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Division of Oncology, Department of Internal Medicine, University Hospital Zürich, CH-8044 Zürich [R. A. O., A. P. S-W., S. H. L., R. A. S., U. Z-W.]; Institute of Biochemistry, Swiss Federal Institute of Technology, CH-8092 Zürich [B. B.]; and Department of Oncology Research, Novartis Pharma AG, CH-4002 Basel [D. F.], Switzerland
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Lung and breast cancer are leading causes of cancer death, and their incidence continues to rise. The main reasons for the unfavorable prognosis of these tumors is their propensity to metastasize early and develop resistance to a wide range of functionally unrelated anticancer agents. Interestingly, lung and breast cancer cells express the highest levels of survivin found in human tumors (1 , 2) , and in agreement with its biological function, survivin expression is correlated with shorter survival in patients with non-small cell lung cancer (5) . Although survivin has been widely recognized as an attractive target for cancer therapy (2, 3, 4, 5, 6, 7, 8, 9, 10) , the use of antisense cDNA and oligonucleotides to inhibit its expression has only recently been described (11, 12, 13) . Whereas these studies were designed to unravel the biological function of survivin, the promise of survivin antisense to facilitate apoptosis of tumor cells and overcome chemoresistance in cancer therapy remains to be determined.
In the present study, we developed a series of 20-mer phosphorothioate oligonucleotides targeting various regions of survivin mRNA. Using real-time PCR and the survivin-overexpressing lung adenocarcinoma cell line A549, one antisense oligonucleotide was identified that most efficiently down-regulated survivin mRNA levels and directly induced apoptosis. Moreover, in a combination experiment with the chemotherapeutic agent etoposide, evidence is provided that antisense-mediated down-regulation of survivin has the potential to sensitize tumor cells to chemotherapy.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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. A 3-base mismatch control to the most potent antisense oligonucleotide
was also used. Oligonucleotides were provided by Genset SA (Paris,
France) in the form of phosphorothioate oligonucleotides. A BLASTN
search of a database containing all sequences of GenBank, European
Molecular Biology Laboratory, DDBJ: DNA Data Base of Japan, and
Protein Data Base was performed to exclude homology of the
antisense and control oligonucleotides to other human genes.
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Treatment of Cells with Antisense and Etoposide.
One day before transfection, A549 cells were plated in 6-, 24-, or
96-well tissue culture plates. Oligonucleotides were delivered in the
form of complexes with Lipofectin (Life Technologies, Glasgow, United
Kingdom) as described previously (16)
. Upon a 20-h
transfection, A549 cells were harvested or the transfection medium was
replaced by medium without transfection reagent, and cells were
harvested 40 or 64 h after the start of transfection. In
combination treatment experiments, etoposide (Sigma, St. Louis, MO) was
added after the medium change at t = 20 h at a final concentration of 1.5 µg/ml. PBMCs were plated
immediately before transfection in 24-well tissue culture plates. In
contrast to the treatment of A549 cells, the transfection medium for
PBMCs was not replaced before harvest of the cells 64 h after the
start of transfection.
Real-Time PCR.
Total RNA was isolated from cells by using the RNeasy Mini Kit (QIAGEN
Inc., Basel, Switzerland). For cDNA synthesis, 0.5 µg extracted
RNA/sample and Taqman Reverse Transcription Reagents (including random
hexamers) were used, as described in the user’s manual of the ABI
Prism 7700 Sequence Detection System (Perkin-Elmer Applied Biosystems,
Foster City, CA). This system was used for real-time monitoring of PCR
amplification of the cDNA following the Taqman Universal PCR Master Mix
protocol (Perkin-Elmer; Refs. 17, 18, 19
). The amplification
of survivin cDNA was performed using two sets of primers and Taqman
probes referred to as S2 and S3. S2 consisted of
5'-AGTGAGGGAGGAAGAAGGCA-3' as a forward primer,
5'-ATTCACTGTGGAAGGCTCTGC-3' as a reverse primer, and
5'-CGCGAACAAAGCTGTCAGCTCTAGCA-3' as the Taqman probe. S3 consisted
of 5'-ATGGGTGCCCCGACGT-3' as a forward primer,
5'-AATGTAGAGATGCGGTGGTCCTT-3' as a reverse primer, and
5'-CCCCTGCCTGGCAGCCCTTTC-3' as the Taqman probe. The region in which S2
interacts with the survivin cDNA is distinct from the sites where the
antisense oligonucleotides hybridize on the mRNA; therefore, this set
of primers and probe was used to screen for the most potent antisense
oligonucleotide. Because the sequence of the survivin gene amplified by
S2 is identical to part of the EPR-1 gene, in principle S2 may
also amplify the EPR-1 cDNA. Therefore, S3, which amplifies a region of
the survivin gene not shared with the EPR-1 gene, was used in addition
to confirm the data obtained with S2 for the most potent antisense
oligonucleotide.
