Cancer Research Meeting Calendar Protein Translation and Cancer
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
[Cancer Research 59, 4200-4203, September 1, 1999]
© 1999 American Association for Cancer Research
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yu, D.-C.
Right arrow Articles by Henderson, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yu, D.-C.
Right arrow Articles by Henderson, D. R.
[Cancer Research 59, 4200-4203, September 1, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

The Addition of Adenovirus Type 5 Region E3 Enables Calydon Virus 787 to Eliminate Distant Prostate Tumor Xenografts

De-Chao Yu, Yu Chen, Monica Seng, Jeanette Dilley and Daniel R. Henderson1

Calydon, Inc., Sunnyvale, California 94089


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
CV787, a novel highly prostate-specific replication-competent adenovirus with improved efficacy, was constructed. CV787 contains the prostate-specific rat probasin promoter, driving the adenovirus type 5 (Ad5) E1A gene, and the human prostate-specific enhancer/promoter, driving the E1B gene. To improve efficacy, we constructed CV787 such that it also contains the entire Ad5 E3 region. CV787 replicates in prostate-specific antigen (PSA)+ cells as well as wild-type adenovirus, but in PSA- cells, CV787 replicates 104–105 times less efficiently. CV787 destroys PSA+ prostate cancer cells 10,000 times more efficiently than PSA- cells. Incorporation of the Ad5 E3 region significantly improves the target cell killing ability or efficacy of CV787. In nu/nu mice carrying s.c. LNCaP xenografts, a single i.v. tail vein injection of CV787 eliminates 300-mm3 tumors within 4 weeks. CV787 could be a powerful therapeutic for human metastatic prostate cancer.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
Prostatic cancer is the second leading cause of cancer-related deaths in men in the United States (39,000 deaths in 1998; Ref. 1 ). Current treatment for metastatic prostate cancer is androgen ablation therapy, which, in 70% of men, provides relief from otherwise uncontrollable bone pain and increases life expectancy by 6–18 months. Clearly, a new approach to metastatic prostate cancer treatment is needed (2, 3, 4) .

We previously constructed a prostate-specific ARCA,2 CN706, in which the Ad5 E1A gene is driven by PSE (5 , 6) . CN706 destroys human PSA+ cells 400 times more efficiently than PSA- cells and eliminates LNCaP xenografts in nu/nu mice with a single i.t. injection. To improve the specificity of CN706, we placed both the Ad5 E1A and E1B genes under the control of prostate-specific transcriptional regulatory elements. CV764 contains the PSE, driving the Ad5 E1A gene, and the promoter/enhancer of a second human prostate-specific gene, the hKLK2 gene, driving the Ad5 E1B gene. CV764 destroys PSA+ cells 10,000 times more efficiently than PSA- cells and cannot productively infect PSA- cells (7) . However, CN706 and CV764 could not eliminate distant preexistent LNCaP xenograft tumors in nu/nu mice by i.v. tail vein administration (data not shown).

