Journal of Clinical Oncology, Vol 17, Issue 7
(July), 1999: 2100
© 1999 American Society for Clinical Oncology
A Novel Anti-Apoptosis Gene: Re-expression of Survivin Messenger RNA as a Prognosis Marker in Non–Small-Cell Lung Cancers
Mariano Monzó,
Rafael Rosell,
Enriqueta Felip,
Julio Astudillo,
José Javier Sánchez,
José Maestre,
Cristina Martín,
Albert Font,
Agustí Barnadas,
Albert Abad
From the Laboratory of Molecular Biology of Cancer, Medical Oncology Service, and Thoracic Surgery Service, University Hospital Germans Trias i Pujol, Badalona; Medical Oncology Service and Thoracic Surgery Service, University Hospital Vall d'Hebron, Barcelona; and Statistical Department, School of Medicine, Free University of Madrid, Madrid, Spain.
Address reprint requests to Rafael Rosell, MD, Medical Oncology Service, Hospital Germans Trias i Pujol, Crtra Canyet, s/n, 08916 Badalona (Barcelona), Spain; email rrosell{at}ns.hugtip.scs.es
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ABSTRACT
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PURPOSE: The survivin gene is a novel apoptosis inhibitor, related to the baculovirus gene, which is believed to play a pivotal role in fetal development and in cancer. We hypothesised that survivin would be expressed in tumors of patients with non–small-cell lung cancer (NSCLC), and we attempted to determine the influence of survivin re-expression on clinical outcome in patients with up to stage IIIA NSCLC who had undergone radical surgery.
METHODS: We designed a reverse transcriptase polymerase chain reaction (RT-PCR) assay to study the expression of the survivin gene in 83 NSCLC tumor samples and compared the results with relevant clinical and pathologic data.
RESULTS: The RT-PCR identified survivin gene transcript in 71 (85.5%) of the tumor samples and in only 10 (12%) of the paired, histopathologically normal lung samples. There was no relationship between histologic subtype (squamous v nonsquamous) and survivin gene expression. The 12 patients without survivin expression had significantly better overall survival than the 71 patients with survivin expression (P = .01 by univariate analysis; relative risk, 2.1). There was no significant correlation between survivin expression and age, sex, cigarette smoking, histologic subtype, tumor differentiation, tumor size, or the presence of mediastinal lymph node metastases in surgical specimens.
CONCLUSION: The survivin gene was expressed in a vast majority of NSCLC tumors. We conclude that survivin transcript is a defining diagnostic marker for NSCLC that may also yield prognostic information and, as an apoptosis inhibitor, be an important target in cancer therapy.
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INTRODUCTION
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THE ANATOMIC EXTENT OF cancer as reflected by the stage of disease has traditionally been the most important determinant of prognosis in non–small-cell lung cancer (NSCLC).1 However, a significant number of tumors in patients with early-stage disease show aggressive behavior and a tendency to relapse. It has been demonstrated that micrometastatic cancer cells are present in the bone marrow of patients with resectable NSCLC,2 which indicates that micrometastases are involved even in early-stage disease. In addition, the prognosis for patients with operable NSCLC remains gloomy in comparison with that observed in gastric, colon, or breast cancer operable tumors when radical surgery is performed.3
Although a variety of clinicopathologic characteristics may affect prognosis, these characteristics have yet to be sufficiently defined, particularly as regards the selection of high-risk patients with early-stage disease.4 Moreover, despite steadily accumulating evidence that numerous genetic markers influence the biologic behavior of NSCLC, the intrinsic nature of gene dysregulation that leads small tumors to metastasize remains highly elusive.5 In this context, research on genetic hallmarks that correlate with a propensity to metastasize is indispensable. It is suspected that tumor invasion and metastasis involve complex alterations of gene expression that, in some instances, may be rather selective for specific cancer types.6,7
Several abnormalities of dominant oncogenes have been described as potential prognostic markers in NSCLC, including K-ras mutations, tumor suppressor genes, such as p53 mutations, and antigenic changes in the major blood group ABH antigens.8-11 In addition, our experience has shown that microsatellite instability at chromosome loci 3p and 2p may also be a prognostic marker, at least in surgical-pathologic stage I NSCLC patients.12,13 However, to date, few cellular genes have been identified whose altered regulation correlates with metastasis formation. Recently, Adachi et al14 showed that several members of the transmembrane 4 or tetraspan multigene family, including several lymphocyte surface antigens (CD9 and CD82), are linked to poor prognosis in operable NSCLC patients when tumor mRNA expression is downregulated, indicating that these genes may be potentially useful metastasis markers.
