anticancer drugs resulted in significant suppression of survivin promoter activity, as determined by analysis of MCF-7 cells transfected with a minimal survivin promoter upstream of a luciferase reporter gene (Fig. 2C)
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under these conditions. In a kinase assay, p34cdc2 immunoprecipitated from Adriamycin-treated cells phosphorylated 32-kDa histone H1 (Fig. 3A)
. Under these experimental conditions, p34cdc2 immunoprecipitates from Adriamycin-treated cells also contained a phosphorylated 16.5-kDa band, which was identified as survivin by Western blotting with an antibody to survivin (Fig. 3A)
and in agreement with the physical association of survivin with p34cdc2 (13)
. The presence of functional p34cdc2 activity in Adriamycin-treated cells correlated with the presence of a residual MCF-7 cell population (20–25%) exhibiting elevated MPM-2 mitotic phosphoepitope expression (Fig. 3B)
, in agreement with previous observations (21)
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and in agreement with the data presented above (Fig. 2)
. At the concentration and time intervals used, flavopiridol alone did not significantly affect survivin levels in MCF-7 cells (Fig. 4A)
. In contrast, sequential treatment of MCF-7 cells with Adriamycin or UVB irradiation for 18 h followed by flavopiridol for 72 h significantly inhibited the increase in survivin expression, which approached background levels of untreated cultures (Fig. 4A)
. Sequential flavopiridol treatment was also associated with suppression of survivin phosphorylation on Thr34 by Western blotting of survivin immunoprecipitates with a Thr34-phosphospecific antibody (Fig. 4B)
. Under these experimental conditions, loss of survivin expression in sequentially treated cultures was associated with significantly enhanced apoptosis induced by UVB (2%, 5%, and 12%) and Adriamycin (2%, 3%, and 10%) to 12%, 26%, and 46% and 22%, 45%, 60%, respectively, as compared with single-agent treatment alone (Fig. 4C)
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. In contrast, sequential combination therapy of Adriamycin (2 mg/kg/day over 2 days) followed by flavopiridol (15 mg/kg/day over 2 days) arrested tumor growth and resulted in indefinite survival of all treated animals (Fig. 5A)
. Significantly increased survival (P < 0.0001) was also observed upon suspension of sequential Adriamycin-flavopiridol treatment, when tumors exhibited de novo growth comparable to that of animals receiving single anticancer regimens (Fig. 5B)
. Mice treated with the sequential administration of Adriamycin-flavopiridol did not exhibit overt signs of systemic toxicity (weight loss, diarrhea, and so forth).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Protein phosphorylation has been implicated in the regulation of cell death pathways, influencing subcellular localization (22) , cytoprotection (23 , 24) , and cell cycle transitions (25 , 26) . There is also ample precedent for a role of phosphorylation in controlling stability/expression of cell death regulators. In this context, phosphorylation of bcl-2 on Thr56, Thr74, and Ser87 (27) or of p53 on Ser15 and Ser37 (28) has been implicated in preventing ubiquitin-dependent proteasome degradation. In the survivin crystal structure (29) , Thr34 is ideally positioned in an acidic knuckle to regulate the binding of potential client proteins controlling survivin stability and/or ubiquitin-dependent degradation. For IAP family proteins, including survivin (30) , ubiquitin-dependent proteasome destruction has been recognized as a critical mechanism to regulate protein levels, influencing IAP-dependent cytoprotection (31) . This suggests that the strong anticancer activity associated with overexpression of nonphosphorylatable survivin (T34A) may derive from inhibition of endogenous survivin phosphorylation (14) , followed by fall of survivin levels and tumor cell apoptosis. A similar phenotype has been observed after treatment with survivin antisense oligonucleotides, which resulted in suppression of endogenous survivin levels, spontaneous tumor cell apoptosis, and enhancement of anticancer regimens in vitro and in vivo (10 , 12 , 17 , 32) .
