Abstract
To generate a replication-competent adenovirus (Ad) with specificity for melanoma, we constructed a tissue-specific promoter restricting E1A expression to melanoma cells. The combination of four copies of a mouse tyrosinase enhancer element (TE) fused to the human tyrosinase promoter (TP) yielded up to 2000-fold higher luciferase reporter activity in tyrosinase-expressing melanoma cells than in nonmelanoma cells. Insertion of the composite TETP construct upstream of the E1A gene was combined with deleting as far as possible the intertwined endogenous Ad enhancer/promoter (EP). The resulting AdΔEP–TETP vector, also deleted for the E3 region, was found to replicate in tyrosinase-positive melanoma cells, such as SK-Mel23 as efficiently as wild-type Ad5, but at a more than 50-fold reduced level in nonmelanoma tumour cells and primary human cells. Injection of AdΔEP–TETP into xenotransplanted melanomas, but not into HeLa-derived tumours led to long-lasting tumour regression in nude mice. This AdΔEP–TETP virus might be useful for the treatment of accessible lesions in advanced melanoma patients.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Landis SH, Murray T, Bolden S, Wingo PA . Cancer statistics, 1998. CA Cancer J Clin 1998; 48: 6–29.
Roth JA, Cristiano RJ . Gene therapy for cancer: what have we done and where are we going? J Natl Cancer Inst 1997; 89: 21–39.
Alemany R, Balague C, Curiel DT . Replicative adenoviruses for cancer therapy. Nat Biotechnol 2000; 18: 723–737.
Kirn D, Martuza RL, Zwiebel J . Replication-selective virotherapy for cancer: biological principles, risk management and future directions. Nat Med 2001; 7: 781–787.
Bischoff JR et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996; 274: 373–376.
Heise C et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nat Med 2000; 6: 1134–1139.
Rodriguez R et al. Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res 1997; 57: 2559–2563.
Chung RY, Saeki Y, Chiocca EA . B-myb promoter retargeting of herpes simplex virus gamma34.5 gene-mediated virulence toward tumor and cycling cells. J Virol 1999; 73: 7556–7564.
Hunter WD et al. Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation of intracerebral injection in nonhuman primates. J Virol 1999; 73: 6319–6326.
Todo T et al. Viral shedding and biodistribution of G207, a multimutated, conditionally replicating herpes simplex virus type 1, after intracerebral inoculation in aotus. Mol Ther 2000; 2: 588–595.
Coffey MC, Strong JE, Forsyth PA, Lee PW . Reovirus therapy of tumors with activated Ras pathway. Science 1998; 282: 1332–1334.
Stojdl DF et al. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat Med 2000; 6: 821–825.
Dummer R et al. Interferon resistance of cutaneous T-cell lymphoma-derived clonal T-helper 2 cells allows selective viral replication. Blood 2001; 97: 523–527.
Ganly I et al. A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res 2000; 6: 798–806.
Heise C, Lemmon M, Kirn D . Efficacy with a replication-selective adenovirus plus cisplatin-based chemotherapy: dependence on sequencing but not p53 functional status or route of administration. Clin Cancer Res 2000; 6: 4908–4914.
Khuri FR et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 2000; 6: 879–885.
Hallenbeck PL et al. A novel tumor-specific replication-restricted adenoviral vector for gene therapy of hepatocellular carcinoma. Hum Gene Ther 1999; 10: 1721–1733.
Kurihara T, Brough DE, Kovesdi I, Kufe DW . Selectivity of a replication-competent adenovirus for human breast carcinoma cells expressing the MUC1 antigen. J Clin Invest 2000; 106: 763–771.
Babiss LE, Friedman JM, Darnell Jr JE . Cellular promoters incorporated into the adenovirus genome. Effect of viral DNA replication on endogenous and exogenous gene transcription. J Mol Biol 1987; 193: 643–650.
Berkner KL . Expression of heterologous sequences in adenoviral vectors. Curr Top Microbiol Immunol 1992; 158: 39–66.
Shi Q, Wang Y, Worton R . Modulation of the specificity and activity of a cellular promoter in an adenoviral vector. Hum Gene Ther 1997; 8: 403–410.