Another potential novel molecular progression marker is survivin, an apoptosis inhibitor related to the bcl-2 family with the particular characteristic of being selectively expressed in all of the most common human cancers, although not in normal tissue counterparts.15-17 Furthermore, as occurs with the Sonic hedgehog gene (Shh),18 survivin is expressed in the embryonic lung as well in other organs in developmental stages. The re-expression of this novel class of genes, which are involved in lung morphogenesis but not in normal adult tissue, prompted us to speculate that survivin expression might be present in NSCLC tumor samples and influence the prognosis of the disease.
In the present study, we investigated survivin transcript in patients with NSCLC by means of a reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Furthermore, we assessed the prognostic value of survivin expression in these patients.
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METHODS
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Total RNA was isolated from tumor samples taken from patients with primary NSCLC. The study included 83 patients with histologically verified NSCLC who had undergone radical surgery at University Hospital Germans Trias i Pujol, Badalona, and University Hospital Vall d'Hebron, Barcelona, Spain, between January 1995 and December 1996. Patients were enrolled exclusively on the basis of the availability of frozen tumors for molecular analysis. Their clinical records and histopathologic diagnoses were fully reviewed. The postsurgical pathologic stage of each tumor was classified according to the revised tumor-node-metastasis (TNM) system.1 Patient follow-up was performed at 2-month intervals in the first year after surgery, at 4-month intervals in the second and third year, and every 6 months thereafter. The end of the follow-up period of this study was defined as June 30, 1998. Fourteen NSCLC patients who had up to stage IIIA disease were excluded for the following reasons: (1) patient had received postoperative chemotherapy (seven patients); (2) patient's death was caused by postsurgical complications (one patient); (3) patient had two or more forms of cancer (two patients); and (4) samples were used for other studies and thus were not available (four patients).
Patient age ranged from 26 to 77 years (median, 65 years); 78 patients (94%) were men and five (6%) were women. Seventy-seven of the 83 had smoked (median, 40 packs/yr; range, 10 to 135 packs/yr). Five patients (6%) were classified as having TNM stage IA, 31 (37.3%) had stage IB disease, five (6%) had stage IIA disease, 10 (12.9%) had stage IIB disease, and 32 (38.5%) had stage IIIA disease. Forty-two tumors (50.6%) were squamous cell carcinomas, 37 (44.5%) were adenocarcinomas, and four (4.9%) were large-cell carcinomas. Seven tumors (8.4%) were well differentiated, 38 (45.8%) were moderately differentiated, and 38 (45.8%) were poorly differentiated. The median follow-up period was 18 months (range, 2 to 31 months) (see Table 1).