Because adenoviral delivery of dominant negative survivin (T34A) may have only limited applications for cancer therapy (15) , we targeted the step of survivin phosphorylation on Thr34 using a broad-spectrum kinase inhibitor, flavopiridol. Kinase inhibitors, including Cdk antagonists, have recently emerged as promising anticancer agents (33 , 34) , and flavopiridol has entered clinical trials (35 , 36) for its ability to trigger apoptosis (37 , 38) and exert anticancer activity in tumor models (35 , 39) . Despite intense investigation, the molecular basis of flavopiridol-mediated anticancer activity has not been completely elucidated and may involve mechanisms unrelated to p34cdc2 inhibition, including global suppression of gene transcription by interfering with Cdk9/cyclin T function (40) . In addition, flavopiridol functions as a relatively broad inhibitor of various Cdks as well as non-cell cycle-regulated kinases (40) , thus potentially producing multiple effects on cell cycle progression, gene expression, or general signaling pathways. Despite these potential limitations, it is tempting to speculate that one of the mechanisms by which flavopiridol may exert its proapoptotic function may involve loss of survivin expression due to suppression of phosphorylation on Thr34. This model may be consistent with recent observations of the ability of flavopiridol to reduce the expression of other IAP family proteins (41) , suggesting that global repression of cytoprotective molecules, including survivin, may contribute to flavopiridol-mediated apoptosis in vivo.
Whereas flavopiridol alone was sufficient to induce loss of survivin expression and apoptosis, the most significant enhancement of tumor cell apoptosis was obtained in sequential combination with selected chemotherapeutic agents. In this context, anticancer drugs inducing G2-M arrest with elevated (taxanes) or residual (Adriamycin) p34cdc2 kinase activity and detectable MPM-2 phosphoepitope expression were shown to cause Thr34 phosphorylation and increased survivin levels. Despite the known cell cycle periodicity of survivin expression at mitosis (18) , modulation of survivin levels by anticancer drugs did not involve changes in survivin mRNA or promoter function. In fact, transcription of the survivin gene was actually repressed by anticancer agents, which is consistent with similar findings observed with other G2-M-regulated genes containing, like survivin, cell-cycle dependent element (CDE)/cell cycle homology region (CHR) promoter elements (42) . Whether this pathway of survivin protein stabilization by anticancer drugs may facilitate the insurgence of chemoresistance, which has been consistently associated with the presence of survivin in tumors, in vivo (4) is currently not known. However, sequential ablation of survivin phosphorylation on Thr34 following Adriamycin treatment resulted in enhanced tumor cell apoptosis, in agreement with previous observations (43) , and significantly increased anticancer activity in a xenograft breast cancer model in vivo. Similar results were obtained when p34cdc2 kinase activity was sequentially suppressed after Taxol treatment, consistent with dephosphorylation of survivin on Thr34 in mitotically arrested cells and apoptosis (44) . On the other hand, UVB-induced G2-M arrest resulted in increased survivin expression despite the absence of MPM-2 phosphoepitope expression and lack of p34cdc2 kinase activity, suggesting that p34cdc2 may not be the only kinase inhibited by flavopiridol and required for survivin stability at G2-M.
The findings described here may have practical implications for anticancer strategies. A simplistic model that survivin may be exclusively involved in mitotic regulation (45) has been discounted by overwhelming experimental evidence demonstrating that survivin targeting provides a viable anticancer approach for potently inducing apoptosis in vivo (4) . Sequential therapy has recently emerged as a strategy to rationally improve the efficacy of anticancer combination therapy. Taken together, our findings may provide a molecular basis for the previously reported efficacy of flavopiridol to enhance chemotherapy-induced apoptosis in a strict sequence-dependent manner (46 , 47) and the recent implementation of sequential combination therapy using flavopiridol in clinical protocols (48) . Indeed, results from Phase II clinical trials using flavopiridol as a single-agent treatment were essentially negative in a variety of solid tumors with unacceptable systemic toxicity. Consistent with the approach presented here, this has prompted a strategy for combining flavopiridol with established chemotherapeutic regimens, i.e., taxanes, for clinical treatment protocols (48) . For the emerging role of kinase inhibitors, including Cdk antagonists, in cancer treatment (33 , 34) and the extreme sensitivity of tumor cells to manipulation of the survivin pathway (4) , sequential ablation of p34cdc2 kinase activity after administration of genotoxic agents (this study) or spindle poisons, i.e., taxanes (44) , may provide a rational approach to destabilize survivin levels in tumor cells and enhance the efficacy of common anticancer regimens in patients.