To improve efficacy by systemic i.v. administration, we, led by preliminary evidence (data not shown), restored the Ad5 E3 region (nucleotides 28133–30818). The E3 region had been deleted in both CN706 and CV764 (6, 7, 8) . The E3 region has long been considered unnecessary for replication of adenovirus in vitro and has been universally deleted from Ad5 gene therapy constructs until recent efforts to reduce the immune response to the vector (9, 10, 11, 12, 13, 14) . The Ad5 E3 region encodes proteins that play a role in assisting virus release and evading or slowing host immune responses to the virus (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25) . CV764 did not have the genome space required to include the entire E3 region, but we wished to retain the specificity of using two independent prostate-specific transcriptional regulatory elements driving the Ad5 E1A and E1B genes. Thus, we constructed CV787 using the rat probasin prostate-specific promoter (26, 27, 28) , driving the E1A gene, and the PSE, driving the E1B gene, and retained the entire Ad5 E3 region. The CV787 genome length is 105% the length of wt Ad5, yet the virus replicates well and is completely stable. CV787 is an ARCA that replicates like wt Ad5 in cells that express PSA but is attenuated 10,000-100,000 times, with respect to replication in PSA- cells. CV787 is highly cytopathogenic in PSA+ cells and is capable of eliminating distantly located preexisting prostate tumors following i.v. injection.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Virus Constructions.
CV787 was constructed by insertion of the rat probasin promoter and the human PSE, driving the Ad5 E1A and E1B genes, respectively. pXC1, pBHG10, and pBHGE3 were purchased from Microbix Biosystems (Ontario, Canada; Refs. 8 and 29 ). pXC1 contains the Ad5 bp 22-5790, including the inverted terminal repeat, the packaging sequence, and the E1A and E1B genes inserted into pBR322 (29) . pBHGE3 contains the entire Ad5 genome, except for a deletion between Ad5 bp 188 and 1339, inserted into pBR322 (8) . pBHG10 is similar to pBHGE3, except that it is E3 deleted ({Delta}Ad5, nucleotides 28133–30818). pXC1 was modified to contain an AgeI site at bp 547 between the E1A mRNA cap site and the E1A translation initiation site by inserting a T between Ad5 bp 551 and 552, yielding CP95 (6) . CP95 was modified to create an EagI site at Ad5 bp 1681 between the E1B promoter and the E1B mRNA cap site. The EagI site was created by inserting a G between Ad5 bp 1681 and 1682 into CP95 using overlap PCR with the following two sets of primers. The first set [primer i, 5' -TCGTCTTCAAGAATTCTC-3'; and primer ii, 5' -GCCCACGGCCGCATTATATAC-3'; EagI site is italicized), amplifies a 2090-bp fragment in CP95, and the second set (primer iii, 5'-GTATATAATGCGGCCGTGGGC-3'; and primer iv, 5'-CCAGAAAATCCAGCAGGTACC-3'), amplifies a 399-bp fragment from the same plasmid. The two PCR products were annealed in equal molar ratios and used as template for PCR with primers i and iv. The 2468-bp overlap product was digested with EcoRI and KpnI and ligated to similarly cut CP95, creating CP124. CP125 was constructed by cloning the PSA 5'-flanking sequence, containing the enhancer domain from -5322 to -3875 from the transcription start site and the promoter from -230 to +7, into the EagI site of CP124 (6) . CP257 was constructed by cloning the rat probasin promoter (positions -426 to +28; Ref. 26 ) into the AgeI site of CP125. The rat probasin promoter was amplified by PCR from rat genomic DNA (Clontech, Palo Alto, CA) with primers (5' -GATCACCGGTAAGCTTCCACAAGTGCATTTAGCC-3' and 5' -GATCACCGGTCTGTAGGTATCTGGACCTCACTG-3') containing AgeI sites (italicized). The PCR product was digested with PinAI (an isoschizomer of AgeI) and cloned into a similarly cut CP125, creating CP257. CV739, CV787, and CV802 were generated by homologous recombinations of CP257 and pBHG10, CP257 and pBHGE3, and pXC1 and pBHGE3, respectively (8 , 10 , 30) . Fig. 1Citation shows the structures of CN702, CN706, CV739, CV787, and CV802. Viruses were grown and purified as described previously (6 , 7) . The particle:pfu ratio of all viruses was 20:1.



View larger version (30K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Structure of viruses. CN706 contains the PSE, driving the Ad5 E1A gene, but is Ad5 E3 region deleted; CV739 contains the rat probasin promoter, driving the Ad5 E1A gene, and the PSE, driving the Ad5 E1B gene, but is Ad5 E3 region deleted; CV787 is identical to CV739 but contains the Ad5 E3 region; and CV802 is a constructed wt Ad5 containing a normal Ad5 E1 region and a normal Ad5 E3 region.

 
Cell Culture.
Cells were obtained and maintained as described previously (6 , 7) . Plaque assays were determined as described previously (6 , 7) . Burst sizes of CN706, CV739, CV787, and CV802 (wt Ad5) in PSA+ and PSA- cells were determined as follows. Cell monolayers (2 x 105 cells/well) in six-well plates were inoculated with 4 x 105 pfu of CN706, CV739, CV787, or CV802 (wt Ad5; Refs. 7 and 8 ). Virus yields were titrated at 48 h after infection. Cells were infected in duplicate; assays were carried out in triplicate.

One-step growth curves of CV787 and CV802 (wt Ad5) were performed in human microvascular endothelial cell (hMVEC) monolayers. Monolayers of hMVEC cells were infected at a multiplicity of 2 pfu/cell with either CV787 or CV802 (wt Ad5). At the indicated times thereafter, duplicate cell samples were harvested and lysed by three cycles of freeze-thawing, and the virus in the supernatants was assayed in triplicate in 293 cell monolayers. One-step growth curves of CV787 in LNCaP cells using medium containing charcoal-stripped serum with or without R1881 (methyltrienolone) were performed similarly. Cytopathogenity of CV787 and CV802 (wt Ad5) was also determined in hMVEC monolayers, as described previously (7)

Cell survival of PSA+ and PSA- cells infected with either CV787 or CV802 (wt Ad5) was determined. Monolayers of LNCaP, HBL-100, and OVCAR-3 cells were infected at a multiplicity of 1 pfu/cell with either CV787 or CV802 (Ad5). Cell survival (viability) comparing the effect of the E3 region with CV739 and CV787 in LNCaP cells was assessed by measuring mitochondrial activity using MTT (17) .

In Vivo Animal Experiments.
LNCaP xenograft tumors in nu/nu were induced in 6–7-week-old BALB/c nu/nu mice and allowed to grow to an average volume of 300 mm3 (6) . Fifty µl of CV787 in PBS-10% glycerol or PBS-10% glycerol alone were injected into the tail vein. Tumor size was measured weekly, as described previously (6) . Serum samples were collected by tail vein incision. PSA levels were measured using an immunoassay kit (Genzyme Diagnostics, San Carlos, CA).