Samples of the tumors were collected at resection and immediately frozen in liquid nitrogen. Two 5-µm-thick sections were stained with hematoxylin and eosin and examined by light microscopy. RNA from normal and tumor tissues were purified by using the Ultraespec RNA kit (Biotecx Laboratories, Houston, TX), according to the manufacturer's instructions, and eluted with 50 µL of diethylpyrocarbonate water containing 50 units of RNase inhibitor (Boehringer Mannheim, Indianapolis, IN). RNA concentration was determined by spectrophotometry and adjusted to a concentration of 250 ng/µL. RNA was reverse transcribed by Moloney murine leukemia virus reverse transcriptase (Gibco BRL, Gaithersburg, MD) and 2-µL random hexamers. Incubation was performed at 23°C for 15 min, 42°C for 30 min, and 94°C for 5 min. cDNA were then amplified by PCR using PCR buffer (10 mmol/L Tris-HCl [pH 9.0]), 1.5 mmol/L MgC12, 200 µmol/L dNTPs, and 1.5 units of AmpliTaq DNA polymerase (Perkin Elmer/Roche Molecular Systems, Branchburg, NJ). On the basis of the nucleotide sequence of survivin (Fig 1), 5'-GCACGGGGACAGCTGGGAAGT-3' was used as the sense primer and 5'-CACTCCTGGCCACTGGTTCATCAC-3' was used as the antisense primer. Cycling conditions were as follows: initial denaturation at 94°C for 5 min, followed by 35 cycles at 94°C for 30 seconds, 68°C for 30 seconds, 72° for 40 seconds, and, finally, 72°C for 5 minutes. Identical PCR conditions were used to amplify the beta-actin cDNA that was used as an internal control; the sense primer used for beta-actin was 5'-GATATCGCCGCGCTCGTCGTC-3' and the antisense primer was 5'-GCACAGCCTGGATAGCAACGTACATG-3'. PCR amplifications were performed in duplicate using independent cDNA preparations. Tubes containing all ingredients except for the templates were incubated in all runs and served as negative controls. Amplified cDNAs were separated on 1% agarose gels, and the bands were visualized by ethidium bromide and photographed with a Polaroid camera (Polaroid, Cambridge, MA).
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Fig 1. Schematic representation of the survivin gene according to GenBank Database accession no. U75285. The survivin gene has 14,796 base pairs, with the origin of the upper primer (UP) in 2,768 base pair and the lower primer (LP) in 3,218 base pair. The cDNA-PCR product has 197 base pairs.
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Survival curves were estimated according to the Kaplan-Meier method from the date of primary tumor surgery to the time of metastatic recurrence or death. The difference in survival curves was examined by means of the log-rank test. The Brookmeyer-Crowley method was used to calculate the 95% confidence interval (CI) for the median period of survival. The Cox proportional hazards model was used to calculate the relative risk. All P values are two-sided and refer to either a  2 test or Fisher's exact probability test for tables and, where appropriate, the Mann-Whitney U test for nonparametric data. Statistical significance was defined as P < .05.
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RESULTS
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We designed an RT-PCR assay to study the expression of the survivin gene in NSCLC. Ethidium bromide staining of the agarose gel after migration of the PCR products identified a band of the expected size for the pair of primers designed (Fig 2). To ensure reproducibility, all PCR amplifications were performed in duplicate. Beta-actin gene expression was determined in parallel (Fig 2). Of the samples from the 83 NSCLC patients studied, 71 (85.5%) of the tumor samples and only 10 (12%) of the paired histopathologically normal lung samples had survivin transcript. There was no relationship between histologic subtype (squamous v nonsquamous) and survivin gene expression: 35 squamous cell carcinomas (83%) and 33 adenocarcinomas (89%) had survivin transcript. There was no significant correlation between positive survivin expression and age, sex, cigarette smoking, histologic subtype, tumor differentiation, tumor size, or the presence of mediastinal lymph node metastases in surgical specimens. The unequal distribution in patient sex is representative of lung cancer incidence in Spain. According to the official data available, the registry-based and age-standardized incidence rate is 42.5 per 100,000 per year for men and 3.6 per 100,000 per year for women.19 The results of all analyses of survivin transcripts and the clinicopathologic features of the 83 patients are summarized in Table 1.
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Fig 2. Ethidium bromide staining of agarose gels after migration of PCR amplification products from normal lung (lanes 1 through 5), adenocarcinomas (lanes 6 and 7), squamous cell carcinomas of the lung (lanes 8 through 10), negative control (lane 11), beta-actin, an internal positive control (lane 12), and a molecular weight marker (lane 13). Arrows indicate molecular weight at 200 and 400 base pairs.
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No differences in survival were observed for histologic subtype, tumor differentiation, or other clinicopathologic features (data not shown). However, the 12 patients without survivin transcript had a significantly longer survival than the 71 patients with survivin transcript (P = .01 by univariate analysis; relative risk, 2.2; 95% CI, 1.1 to 4.5). The median overall survival period was 19 months (95% CI, 14.2 to 23.7 months) in the positive survivin group and had not yet been reached in the negative survivin group (Fig 3). Thirty-one survivin-positive patients (43.6%) and 10 survivin-negative patients (83.3%) were alive at 1 year.