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FOOTNOTES |
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1 Supported by NIH Grants CA78810, CA90917, and HL54131. N. R. W. is supported by NIH National Research Service Award 1 F32 CA097802 from the Cancer Training Branch/National Cancer Institute. 
2 To whom requests for reprints should be addressed, at University of Massachusetts Medical School, LRB 428, 364 Plantation Street, Worcester, MA 01605. Phone: (508) 856-5775; Fax: (508) 856-5792; E-mail: dario.altieri{at}umassmed.edu
3 The abbreviations used are: IAP, inhibitor of apoptosis; Cdk, cyclin-dependent kinase; GFP, green fluorescence protein; PI, propidium iodide; TNF, tumor necrosis factor; SCID, severe combined immunodeficient; Z-VAD-fmk, Z-Val-Ala-Asp(OMe)-fmk.
Received 6/12/02. Accepted 10/24/02.
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J. Wu, X. Ling, D. Pan, P. Apontes, L. Song, P. Liang, D. C. Altieri, T. Beerman, and F. Li Molecular Mechanism of Inhibition of Survivin Transcription by the GC-rich Sequence-selective DNA Binding Antitumor Agent, Hedamycin: EVIDENCE OF SURVIVIN DOWN-REGULATION ASSOCIATED WITH DRUG SENSITIVITY J. Biol. Chem., March 11, 2005; 280(10): 9745 - 9751. [Abstract] [Full Text] [PDF]
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Y.-T. Huang, D.-M. Huang, J.-H. Guh, I-L. Chen, C.-C. Tzeng, and C.-M. Teng CIL-102 Interacts with Microtubule Polymerization and Causes Mitotic Arrest following Apoptosis in the Human Prostate Cancer PC-3 Cell Line J. Biol. Chem., January 28, 2005; 280(4): 2771 - 2779. [Abstract] [Full Text] [PDF]
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P.-C. Kuo, H.-F. Liu, and J.-I Chao Survivin and p53 Modulate Quercetin-induced Cell Growth Inhibition and Apoptosis in Human Lung Carcinoma Cells J. Biol. Chem., December 31, 2004; 279(53): 55875 - 55885. [Abstract] [Full Text] [PDF]
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N. Gao, Y. Dai, M. Rahmani, P. Dent, and S. Grant Contribution of Disruption of the Nuclear Factor-{kappa}B Pathway to Induction of Apoptosis in Human Leukemia Cells by Histone Deacetylase Inhibitors and Flavopiridol Mol. Pharmacol., October 1, 2004; 66(4): 956 - 963. [Abstract] [Full Text] [PDF]
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R. I. Haddad, L. J. Weinstein, T. J. Wieczorek, N. Bhattacharya, H. Raftopoulos, M. W. Oster, X. Zhang, V. M. Latham Jr., R. Costello, J. Faucher, et al. A Phase II Clinical and Pharmacodynamic Study of E7070 in Patients with Metastatic, Recurrent, or Refractory Squamous Cell Carcinoma of the Head and Neck: Modulation of Retinoblastoma Protein Phosphorylation by a Novel Chloroindolyl Sulfonamide Cell Cycle Inhibitor Clin. Cancer Res., July 15, 2004; 10(14): 4680 - 4687. [Abstract] [Full Text] [PDF]
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S. Grant and P. Dent Gene profiling and the cyclin-dependent kinase inhibitor flavopiridol: What's in a name? Mol. Cancer Ther., July 1, 2004; 3(7): 873 - 875. [Full Text] [PDF]
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 M. Pennati, M. Binda, M. De Cesare, G. Pratesi, M. Folini, L. Citti, M. G. Daidone, F. Zunino, and N. Zaffaroni Ribozyme-mediated down-regulation of survivin expression sensitizes human melanoma cells to topotecan in vitro and in vivo Carcinogenesis, July 1, 2004; 25(7): 1129 - 1136. [Abstract] [Full Text] [PDF]