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
Specificity of CV787.
The target cell specificity of CV787, relative to that of wt Ad5, was tested in Ad5 E1A+ and E1B+ 293 cells, PSA+ human LNCaP prostate cells, and a panel of PSA- cells, including human breast epithelial HBL-100 cells, ovarian cancer OVCAR-3 cells, and PA-1 cells. Fig. 2Citation shows the 48-h burst sizes of CN706, CV739, CV787, and CV802 (wt Ad5). The burst size of CV802 (wt Ad5) in these cells ranged from 3 x 103 to 2 x 104, and the burst size of CN706 ranged from 3 x 103 to 1 x 104 in 293 cells and the PSA+ cell line LNCaP; however, in all PSA- cell lines, the burst size ranged from 1 x 101 to 8 x 101. The burst sizes of CV739 and CV787 were ~ 104 in 293 cells and the PSA+ cell line LNCaP and were less than 1 to 1 x 10-2 in all PSA- cell lines. Failure of CV787 to reach a burst size of 1 by 48 h following infection with a multiplicity of 2 indicates an essentially complete inability to replicate in cells lacking transcription factors that are capable of interacting with PSE. CV787 is capable of replicating but to an extremely limited extent in PSA- cells, as shown by its growth curve in hMVEC cells (Fig. 3)Citation . In these cells, CV787 replicated 10–20-fold during 4 days following infection with a multiplicity of 2 pfu/cell, but in which the burst size, in agreement with the results presented above, failed to reach 1. In contrast, CV802 (wt Ad5) replicated 106-fold and reached a burst size of 104.



View larger version (51K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Burst sizes of CN706, CV739, CV787, and CV802 (wt Ad5) in PSA+ and PSA- cells. Cells were infected at a multiplicity of infection of 2, virus was harvested 48 h after infection, and virus yield was determined by plaque assay on 293 cells.

 


View larger version (20K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 3. Growth curves of CV787 and CV802 (wt Ad5) in hMVEC cells. Cells were infected at a multiplicity of infection of 2, virus was harvested at indicated times after infection, and virus yield was determined by plaque assay on 293 cells.

 
Specificity of CV787 was also shown by cell survival of PSA- HBL-100 and OVCAR-3 cells, as measured by the MTT assay, compared with the destruction of PSA+ LNCaP cells. Whereas CV802 destroyed all three cell types, CV787 only destroyed PSA+ LNCaP cells (data not shown). Specific cell destruction was also measured in hMVEC monolayers infected for 10 days with multiplicities ranging from 0.01 to 10. Data similar to those previously published for CV764 (7) show that, even at an infecting multiplicity of 0.01, CV802 (wt Ad5) caused very substantial cytopathic effects; in contrast, CV787 caused minimal cytopathic effects in 10 days, even at an infecting multiplicity of 10 (data not shown). Together, these results confirm the conclusion that CV787 is almost totally attenuated for PSA- cells but replicates normally in PSA+ cells.

Increased Efficacy of CV787 Due to the Ad5 E3 region.
The increased efficacy resulting from the incorporation of the Ad5 E3 region was first shown by in vitro tests. A representative plaque assay of CV739 (E3-) and CV787 (E3+) on 293 cells is shown in Fig. 4Citation . Plaques of E3-deleted Ad5 are substantially smaller and less distinct than those of E3-containing adenovirus 10 days after infection. Plaques of CV787 appear more than 3-fold larger than plaques of CV739. E3- CN702 and E3- CN706 produced plaques similar to those shown for E3- CV739, whereas E3+ CV802 produced plaques similar to those shown for E3+ CV787 (data not shown). A similar picture of efficacy emerged when LNCaP cell survival was assessed by measuring mitochondrial activity (17) . CV787 completely eliminated mitochondrial activity 7 days after infection, whereas CV739 cells still had 67% the mitochondrial activity of uninfected cells 7 days after infection (Fig. 5)Citation .



View larger version (85K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 4. Plaque morphology of CV739 and CV787. 293 cells were infected with CV739 and CV787. After a 4-h adsorption period, plates were overlayed with agar and incubated for 10 days. After 10 days, the agar overlay was removed, and the cells were stained with crystal violet.

 


View larger version (20K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 5. Comparison of CV739 and CV787 on mitochondrial activity of infected LNCaP cells. Cells were infected with CV739 and CV787 at a multiplicity of infection of 1, and mitochondrial activity was measured by the MTT assay at the indicated time intervals.

 
The increased efficacy of incorporation of the Ad5 E3 region was also shown in vivo, as measured in the LNCaP nu/nu mouse xenograft model. BALB/c nu/nu mice harboring s.c. 300-mm3 LNCaP xenografts located on the back were injected either i.t. or i.v. into their tail veins with either vehicle (50 µl of PBS-10% glycerol) or the same volume of vehicle containing CN706, CV739, or CV787. Fig. 6Citation shows the result of a single i.t. treatment of LNCaP tumors with 1 x 108 particles/mm3 tumor CN706 or 1 x 106 particles/mm3 tumor CV787. Both viruses yielded the same degree of tumor reduction, implying a 100-fold increase in efficacy of CV787, compared with CN706. In addition, 1 x 108 particles/mm3 tumor CV787 completely eliminated LNCaP tumors by a single i.t. injection (data not shown). Differential efficacy toward LNCaP tumors between CV739 and CV787 was also shown following a single i.v. administration of 5 x 1010 particles. Fig. 7Citation shows that CV739 could stop tumor growth at this dose level but that CV787 caused a 4-fold reduction in tumor volume.