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Fig 3. Overall survival was significantly longer among those NSCLC patients without survivin transcript than among those with survivin transcript (P = .01 by univariate analysis).
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DISCUSSION
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In the present study, the basal level of survivin mRNA was analyzed for the first time in tumor samples from patients with primary NSCLC who had clinical follow-up. It had previously been shown that the human survivin gene is expressed in a variety of tissues,15 in a similar fashion to other genes involved in development, such as Shh and the patched (PTC) genes, which are expressed primarily in embryonic tissues.20-23 Shh intervenes in the morphogenesis of vertebrates,20 and PTC was initially identified as the Drosophila segment polarity gene.21 PTC constitutively represses downstream targets and the Shh signal relieves ptc repression, thereby inducing transcription of the downstream genes in Drosophila.22,23 The relationship between the gene pathways of Shh-PTC that control embryonic development and those involved in regulating cell proliferation has been studied in the basal cell nevus syndrome,22 and overexpression of Shh has been detected in human lung squamous cell carcinoma but not in normal lung tissue.24 Similarly, survivin, a new gene spanning approximately 15 kilobases (Fig 1) and located at band 17q25, was discovered by chance during hybridization screening of a human P1 genomic library with the cDNA of effector cell protease receptor 1.15 Survivin represents a new apoptosis inhibitor related to the baculovirus gene; it is present during fetal development but undetectable in adult tissues. Immunostaining and in situ hybridization have, however, shown survivin to be prominently expressed in various human cancers, including lung adenocarcinoma and squamous lung carcinoma cells from archival tissue (15 cases).15
Changes in gene expression are at the basis of many crucial physiologic and pathologic processes, such as differentiation or neoplastic transformation. Assuming that a cell transcribes an average 1.4 x 104 genes at a given time,7 we can extrapolate that a few hundred genes could be modulated in the lung upon induction of growth arrest. In this study, we have investigated whether survivin transcript is related to the histologic and clinical characteristics of NSCLC. It is noteworthy that from the 83 patients analyzed, 71 (85.5%) of the tumor samples and only 10 (12%) of the paired histopathologically normal lung samples had survivin transcript. Although revision in stage grouping of the TNM subsets has enabled patients with similar prognoses to be pinpointed more accurately, survival rates for pathologic stage IA (T1N0M0) and stage IB (T2N0M0) still remains close (67% and 57%, respectively, at 5 years in a total number of 1,060 patients).1 The closeness of these survival rates indicates that additional tools, such as molecular classification, are needed to identify patients with less favorable prognoses. Our results confirm the lack of prognostic importance of histologic subtype and tumor differentiation and suggest that survivin transcript may be a prognostic marker in NSCLC, as tumor cells could trigger de novo synthesis of survivin. This result does not seem to be biased by an unequal distribution of the patients, because we found no significant differences in the distribution of other possible prognostic factors according to the presence or absence of survivin transcripts.
The biologic basis for the presence of survivin expression in NSCLC as demonstrated in our results is still unclear and could be due to several reasons. One hypothesis is that in response to lung oncogenesis stimuli, transformed NSCLC cells neutralize molecular mechanisms that normally abrogate survivin. Upregulation of survivin mRNA could be related to an increased transcription of certain genes, similar to the activity of the tumor suppressor PTC and Shh pathways. Most of the previous studies that determined survivin expression have used immunostaining, but the method is still unreliable. In recent studies, only 34.5% of gastric carcinomas and 53% of colorectal tumors stained positively.25,26 This incidence is clearly lower than the 85.5% that was found in the present study using mRNA transcript. On the other hand, conflicting results have been reported concerning positive immunostaining coexpression of p53 and Bcl-2.25,26
In conclusion, the majority of NSCLC tumors express survivin, whereas survivin was undetectable in most nonneoplastic lung tissues, which suggests that far from being a mere relic of the embryonic lineage, survivin could be secondarily reactivated in NSCLC. Furthermore, survivin expression seems to influence clinical outcome. Recent results show that survivin is expressed in the G2/M phase of the cell cycle. At the beginning of mitosis, survivin associates with microtubules of the mitotic spindle. Hence, the overexpression of survivin may overcome this apoptotic checkpoint and promote aberrant progression of the transformed cell through mitosis. Moreover, survivin inhibits apoptosis of NIH3T3 transfectants induced by the microtubule-binding paclitaxel, but it is ineffective against microtubule depolymerizing agents such as vincristine.27 The possibility that survivin can efficiently inhibit paclitaxel-induced apoptosis warrants further investigation in the clinical setting.