The survivin probes were labeled at the 5' end with the reporter molecule 6-carboxy-fluorescein and labeled at the 3' end with the quencher molecule 6-carboxy-tetramethylrhodamine. Relative quantification of gene expression was performed as described in the above-mentioned user’s manual, using rRNA as an internal standard. Briefly, ribosomal cDNA was amplified separately as indicated in the Taqman rRNA Control Reagents protocol (Perkin-Elmer). The comparative CT (cycle threshold) method was used for relative quantification of survivin mRNA using S2, after confirming that survivin cDNA and ribosomal cDNA were amplified with the same efficiency. Using S3, survivin cDNA was not amplified with the same efficiency as ribosomal cDNA; therefore, the calibration curve method was used for relative quantification of survivin mRNA.
Measurement of Cell Growth and Viability.
Growth inhibition of A549 cells was determined by use of the
colorimetric MTT cell viability/proliferation assay as described
previously (20
, 21)
. Cells were transfected for 20 h
at 37°C and incubated for another 44 h at 37°C. Subsequently,
10 µl of MTT reagent (Sigma; 10 mg/ml) was added and allowed to react
for 1.5 h at 37°C before the addition of solubilization reagent
[100 µl of 20% SDS in 50% dimethyl formamide and 50%
H2O (pH 4.7); pH adjusting solution, 80% acetate
and 20% 1 M HCl]. Substrate cleavage was monitored
at 570 nm by use of a SPECTRAmax 340 microplate reader and analyzed
using SOFTmax PRO software (Molecular Devices, Sunnyvale, CA). The
viability of A549 cells was assessed by morphology analysis using an
inverted phase-contrast microscope (Leitz, Wetzlar, Germany) and trypan
blue exclusion assays.
To evaluate the effect of Lipofectin or oligonucleotides on PBMCs, cells were transfected for 64 h at 37°C. Subsequently, cells were harvested, and the percentage of trypan blue-positive cells in the cultures was analyzed.
Measurement of Caspase Activation.
Caspase-3-like protease activity in cells was analyzed by use of a
colorimetric test system. Detached and attached cells were harvested as
described above and pooled and lysed in buffer by freezing/thawing
essentially as described previously (22)
. Lysates were
centrifuged at 17,500 x g at 4°C for 15
min. Cytosolic protein (40 µg) was mixed with 80
µM of the caspase-3-specific substrate
DEVD-para-Nitroanilide (Bachem, Dübendorf,
Switzerland) and incubated at 37°C. Subsequently, substrate
cleavage was monitored at 405 nm using a SPECTRAmax 340 microplate
reader and analyzed using SOFTmax PRO software (Molecular Devices). To
confirm that substrate cleavage was due to caspase activity, extracts
were incubated in the presence of 10 µM of the
caspase-3-specific inhibitor DEVD-CHO (Bachem) for 30 min at
37°C, before the addition of substrate. The value (in arbitrary
absorbance units) of the absorbance signal of the inhibited sample was
subtracted from that of the noninhibited sample.
Nuclear Staining.
Detached cells harvested from the culture medium by centrifugation at
1000 rpm (170 x g) for 5 min were
pooled with attached cells collected in a similar way after
trypsinization. Cells were pelleted, resuspended, and fixed in 4%
paraformaldehyde/0.05% saponin/5 µg/ml Hoechst 33342 (Sigma) for 15
min before cytospin centrifugation (400 rpm, 3 min). Cells were mounted
with Mowiol (Calbiochem, La Jolla, CA), and nuclei were observed by
using a Leica confocal laserscan microscope equipped with SCANware
software (Leitz). Images were processed using Imaris software
(Bitplane, Zürich, Switzerland).
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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. By using real-time PCR with the S2
primers and probe set, antisense oligonucleotides were examined for
their effects on survivin mRNA in A549 cells, which overexpress the
survivin protein (1)
. Antisense oligonucleotide 4003,
which targets nucleotides 232–251, revealed the strongest effect, and
at a concentration of 600 nM, it reduced the survivin mRNA
level by 70% at 20 h after the start of transfection (Fig. 1
A). Based on this finding, only oligonucleotide 4003 was used
in the following experiments.