View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 6. Comparison of CN706 and CV787 i.t. injection activity toward LNCaP xenografts. nu/nu mice with s.c. LNCaP tumors (average size, 300 mm3) were injected once into the tumor with 1 x 108 particles/mm3 tumor of CN706 or 1 x 106 particles/mm3 tumor of CV787.

 


View larger version (20K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 7. Comparison of CV739 and CV787 i.v. injection activity toward LNCaP xenografts. nu/nu mice with s.c. LNCaP tumor xenografts (average size, 300 mm3) were injected once into the tail vein with 5 x 1010 particles of CV739 or CV787.

 
i.v. Administration of CV787.
Perhaps most importantly, CV787 could eliminate preexistent distantly located LNCaP tumors. Six weeks following a single i.v. injection of 1 x 1011 CV787 particles, the sizes of the tumors were reduced to less than 5% of their original size (Fig. 8A)Citation , and 8 of 14 mice were visually free of tumors. Those tumors that were still present were immunohistologically devoid of PSA (data not shown). The serum PSA levels in mice injected with buffer increased (Fig. 8B)Citation , whereas the levels in mice injected with CV787 decreased to ~5% of their starting values within 3 weeks. Virus replication within LNCaP xenografts could be shown at both 7 and 28 days after injection, as evidenced by Ad5 immunostaining (Fig. 8C)Citation . As controls, similar experiments were carried out with nu/nu mice carrying LoVo (colon cancer) or Hep3B (hepatoma) xenografts. These xenografts continued to grow normally following tail vein injection of CV787 (data not shown).



View larger version (81K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 8. LNCaP xenograft tumors in nu/nu mice following one i.v. tail vein injection of CV787. A, tumor size, measured weekly. B, serum PSA, measured weekly by immunoassay. C, replication of adenovirus in LNCaP tumors determined by immunohistochemistry with rabbit polycolonal antibody to Ad5.

 
Finally, hormone-refractory patients continue hormone therapy, even if such hormone ablation therapy is no longer effective (2 , 3) . If CV787 is to be considered to treat end-stage metastatic hormone-refractory prostate cancer, it is important to know whether CV787 can grow in the absence of testosterone. Fig. 9Citation shows the one-step growth curve of CV787 in LNCaP cells in the presence of the stable but biologically active testosterone analogue R1881 at 1 nM and in the absence of R1881. CV787 grows normally in the absence of R1881 and achieved a burst size in excess of 104 pfu/cell.



View larger version (20K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 9. Growth of CV787 in LNCaP cells with or without R1881. LNCaP cells were infected with CV787 at a multiplicity of infection of 2. Following adsorption, the cells were washed twice with PBS, and medium with or without R1881 was added. Duplicate cultures were harvested at the indicated time points and subjected to three cycles of freeze-thaw, and virus titers were determined in triplicate on 293 cells.

 
In summary, CV787 is an ARCA that replicates like wt Ad5 in cells that express PSA but that is attenuated 10,000–100,000-fold with respect to replication in PSA- cells. CV787 is highly cytopathogenic in PSA+ cells and is capable of eliminating distantly located preexisting prostate tumors following i.v. injection. The addition of the Ad5 E3 region increases efficacy 10–100-fold both in vitro and in vivo. Furthermore, CV787 with the complete E3 region can be expected to resist many of the host antiviral MHC-1 defense mechanisms of wt Ad5 (15, 16, 17 , 25) . Finally, CV787 can replicate normally in the absence of testosterone and could, thereby, help patients continuing hormonal ablation therapy. CV787 is a potentially powerful therapeutic for human metastatic cancer.


   ACKNOWLEDGMENTS
 
We thank Young Kim, Heather Conners, and Andy Little for technical assistance. We also thank Dr. W.K. Joklik for suggestions in preparing and editing the manuscript.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Calydon Inc., 1324 Chesapeake Terrace, Sunnyvale, CA 94089. Phone: (408) 734-0733; Fax: (408) 734-2808; E-mail: dhenderson{at}calydon.com Back

2 The abbreviations used are: ARCA, attenuated replication-competent adenovirus; Ad5, adenovirus type 5; P, virus particle; PSA, prostate-specific antigen; PSE, PSA promoter and enhancer; i.t., intratumoral(ly); wt, wild-type; pfu, plaque-forming unit(s); MTT, 3-[4,5-dimethylthiazole-2–4]-2,5-diphenyl-2H-tetrazolium bromide. Back

Received 4/21/99. Accepted 7/20/99.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