Analysis of survivin transcript could prove to be both a useful diagnostic marker and an important source of prognostic information in NSCLC; moreover, as an apoptosis inhibitor, survivin is a potential new target in anticancer therapy.
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ACKNOWLEDGMENTS
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We thank Juan Carlos Lacal (Centro Superior Investigaciones Científicas, Madrid, Spain) for support, discussion, and critical reading of the manuscript and Renée O'Brate and Nicole Wirtz for their assistance in editing the manuscript.
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NOTES
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Research was conducted at Hospital Germans Trias i Pujol, Badalona, and supported in part by grant no. 97/1064 from the Fondo Investigaciones Sanitarias de la Seguridad Social and a grant from Rhône-Poulenc Rorer, Madrid, Spain.
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Submitted October 8, 1998;
accepted February 26, 1999.
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Effects of JC Virus Infection on Anti-Apoptotic Protein Survivin in Progressive Multifocal Leukoencephalopathy
Am. J. Pathol.,
April 1, 2007;
170(4):
1291 - 1304.
[Abstract]
[Full Text]
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S. Fukuda and L. M. Pelus
Survivin, a cancer target with an emerging role in normal adult tissues
Mol. Cancer Ther.,
May 1, 2006;
5(5):
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[Abstract]
[Full Text]
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B. M. Ryan, G. E. Konecny, S. Kahlert, H.-J. Wang, M. Untch, G. Meng, M. D. Pegram, K. C. Podratz, J. Crown, D. J. Slamon, et al.
Survivin expression in breast cancer predicts clinical outcome and is associated with HER2, VEGF, urokinase plasminogen activator and PAI-1
Ann. Onc.,
April 1, 2006;
17(4):
597 - 604.
[Abstract]
[Full Text]
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H. Asanuma, T. Torigoe, K. Kamiguchi, Y. Hirohashi, T. Ohmura, K. Hirata, M. Sato, and N. Sato
Survivin Expression Is Regulated by Coexpression of Human Epidermal Growth Factor Receptor 2 and Epidermal Growth Factor Receptor via Phosphatidylinositol 3-Kinase/AKT Signaling Pathway in Breast Cancer Cells
Cancer Res.,
December 1, 2005;
65(23):
11018 - 11025.
[Abstract]
[Full Text]
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Y. Fujie, H. Yamamoto, C. Y. Ngan, A. Takagi, T. Hayashi, R. Suzuki, K. Ezumi, I. Takemasa, M. Ikeda, M. Sekimoto, et al.
Oxaliplatin, a Potent Inhibitor of Survivin, Enhances Paclitaxel-induced Apoptosis and Mitotic Catastrophe in Colon Cancer Cells
Jpn. J. Clin. Oncol.,
August 1, 2005;
35(8):
453 - 463.
[Abstract]
[Full Text]
[PDF]
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D. A. Fennell
Caspase Regulation in Non-Small Cell Lung Cancer and its Potential for Therapeutic Exploitation
Clin. Cancer Res.,
March 15, 2005;
11(6):
2097 - 2105.
[Abstract]
[Full Text]
[PDF]
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S. Idenoue, Y. Hirohashi, T. Torigoe, Y. Sato, Y. Tamura, H. Hariu, M. Yamamoto, T. Kurotaki, T. Tsuruma, H. Asanuma, et al.
A Potent Immunogenic General Cancer Vaccine That Targets Survivin, an Inhibitor of Apoptosis Proteins
Clin. Cancer Res.,
February 15, 2005;
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[Abstract]
[Full Text]
[PDF]
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H. Hariu, Y. Hirohashi, T. Torigoe, H. Asanuma, M. Hariu, Y. Tamura, K. Aketa, C. Nabeta, K. Nakanishi, K. Kamiguchi, et al.