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G. I. Shapiro Preclinical and Clinical Development of the Cyclin-Dependent Kinase Inhibitor Flavopiridol Clin. Cancer Res., June 15, 2004; 10(12): 4270S - 4275S. [Abstract] [Full Text] [PDF]
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J.-I Chao, P.-C. Kuo, and T.-S. Hsu Down-regulation of Survivin in Nitric Oxide-induced Cell Growth Inhibition and Apoptosis of the Human Lung Carcinoma Cells J. Biol. Chem., May 7, 2004; 279(19): 20267 - 20276. [Abstract] [Full Text] [PDF]
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E. J. Schlette, L. J. Medeiros, A. Goy, R. Lai, and G. Z. Rassidakis Survivin Expression Predicts Poorer Prognosis in Anaplastic Large-Cell Lymphoma J. Clin. Oncol., May 1, 2004; 22(9): 1682 - 1688. [Abstract] [Full Text] [PDF]
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B. Lu, Y. Mu, C. Cao, F. Zeng, S. Schneider, J. Tan, J. Price, J. Chen, M. Freeman, and D. E. Hallahan Survivin As a Therapeutic Target for Radiation Sensitization in Lung Cancer Cancer Res., April 15, 2004; 64(8): 2840 - 2845. [Abstract] [Full Text] [PDF]
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X. Ling, R. J. Bernacki, M. G. Brattain, and F. Li Induction of Survivin Expression by Taxol (Paclitaxel) Is an Early Event, Which Is Independent of Taxol-mediated G2/M Arrest J. Biol. Chem., April 9, 2004; 279(15): 15196 - 15203. [Abstract] [Full Text] [PDF]
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D. M. Nguyen, W. D. Schrump, G. A. Chen, W. Tsai, P. Nguyen, J. B. Trepel, and D. S. Schrump Abrogation of p21 Expression by Flavopiridol Enhances Depsipeptide-Mediated Apoptosis in Malignant Pleural Mesothelioma Cells Clin. Cancer Res., March 1, 2004; 10(5): 1813 - 1825. [Abstract] [Full Text] [PDF]
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S. Fulda and K.-M. Debatin Sensitization for Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by the Chemopreventive Agent Resveratrol Cancer Res., January 1, 2004; 64(1): 337 - 346. [Abstract] [Full Text] [PDF]
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S. P. Tu, X. H. Jiang, M. C. M. Lin, J. T. Cui, Y. Yang, C. T. Lum, B. Zou, Y. B. Zhu, S. H. Jiang, W. M. Wong, et al. Suppression of Survivin Expression Inhibits in Vivo Tumorigenicity and Angiogenesis in Gastric Cancer Cancer Res., November 15, 2003; 63(22): 7724 - 7732. [Abstract] [Full Text] [PDF]
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L. Yang, Z. Cao, H. Yan, and W. C. Wood Coexistence of High Levels of Apoptotic Signaling and Inhibitor of Apoptosis Proteins in Human Tumor Cells: Implication for Cancer Specific Therapy Cancer Res., October 15, 2003; 63(20): 6815 - 6824. [Abstract] [Full Text] [PDF]
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L. Zhang, S. Sharma, L. X. Zhu, T. Kogai, J. M. Hershman, G. A. Brent, S. M. Dubinett, and M. Huang Nonradioactive Iodide Effectively Induces Apoptosis in Genetically Modified Lung Cancer Cells Cancer Res., August 15, 2003; 63(16): 5065 - 5072. [Abstract] [Full Text] [PDF]
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