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,
oligonucleotide 4003 down-regulated the survivin mRNA level in a
dose-dependent manner with an IC50 of about 200
nM. At a concentration of 400
nM, a maximum down-regulation to 30% of the
initial mRNA level was achieved. A further increase in oligonucleotide
concentration did not result in increased antisense efficacy. The
mismatch control 4003mis, even when used at 600
nM, did not down-regulate the survivin mRNA
level.
The coding strand of the survivin gene shows extensive complementarity
to the EPR-1 gene (11)
, and S2 amplifies a region that is
identical in both genes. Therefore S2 is also likely to amplify EPR-1
cDNA, which may lead to a false positive survivin signal in cases where
only EPR-1 is expressed or to an underestimation of survivin
down-regulation on antisense treatment if both genes are
coexpressed. The expression of both genes, however, is reported
to be mutually exclusive (2
, 3)
, and the use of antisense
oligonucleotide 4003 strongly reduced the survivin mRNA signal measured
by real-time PCR. This suggests that the S2-amplified transcript
corresponds to the survivin mRNA and not the EPR-1 mRNA. To confirm the
data obtained with S2, the effect of the most potent antisense
oligonucleotide, 4003, at a dose of 600 nM was also
analyzed using the S3 primers and probe set, which amplifies a region
unique to survivin and not shared with EPR-1. As
shown in the inset in Fig. 1B
, the data obtained
with S3 confirm the ability of 4003 to specifically down-regulate
survivin mRNA expression in A549 cells.
Inhibition of Cell Growth by Oligonucleotide 4003.
To analyze the biological effect associated with the down-regulation of
survivin expression, the growth of A549 cells on treatment with
oligonucleotide 4003 was investigated by use of the MTT assay. As shown
in Fig. 2
A, 64 h after the start of transfection, oligonucleotide
4003 had reduced A549 cell growth dose dependently, with an
IC50 of 300 nM. The
unspecific growth-inhibitory effect of the mismatch control
oligonucleotide was comparatively low. Oligonucleotide 4003 induced
death in A549 cells, as revealed by detachment from the culture surface
(Fig. 2, B–D)
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, lysates from oligonucleotide 4003-treated cells revealed increased
caspase-3-like protease activity compared with untreated cells.
Moreover, on treatment with oligonucleotide 4003, cells contained
nuclei with condensed and fragmented chromatin, providing further
evidence for the induction of apoptosis as a consequence of
survivin antisense treatment (inset in Fig. 3
). In cultures
treated with the mismatch control oligonucleotide, very few cells
showed signs of apoptosis.
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A). Trypan blue exclusion assays revealed that PBMCs, in
contrast to A549 cells, were not susceptible to death induction by
oligonucleotide 4003 (Fig. 4A
).
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shows that in cultures treated with a
combination of 600 nM antisense oligonucleotide
and 1.5 µg/ml etoposide, approximately 85% of the cells showed signs
of cell death 64 h after the start of transfection. Compared to
treatments with either oligonucleotide or etoposide alone, this
represents about twice or even six times the number of dead cells,
respectively. Similarly, nuclear fragmentation and condensation were
also increased in combination-treated cells compared with single-agent
treated cells (data not shown). |
Discussion |
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Most antisense approaches rely on empirical targeting of oligonucleotides against the translation initiation site of mRNAs, where the ATG start codon lies. The rationale for choosing this site is that it likely presents in single-stranded conformation and thus should be accessible to antisense oligonucleotides. In a previous bcl-2 antisense study, we have shown that oligonucleotides hybridizing to the coding region of the mRNA may offer additional targeting options that are equally or even more effective (20) . To predict putative binding sites likely to present in single-stranded confirmation, the RNAdraw program (14) was used as described previously (15) . One of the phosphorothioate antisense oligonucleotides developed in the present study targets the ATG start codon site (4018), whereas the others were designed to hybridize to sequences located in the coding region. From these oligonucleotides, 4003 most efficiently down-regulated the survivin mRNA level in A549 cells, achieving its maximum effect at a concentration of 400 nM, at which mRNA was down-regulated by 70%.