Aberrant Expression and Potency as a Cancer Immunotherapy Target of Inhibitor of Apoptosis Protein Family, Livin/ML-IAP in Lung Cancer
Clin. Cancer Res.,
February 1, 2005;
11(3):
1000 - 1009.
[Abstract]
[Full Text]
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M. E. Johnson and E. W. Howerth
Survivin: A Bifunctional Inhibitor of Apoptosis Protein
Vet. Pathol.,
November 1, 2004;
41(6):
599 - 607.
[Abstract]
[Full Text]
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B. Vischioni, P. van der Valk, S. W. Span, F. A. E. Kruyt, J. A. Rodriguez, and G. Giaccone
Nuclear localization of survivin is a positive prognostic factor for survival in advanced non-small-cell lung cancer
Ann. Onc.,
November 1, 2004;
15(11):
1654 - 1660.
[Abstract]
[Full Text]
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P. N. Span, F. C.G.J. Sweep, E. T.G. Wiegerinck, V. C.G. Tjan-Heijnen, P. Manders, L. V.A.M. Beex, and J. B. de Kok
Survivin Is an Independent Prognostic Marker for Risk Stratification of Breast Cancer Patients
Clin. Chem.,
November 1, 2004;
50(11):
1986 - 1993.
[Abstract]
[Full Text]
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F. Altznauer, S. Martinelli, S. Yousefi, C. Thurig, I. Schmid, E. M. Conway, M. H. Schoni, P. Vogt, C. Mueller, M. F. Fey, et al.
Inflammation-associated Cell Cycle-independent Block of Apoptosis by Survivin in Terminally Differentiated Neutrophils
J. Exp. Med.,
May 17, 2004;
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1343 - 1354.
[Abstract]
[Full Text]
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Z.-X. Xu, R.-X. Zhao, T. Ding, T. T. Tran, W. Zhang, P. P. Pandolfi, and K.-S. Chang
Promyelocytic Leukemia Protein 4 Induces Apoptosis by Inhibition of Survivin Expression
J. Biol. Chem.,
January 16, 2004;
279(3):
1838 - 1844.
[Abstract]
[Full Text]
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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;
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[Abstract]
[Full Text]
[PDF]
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C. Tanaka, K. Uzawa, T. Shibahara, H. Yokoe, H. Noma, and H. Tanzawa
Expression of an Inhibitor of Apoptosis, Survivin, in Oral Carcinogenesis
Journal of Dental Research,
August 1, 2003;
82(8):
607 - 611.
[Abstract]
[Full Text]
[PDF]
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C. Casati, P. Dalerba, L. Rivoltini, G. Gallino, P. Deho, F. Rini, F. Belli, D. Mezzanzanica, A. Costa, S. Andreola, et al.
The Apoptosis Inhibitor Protein Survivin Induces Tumor-specific CD8+ and CD4+ T Cells in Colorectal Cancer Patients
Cancer Res.,
August 1, 2003;
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4507 - 4515.
[Abstract]
[Full Text]
[PDF]
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M. Kappler, M. Kotzsch, F. Bartel, S. Fussel, C. Lautenschlager, U. Schmidt, P. Wurl, M. Bache, H. Schmidt, H. Taubert, et al.
Elevated Expression Level of Survivin Protein in Soft-Tissue Sarcomas Is a Strong Independent Predictor of Survival
Clin. Cancer Res.,
March 1, 2003;
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[Abstract]
[Full Text]
[PDF]
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M. Ikeguchi, T. Ueta, Y. Yamane, Y. Hirooka, and N. Kaibara
Inducible Nitric Oxide Synthase and Survivin Messenger RNA Expression in Hepatocellular Carcinoma
Clin. Cancer Res.,
October 1, 2002;
8(10):
3131 - 3136.
[Abstract]
[Full Text]
[PDF]
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C. Xia, Z. Xu, X. Yuan, K. Uematsu, L. You, K. Li, L. Li, F. McCormick, and D. M. Jablons
Induction of Apoptosis in Mesothelioma Cells by Antisurvivin Oligonucleotides
Mol. Cancer Ther.,
July 1, 2002;
1(9):
687 - 694.