  1. Landis S. H., Murray T., Bolden S., Wingo P. A. Cancer statistics, 1998. CA Cancer J. Clin., 48: 6-29, 1998.[Abstract]
  2. Small E. J. Prostate cancer, incidence, management and outcomes. Drugs Aging, 13: 71-81, 1998.[Medline]
  3. Bare R. L., Torti F. M. Endocrine therapy of prostate cancer. Cancer Treat Res., 94: 69-87, 1998.[Medline]
  4. Tyrrell C. J., Kaisary A. V., Iversen P., Anderson J. B., Baert L., Tammela T., Chamberlain M., Webster A., Blackledge G. A randomised comparison of "Casodex" (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur. Urol., 33: 447-456, 1998.[Medline]
  5. Schuur E. R., Henderson G. A., Kmetec L. A., Miller J. D., Lamparski H. G., Henderson D. R. Prostate-specific antigen expression in regulated by an upstream enhancer. J. Biol. Chem., 271: 7043-7051, 1996.[Abstract/Free Full Text]
  6. Rodriguez R., Schuur E. R., Lim H. Y., Henderson G. A., Simons J. W., Henderson D. R. Prostate-attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen positive prostate cancer cells. Cancer Res., 57: 2559-2563, 1997.[Abstract/Free Full Text]
  7. Yu D-C., Sakamoto G. T., Henderson D. R. Identification of the transcriptional regulatory sequences of human kallikrein 2 and their use in the construction of calydon virus 764, an attenuated replication competent adenovirus for prostate cancer therapy. Cancer Res., 59: 1498-1504, 1999.[Abstract/Free Full Text]
  8. Bett A. J., Haddara W., Prevec L., Graham F. L. An efficient and flexible system for construction of adenovirus vectors with insertions or deletions in early regions 1 and 3. Proc. Natl. Acad. Sci. USA, 91: 8802-8806, 1994.[Abstract/Free Full Text]
  9. Haj-Ahmad Y., Graham F. L. Development of a helper-independent human adenovirus vector and its use in the transfer of the herpes simplex virus thymidine kinase gene. J. Virol., 57: 267-274, 1986.[Abstract/Free Full Text]
  10. Ghosh-Choudhury G., Haj-Ahmad Y., Brinkley P., Rudy J., Graham F. L. Human adenovirus cloning vectors based on infectious bacterial plasmids. Gene, 50: 161-171, 1986.[Medline]
  11. Graham F. L. Adenoviruses as expression vectors and recombinant vaccines. Trends Biotechnol., 8: 85-87, 1990.[Medline]
  12. Robbins P. D., Tahara H., Ghivizzani S. C. Viral vectors for gene therapy. Trends Biotechnol., 16: 35-40, 1998.[Medline]
  13. Wivel N. A., Wilson J. M. Methods of gene delivery. Hematol. Oncol. Clin. North Am., 12: 483-501, 1998.[Medline]
  14. Ilan Y., Droguett G., Chowdhury N. R., Li Y., Sengupta K., Thummala N. R., Davidson A., Chowdhury J. R., Horwitz M. S. Insertion of the adenoviral E3 region into a recombinant viral vector prevents antiviral humoral and cellular immune responses and permits long-term gene expression. Proc. Natl. Acad. Sci. USA, 94: 2587-2592, 1997.[Abstract/Free Full Text]
  15. Ginsberg H. S., Lundholm-Beauchamp U., Horswood R. L., Pernis B., Wold W. S., Chanock R. M., Prince G. A. Role of early region 3 (E3) in pathogenesis of adenovirus disease. Proc. Natl. Acad. Sci. USA, 86: 3823-3827, 1989.[Abstract/Free Full Text]
  16. Wold W. S., Tollefson A. E., Hermiston T. W. E3 transcription unit of adenovirus. Curr. Top. Microbiol. Immunol., 199: 237-274, 1995.
  17. Tollefson A. E., Ryerse J. S., Scaria A., Hermiston T. W., Wold W. S. The E3-11.6-kDa adenovirus death protein (ADP) is required for efficient cell death: characterization of cells infected with adp mutants. Virology, 220: 152-162, 1996.[Medline]
  18. Tollefson A. E., Scaria A., Hermiston T. W., Ryerse J. S., Wold L. J., Wold W. S. The adenovirus death protein (E3-11.6K) is required at very late stages of infection for efficient cell lysis and release of adenovirus from infected cells. J. Virol., 70: 2296-2306, 1996.[Abstract]
  19. Hausmann J., Ortmann D., Witt E., Veit M., Seidel W. Adenovirus death protein, a transmembrane protein encoded in the E3 region, is palmitoylated at the cytoplasmic tail. Virology, 244: 343-351, 1998.[Medline]
  20. Korner H., Burgert H. G. Down-regulation of HLA antigens by the adenovirus type 2 E3/19K protein in a T-lymphoma cell line. J. Virol., 68: 1442-1448, 1994.[Abstract/Free Full Text]
  21. Flomenberg P., Gutierrez E., Hogan K. T. Identification of class I MHC regions which bind to the adenovirus E3-19k protein. Mol. Immunol., 31: 1277-1284, 1994.[Medline]
  22. Li Y., Kang J., Horwitz M. S. Interaction of an adenovirus E3 14.7-kilodalton protein with a novel tumor necrosis factor {alpha}-inducible cellular protein containing leucine zipper domains. Mol. Cell. Biol., 18: 1601-1610, 1998.[Abstract/Free Full Text]
  23. Elsing A., Burgert H. G. The adenovirus E3/10.4K-14.5K proteins down-modulate the apoptosis receptor Fas/Apo-1 by inducing its internalization. Proc. Natl. Acad. Sci. USA, 95: 10072-10077, 1998.[Abstract/Free Full Text]
  24. Dimitrov T., Krajcsi P., Hermiston T. W., Tollefson A. E., Hannink M., Wold W. S. Adenovirus E3-10.4K/14.5K protein complex inhibits tumor necrosis factor-induced translocation of cytosolic phospholipase A2 to membranes. J. Virol., 71: 2830-2837, 1997.[Abstract]
  25. Vinogradova O., Carlin C., Sonnichsen F. D., Sanders C. R., II present in the adenovirus E3-13.7 protein which down-regulates the epidermal growth factor receptor. J. Biol. Chem., 273: 17343-17350, 1998.[Abstract/Free Full Text]
  26. Greenberg N. M., DeMayo F. J., Sheppard P. C., Barrios R., Lebovitz R., Finegold M., Angelopoulou R., Dodd J. G., Duckworth M. L., Rosen J. M., Matusik R. J. The rat probasin gene promoter directs hormonally and developmentally regulated expression of a heterologous gene specifically to the prostate in transgenic mice. Mol. Endocrinol., 8: 230-239, 1994.[Abstract/Free Full Text]
  27. Yan Y., Sheppard P. C., Kasper S., Lin L., Hoare S., Kapoor A., Dodd J. G., Duckworth M. L., Matusik R. J. Large fragment of the probasin promoter targets high levels of transgene expression to the prostate of transgenic mice. Prostate, 32: 129-139, 1997.[Medline]
  28. Brookes D. E., Zandvliet D., Watt F., Russell P. J., Molloy P. L. Relative activity and specificity of promoters from prostate-expressed genes. Prostate, 35: 18-26, 1998.[Medline]
  29. McKinnon R. D., Bacchetti S., Graham F. L. Tn5 mutagenesis of the transforming genes of human adenovirus type 5. Gene, 19: 33-42, 1982.[Medline]
  30. Graham F. L., Smiley J., Russell W. C., Nairn R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J. Gen. Virol., 36: 59-74, 1977.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Cancer Res.Home page
L. R. Paiva, C. Binny, S. C. Ferreira Jr., and M. L. Martins
A Multiscale Mathematical Model for Oncolytic Virotherapy
Cancer Res., February 1, 2009; 69(3): 1205 - 1211.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
E. V. Shashkova, K. Doronin, J. S. Senac, and M. A. Barry
Macrophage Depletion Combined with Anticoagulant Therapy Increases Therapeutic Window of Systemic Treatment with Oncolytic Adenovirus
Cancer Res., July 15, 2008; 68(14): 5896 - 5904.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. Leja, H. Dzojic, E. Gustafson, K. Oberg, V. Giandomenico, and M. Essand
A Novel Chromogranin-A Promoter-Driven Oncolytic Adenovirus for Midgut Carcinoid Therapy
Clin. Cancer Res., April 15, 2007; 13(8): 2455 - 2462.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
G. Glockzin, K. Mantwill, K. Jurchott, A. Bernshausen, A. Ladhoff, H.-D. Royer, B. Gansbacher, and P. S. Holm
Characterization of the Recombinant Adenovirus Vector AdYB-1: Implications for Oncolytic Vector Development.
J. Virol., April 1, 2006; 80(8): 3904 - 3911.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
N. Ramesh, Y. Ge, D. L. Ennist, M. Zhu, M. Mina, S. Ganesh, P. S. Reddy, and D.-C. Yu
CG0070, a Conditionally Replicating Granulocyte Macrophage Colony-Stimulating Factor-Armed Oncolytic Adenovirus for the Treatment of Bladder Cancer
Clin. Cancer Res., January 1, 2006; 12(1): 305 - 313.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Y. Li, N. Idamakanti, T. Arroyo, S. Thorne, T. Reid, S. Nichols, M. VanRoey, G. Colbern, N. Nguyen, O. Tam, et al.
Dual Promoter-Controlled Oncolytic Adenovirus CG5757 Has Strong Tumor Selectivity and Significant Antitumor Efficacy in Preclinical Models
Clin. Cancer Res., December 15, 2005; 11(24): 8845 - 8855.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
X. Li, J. Zhang, H. Gao, E. Vieth, K.-H. Bae, Y.-P. Zhang, S.-J. Lee, S. Raikwar, T. A. Gardner, G. D. Hutchins, et al.
Transcriptional targeting modalities in breast cancer gene therapy using adenovirus vectors controlled by {alpha}-lactalbumin promoter
Mol. Cancer Ther., December 1, 2005; 4(12): 1850 - 1859.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
M. Zhu, J. A. Bristol, Y. Xie, M. Mina, H. Ji, S. Forry-Schaudies, and D. L. Ennist
Linked Tumor-Selective Virus Replication and Transgene Expression from E3-Containing Oncolytic Adenoviruses
J. Virol., May 1, 2005; 79(9): 5455 - 5465.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
X. Li, Y.-P. Zhang, H.-S. Kim, K.-H. Bae, K. M. Stantz, S.-J. Lee, C. Jung, J. A. Jimenez, T. A. Gardner, M.-H. Jeng, et al.
Gene Therapy for Prostate Cancer by Controlling Adenovirus E1a and E4 Gene Expression with PSES Enhancer
Cancer Res., March 1, 2005; 65(5): 1941 - 1951.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Y. Wang, S. Thorne, J. Hannock, J. Francis, T. Au, T. Reid, N. Lemoine, D. Kirn, and G. Hallden
A Novel Assay to Assess Primary Human Cancer Infectibility by Replication-Selective Oncolytic Adenoviruses
Clin. Cancer Res., January 1, 2005; 11(1): 351 - 360.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. L. Chu, D. E. Post, F. R. Khuri, and E. G. Van Meir
Use of Replicating Oncolytic Adenoviruses in Combination Therapy for Cancer
Clin. Cancer Res., August 15, 2004; 10(16): 5299 - 5312.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
K. Toth, H. Djeha, B. Ying, A. E. Tollefson, M. Kuppuswamy, K. Doronin, P. Krajcsi, K. Lipinski, C. J. Wrighton, and W. S. M. Wold
An Oncolytic Adenovirus Vector Combining Enhanced Cell-to-Cell Spreading, Mediated by the ADP Cytolytic Protein, with Selective Replication in Cancer Cells with Deregulated Wnt Signaling
Cancer Res., May 15, 2004; 64(10): 3638 - 3644.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Q. Huang, X. Zhang, H. Wang, B. Yan, J. Kirkpatrick, M. W. Dewhrist, and C.-Y. Li
A Novel Conditionally Replicative Adenovirus Vector Targeting Telomerase-Positive Tumor Cells
Clin. Cancer Res., February 15, 2004; 10(4): 1439 - 1445.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
L. Barzon, M. Boscaro, and G. Palu
Endocrine Aspects of Cancer Gene Therapy
Endocr. Rev., February 1, 2004; 25(1): 1 - 44.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. Jounaidi and D. J. Waxman
Use of Replication-Conditional Adenovirus as a Helper System to Enhance Delivery of P450 Prodrug-Activation Genes for Cancer Therapy
Cancer Res., January 1, 2004; 64(1): 292 - 303.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
Y. Li, Y. Chen, J. Dilley, T. Arroyo, D. Ko, P. Working, and D.-C. Yu
Carcinoembryonic antigen-producing cell-specific oncolytic adenovirus, OV798, for colorectal cancer therapy
Mol. Cancer Ther., October 1, 2003; 2(10): 1003 - 1009.
[Abstract] [Full Text]