Cells harboring multiple genetic alterations are normally eliminated by apoptosis. For survival, they depend on the overexpression of antiapoptotic molecules such as bcl-2, bcl-xL, or survivin, and down-regulation of these proteins is likely to reduce the apoptotic threshold in cells. Oligonucleotide 4003 indeed induced a strong growth-inhibitory effect and apoptosis in A549 cells in the absence of any further cytotoxic stimulus. Similar results were obtained with various other tumor cell lines (data not shown). This observation is in agreement with the findings of others (4) describing the necessity of interaction between survivin and microtubules of the mitotic spindle apparatus to prevent a default induction of apoptosis at the G2-M phase of the cell cycle. This mode of action may constitute a safeguard mechanism against the proliferation of cells with unwanted properties. Whether down-regulation of survivin expression sensitizes cells to apoptosis only when passing the G2-M checkpoint remains to be investigated. The specificity of our survivin antisense approach was further corroborated by the finding that oligonucleotide 4003 did not induce death in normal PBMCs. In these cells, survivin mRNA was hardly detectable using real-time PCR, in agreement with the reported lack of survivin expression in PBMCs (2) .
Two major apoptosis signaling pathways are known: (a) the mitochondrial pathway; and (b) the death receptor pathway. The antiapoptotic proteins bcl-2 and bcl-xL block the apoptotic event of mitochondrial cytochrome c release into the cytosol and have been shown to inhibit mainly the first of these two pathways. We have previously shown that in lung cancer cells, antisense oligonucleotides down-regulating bcl-2 or bcl-xL expression induce apoptosis and synergistically interact with chemotherapy (20 , 21 , 23) . Because survivin directly blocks the processing and activation of effector caspase-3 and -7, which act at a common downstream part of the two major apoptosis pathways, the survivin antisense approach has the potential to facilitate apoptosis through both pathways. Using oligonucleotide 4003 in combination with etoposide, which triggers cell death via cytochrome c release (24) , we provide evidence that down-regulation of survivin expression sensitizes cells to death induction via the mitochondrial pathway. Whether it also increases cell death induced by the death receptor pathway and whether it sensitizes other survivin-overexpressing tumor cells to chemotherapy are currently under investigation.
We demonstrate that down-regulation of survivin expression by use of the novel antisense oligonucleotide 4003 facilitates apoptosis and sensitizes lung cancer cells to chemotherapy. Oligonucleotide 4003 does not induce death in a normal cell population lacking survivin expression. Our data suggest that the use of oligonucleotide 4003 deserves further investigation as a novel approach to selective cancer therapy.
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Acknowledgments |
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FOOTNOTES |
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1 Supported by Grant 31-40473.94 from the Swiss
National Science Foundation, Grant 549-9-1997 from the Krebsforschung
Schweiz, and the Stiftung zum Baugarten (Zürich, Switzerland). 
2 To whom requests for reprints should be
addressed, at Division of Oncology, Department of Internal Medicine,
University Hospital Zürich, Häldeliweg 4, CH-8044
Zürich, Switzerland. Phone: 41-1-6342877; Fax: 41-1-6342872;
E-mail: uwe.zangemeister{at}dim.usz.ch
3 The abbreviations used are: IAP, inhibitor of
apoptosis protein; MTT,
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBMC,
peripheral blood mononuclear cell; EPR-1, effector cell protease
receptor 1.
Received 12/10/99. Accepted 4/11/00.