[Abstract]
[Full Text]
[PDF]
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A. Chakravarti, E. Noll, P. McL. Black, D. F. Finkelstein, D. M. Finkelstein, N. J. Dyson, and J. S. Loeffler
Quantitatively Determined Survivin Expression Levels Are of Prognostic Value in Human Gliomas
J. Clin. Oncol.,
February 15, 2002;
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1063 - 1068.
[Abstract]
[Full Text]
[PDF]
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J. R. Kanwar, W.-P. Shen, R. K. Kanwar, R. W. Berg, and G. W. Krissansen
Effects of Survivin Antagonists on Growth of Established Tumors and B7-1 Immunogene Therapy
J Natl Cancer Inst,
October 17, 2001;
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[Abstract]
[Full Text]
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S. Fukuda and L. M. Pelus
Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34+ cells by hematopoietic growth factors: implication of survivin expression in normal hematopoiesis
Blood,
October 1, 2001;
98(7):
2091 - 2100.
[Abstract]
[Full Text]
[PDF]
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M. H. Andersen, L. O. Pedersen, B. Capeller, E.-B. Brocker, J. C. Becker, and P. thor Straten
Spontaneous Cytotoxic T-Cell Responses against Survivin-derived MHC Class I-restricted T-Cell Epitopes in Situ As Well As ex Vivo in Cancer Patients
Cancer Res.,
August 1, 2001;
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5964 - 5968.
[Abstract]
[Full Text]
[PDF]
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C. G. Ferreira, P. van der Valk, S. W. Span, I. Ludwig, E. F. Smit, F. A. E. Kruyt, H. M. Pinedo, H. van Tinteren, and G. Giaccone
Expression of X-linked Inhibitor of Apoptosis as a Novel Prognostic Marker in Radically Resected Non-Small Cell Lung Cancer Patients
Clin. Cancer Res.,
August 1, 2001;
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[Abstract]
[Full Text]
[PDF]
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S. D. Smith, M. A. Wheeler, J. Plescia, J. W. Colberg, R. M. Weiss, and D. C. Altieri
Urine Detection of Survivin and Diagnosis of Bladder Cancer
JAMA,
January 17, 2001;
285(3):
324 - 328.
[Abstract]
[Full Text]
[PDF]
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D. Grossman, P. J. Kim, J. S. Schechner, and D. C. Altieri
Inhibition of melanoma tumor growth in vivo by survivin targeting
PNAS,
January 5, 2001;
(2001)
230450097.
[Abstract]
[Full Text]
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M MILLER, D SMITH, A WINDSOR, A KESSLING, A I SARELA, S M FARMERY, and P J GUILLOU
Survivin gene expression and prognosis in recurrent colorectal cancer Reply
Gut,
January 1, 2001;
48(1):
137 - 138.
[Full Text]
[PDF]
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C. Adida, C. Haioun, P. Gaulard, E. Lepage, P. Morel, J. Briere, H. Dombret, F. Reyes, J. Diebold, C. Gisselbrecht, et al.
Prognostic significance of survivin expression in diffuse large B-cell lymphomas
Blood,
September 1, 2000;
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1921 - 1925.
[Abstract]
[Full Text]
[PDF]
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R. A. Olie, A. P. Simoes-Wust, B. Baumann, S. H. Leech, D. Fabbro, R. A. Stahel, and U. Zangemeister-Wittke
A Novel Antisense Oligonucleotide Targeting Survivin Expression Induces Apoptosis and Sensitizes Lung Cancer Cells to Chemotherapy
Cancer Res.,
June 1, 2000;
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2805 - 2809.
[Abstract]
[Full Text]
[PDF]
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D. Grossman, P. J. Kim, J. S. Schechner, and D. C. Altieri
Inhibition of melanoma tumor growth in vivo by survivin targeting
PNAS,
January 16, 2001;
98(2):
635 - 640.
[Abstract]
[Full Text]
[PDF]
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TOP
ABSTRACT
INTRODUCTION