Home page
 Cancer Res.Home page
G. W. Demers, D. E. Johnson, V. Tsai, S.-F. Wen, E. Quijano, T. Machemer, J. Philopena, M. Ramachandra, J. A. Howe, P. Shabram, et al.
Pharmacologic Indicators of Antitumor Efficacy for Oncolytic Virotherapy
Cancer Res., July 15, 2003; 63(14): 4003 - 4008.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
S. P. Balk, Y.-J. Ko, and G. J. Bubley
Biology of Prostate-Specific Antigen
J. Clin. Oncol., January 15, 2003; 21(2): 383 - 391.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
K. Suzuki, R. Alemany, M. Yamamoto, and D. T. Curiel
The Presence of the Adenovirus E3 Region Improves the Oncolytic Potency of Conditionally Replicative Adenoviruses
Clin. Cancer Res., November 1, 2002; 8(11): 3348 - 3359.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. M. Nettelbeck, A. A. Rivera, C. Balague, R. Alemany, and D. T. Curiel
Novel Oncolytic Adenoviruses Targeted to Melanoma: Specific Viral Replication and Cytolysis by Expression of E1A Mutants from the Tyrosinase Enhancer/Promoter
Cancer Res., August 15, 2002; 62(16): 4663 - 4670.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. Zhang, N. Ramesh, Y. Chen, Y. Li, J. Dilley, P. Working, and D.-C. Yu
Identification of Human Uroplakin II Promoter and Its Use in the Construction of CG8840, a Urothelium-specific Adenovirus Variant That Eliminates Established Bladder Tumors in Combination with Docetaxel
Cancer Res., July 1, 2002; 62(13): 3743 - 3750.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
K. A. Rauen, D. Sudilovsky, J. L. Le, K. L. Chew, B. Hann, V. Weinberg, L. D. Schmitt, and F. McCormick
Expression of the Coxsackie Adenovirus Receptor in Normal Prostate and in Primary and Metastatic Prostate Carcinoma: Potential Relevance to Gene Therapy
Cancer Res., July 1, 2002; 62(13): 3812 - 3818.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C.-L. Hsieh, L. Yang, L. Miao, F. Yeung, C. Kao, H. Yang, H. E. Zhau, and L. W. K. Chung
A Novel Targeting Modality to Enhance Adenoviral Replication by Vitamin D3 in Androgen-independent Human Prostate Cancer Cells and Tumors
Cancer Res., June 1, 2002; 62(11): 3084 - 3092.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
K. Tsukuda, R. Wiewrodt, K. Molnar-Kimber, V. P. Jovanovic, and K. M. Amin
An E2F-responsive Replication-selective Adenovirus Targeted to the Defective Cell Cycle in Cancer Cells: Potent Antitumoral Efficacy but No Toxicity to Normal Cell
Cancer Res., June 1, 2002; 62(12): 3438 - 3447.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
J. T. Mullen and K. K. Tanabe
Viral Oncolysis
Oncologist, April 1, 2002; 7(2): 106 - 119.
[Abstract] [Full Text] [PDF]