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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] [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. Fukuda, C. R. Mantel, and L. M. Pelus Survivin regulates hematopoietic progenitor cell proliferation through p21WAF1/Cip1-dependent and -independent pathways Blood, January 1, 2004; 103(1): 120 - 127. [Abstract] [Full Text] [PDF]
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M. Fornaro, J. Plescia, S. Chheang, G. Tallini, Y.-M. Zhu, M. King, D. C. Altieri, and L. R. Languino Fibronectin Protects Prostate Cancer Cells from Tumor Necrosis Factor-{alpha}-induced Apoptosis via the AKT/Survivin Pathway J. Biol. Chem., December 12, 2003; 278(50): 50402 - 50411. [Abstract] [Full Text] [PDF]
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B. Z. Carter, S. M. Kornblau, T. Tsao, R.-Y. Wang, W. D. Schober, M. Milella, H.-G. Sung, J. C. Reed, and M. Andreeff Caspase-independent cell death in AML: caspase inhibition in vitro with pan-caspase inhibitors or in vivo by XIAP or Survivin does not affect cell survival or prognosis Blood, December 1, 2003; 102(12): 4179 - 4186. [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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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; 9(3): 1098 - 1104. [Abstract] [Full Text] [PDF]
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S. Wittmann, P. Bali, S. Donapaty, R. Nimmanapalli, F. Guo, H. Yamaguchi, M. Huang, R. Jove, H. G. Wang, and K. Bhalla Flavopiridol Down-Regulates Antiapoptotic Proteins and Sensitizes Human Breast Cancer Cells to Epothilone B-induced Apoptosis Cancer Res., January 1, 2003; 63(1): 93 - 99. [Abstract] [Full Text] [PDF]
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N. R. Wall, D. S. O'Connor, J. Plescia, Y. Pommier, and D. C. Altieri Suppression of Survivin Phosphorylation on Thr34 by Flavopiridol Enhances Tumor Cell Apoptosis Cancer Res., January 1, 2003; 63(1): 230 - 235. [Abstract] [Full Text] [PDF]
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 M. Zhou, L. Gu, F. Li, Y. Zhu, W. G. Woods, and H. W. Findley DNA Damage Induces a Novel p53-Survivin Signaling Pathway Regulating Cell Cycle and Apoptosis in Acute Lymphoblastic Leukemia Cells J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 124 - 131. [Abstract] [Full Text] [PDF]
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S. Fukuda, R. G. Foster, S. B. Porter, and L. M. Pelus The antiapoptosis protein survivin is associated with cell cycle entry of normal cord blood CD34+ cells and modulates cell cycle and proliferation of mouse hematopoietic progenitor cells Blood, September 18, 2002; 100(7): 2463 - 2471. [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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C. G. Ferreira, M. Epping, F. A. E. Kruyt, and G. Giaccone Apoptosis: Target of Cancer Therapy Clin. Cancer Res., July 1, 2002; 8(7): 2024 - 2034. [Abstract] [Full Text] [PDF]
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F. Guo, R. Nimmanapalli, S. Paranawithana, S. Wittman, D. Griffin, P. Bali, E. O'Bryan, C. Fumero, H. G. Wang, and K. Bhalla Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis Blood, May 1, 2002; 99(9): 3419 - 3426. [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; 20(4): 1063 - 1068. [Abstract] [Full Text] [PDF]
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 P. Fortugno, N. R. Wall, A. Giodini, D. S. O'Connor, J. Plescia, K. M. Padgett, S. Tognin, P. C. Marchisio, and D. C. Altieri Survivin exists in immunochemically distinct subcellular pools and is involved in spindle microtubule function J. Cell Sci., January 2, 2002; 115(3): 575 - 585. [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; 93(20): 1541 - 1552. [Abstract] [Full Text] [PDF]
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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. Mesri, M. Morales-Ruiz, E. J. Ackermann, C. F. Bennett, J. S. Pober, W. C. Sessa, and D. C. Altieri Suppression of Vascular Endothelial Growth Factor-Mediated Endothelial Cell Protection by Survivin Targeting Am. J. Pathol., May 1, 2001; 158(5): 1757 - 1765. [Abstract] [Full Text] [PDF]
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 A. O'Brate, M. Tarón, D. Gandara, and R. Rosell Sharing New Approaches to Translational Research in Non-Small Cell Lung Cancer Oncologist, December 1, 2000; 5(6): 514 - 519. [Full Text]
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D. P. Banks, J. Plescia, D. C. Altieri, J. Chen, S. H. Rosenberg, H. Zhang, S.-C. Ng;, E. M. Conway, D. Collen, and A. Schuh Survivin does not inhibit caspase-3 activity Blood, December 1, 2000; 96(12): 4002 - 4003. [Full Text] [PDF]
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G. M. Kasof and B. C. Gomes Livin, a Novel Inhibitor of Apoptosis Protein Family Member J. Biol. Chem., January 26, 2001; 276(5): 3238 - 3246. [Abstract] [Full Text] [PDF]
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W. H. Hoffman, S. Biade, J. T. Zilfou, J. Chen, and M. Murphy Transcriptional Repression of the Anti-apoptotic survivin Gene by Wild Type p53 J. Biol. Chem., January 25, 2002; 277(5): 3247 - 3257. [Abstract] [Full Text] [PDF]
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 C. S. Detweiler, D. B. Cunanan, and S. Falkow Host microarray analysis reveals a role for the Salmonella response regulator phoP in human macrophage cell death PNAS, May 8, 2001; 98(10): 5850 - 5855. [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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