Home page
 J. Gen. Virol.Home page
C. J. A. Ring
Cytolytic viruses as potential anti-cancer agents
J. Gen. Virol., March 1, 2002; 83(3): 491 - 502.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. Li, D.-C. Yu, Y. Chen, P. Amin, H. Zhang, N. Nguyen, and D. R. Henderson
A Hepatocellular Carcinoma-specific Adenovirus Variant, CV890, Eliminates Distant Human Liver Tumors in Combination with Doxorubicin
Cancer Res., September 1, 2001; 61(17): 6428 - 6436.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Matsubara, Y. Wada, T. A. Gardner, M. Egawa, M.-S. Park, C.-L. Hsieh, H. E. Zhau, C. Kao, S. Kamidono, J. Y. Gillenwater, et al.
A Conditional Replication-competent Adenoviral Vector, Ad-OC-E1a, to Cotarget Prostate Cancer and Bone Stroma in an Experimental Model of Androgen-independent Prostate Cancer Bone Metastasis
Cancer Res., August 1, 2001; 61(16): 6012 - 6019.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. Chen, T. DeWeese, J. Dilley, Y. Zhang, Y. Li, N. Ramesh, J. Lee, R. Pennathur-Das, J. Radzyminski, J. Wypych, et al.
CV706, a Prostate Cancer-specific Adenovirus Variant, in Combination with Radiotherapy Produces Synergistic Antitumor Efficacy without Increasing Toxicity
Cancer Res., July 1, 2001; 61(14): 5453 - 5460.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
K. Doronin, M. Kuppuswamy, K. Toth, A. E. Tollefson, P. Krajcsi, V. Krougliak, and W. S. M. Wold
Tissue-Specific, Tumor-Selective, Replication-Competent Adenovirus Vector for Cancer Gene Therapy
J. Virol., April 1, 2001; 75(7): 3314 - 3324.
[Abstract] [Full Text]

Home page
 Cancer Res.Home page
T. P. Cripe, E. J. Dunphy, A. D. Holub, A. Saini, N. H. Vasi, Y. Y. Mahller, M. H. Collins, J. D. Snyder, V. Krasnykh, D. T. Curiel, et al.
Fiber Knob Modifications Overcome Low, Heterogeneous Expression of the Coxsackievirus-Adenovirus Receptor That Limits Adenovirus Gene Transfer and Oncolysis for Human Rhabdomyosarcoma Cells
Cancer Res., April 1, 2001; 61(7): 2953 - 2960.
[Abstract] [Full Text]

Home page
 Cancer Res.Home page
D.-C. Yu, Y. Chen, J. Dilley, Y. Li, M. Embry, H. Zhang, N. Nguyen, P. Amin, J. Oh, and D. R. Henderson
Antitumor Synergy of CV787, a Prostate Cancer-specific Adenovirus, and Paclitaxel and Docetaxel
Cancer Res., January 1, 2001; 61(2): 517 - 525.
[Abstract] [Full Text]

Home page
 J. Gen. Virol.Home page
W. C. Russell
Update on adenovirus and its vectors
J. Gen. Virol., November 1, 2000; 81(11): 2573 - 2604.
[Full Text]

Home page
 Clin. Cancer Res.Home page
D. T. Curiel
The Development of Conditionally Replicative Adenoviruses for Cancer Therapy
Clin. Cancer Res., September 1, 2000; 6(9): 3395 - 3399.
[Abstract] [Full Text]

Home page
 J. Virol.Home page
K. Doronin, K. Toth, M. Kuppuswamy, P. Ward, A. E. Tollefson, and W. S. M. Wold
Tumor-Specific, Replication-Competent Adenovirus Vectors Overexpressing the Adenovirus Death Protein
J. Virol., July 1, 2000; 74(13): 6147 - 6155.
[Abstract] [Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yu, D.-C.
Right arrow Articles by Henderson, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yu, D.-C.
Right arrow Articles by Henderson, D. R.

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