Rubinchik S et al. Creation of a new transgene cloning site near the right ITR of Ad5 results in reduced enhancer interference with tissue-specific and regulatable promoters. Gene Ther 2001; 8: 247–253.
Hearing P, Shenk T . The adenovirus type 5 E1A transcriptional control region contains a duplicated enhancer element. Cell 1983; 33: 695–703.
Schmid SI, Hearing P . Bipartite structure and functional independence of adenovirus type 5 packaging elements. J Virol 1997; 71: 3375–3384.
Geertsen RC et al. Higher frequency of selective losses of HLA-A and -B allospecificities in metastasis than in primary melanoma lesions. J Invest Dermatol 1998; 111: 497–502.
Hemmi S et al. The presence of HCAR (human coxsackievirus and adenovirus receptor) is associated with efficient adenovirus-mediated transgene expression in human melanoma cell cultures. Hum Gene Ther 1998; 9: 2363–2373.
Fallaux FJ et al. Characterization of 911: a new helper cell line for the titration and propagation of early region 1-deleted adenoviral vectors. Hum Gene Ther 1996; 7: 215–222.
Bentley NJ, Eisen T, Goding CR . Melanocyte-specific expression of the human tyrosinase promoter: activation by the microphthalmia gene product and role of the initiator. Mol Cell Biol 1994; 14: 7996–8006.
Ganss R, Montoliu L, Monaghan AP, Schutz G . A cell-specific enhancer far upstream of the mouse tyrosinase gene confers high level and copy number-related expression in transgenic mice. EMBO J 1994; 13: 3083–3093.
Yasumoto K et al. Microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene. Mol Cell Biol 1994; 14: 8058–8070.
Haj-Ahmad Y, Graham FL . Development of a helper-independent human adenovirus vector and its use in the transfer of the herpes simplex virus thymidine kinase gene. J Virol 1986; 57: 267–274.
Maizel Jr JV, White DO, Scharff MD . The polypeptides of adenovirus. I. Evidence for multiple protein components in the virion and a comparison of types 2, 7A, and 12. Virology 1968; 36: 115–125.
Urosevic M et al. HLA-G protein up-regulation in primary cutaneous lymphomas is associated with interleukin-10 expression in large cell T-cell lymphomas and indolent B-cell lymphomas. Blood 2002; 99: 609–617.
Cormier JN et al. Comparative analysis of the in vivo expression of tyrosinase, MART- 1/Melan-A, and gp100 in metastatic melanoma lesions: implications for immunotherapy. J Immunother 1998; 21: 27–31.
Hofbauer GF et al. Tyrosinase immunoreactivity in formalin-fixed,paraffin-embedded primary and metastatic melanoma: frequency and distribution. J Cutan Pathol 1998; 25: 204–209.
Artuc M, Nurnberg W, Czarnetzki BM, Schadendorf D . Characterization of gene regulatory elements for selective gene expression in human melanoma cells. Biochem Biophys Res Commun 1995; 213: 699–705.
Hitt MM, Graham FL . Adenovirus E1A under the control of heterologous promoters: wide variation in E1A expression levels has little effect on virus replication. Virology 1990; 179: 667–678.
Hearing P, Shenk T . Functional analysis of the nucleotide sequence surrounding the cap site for adenovirus type 5 region E1A messenger RNAs. J Mol Biol 1983; 167: 809–822.
Hearing P, Samulski RJ, Wishart WL, Shenk T . Identification of a repeated sequence element required for efficient encapsidation of the adenovirus type 5 chromosome. J Virol 1987; 61: 2555–2558.
Zhang WW . Development and application of adenoviral vectors for gene therapy of cancer. Cancer Gene Ther 1999; 6: 113–138.
Graham FL, Prevec L . Manipulation of adenovirus vectors. In: Murray EJ (ed). Methods in Molecular Biology. 1991, pp 109–128. The Humana Press Inc., Clifton, NJ
Harlow E, Franza Jr BR, Schley C . Monoclonal antibodies specific for adenovirus early region 1A proteins: extensive heterogeneity in early region 1A products. J Virol 1985; 55: 533–546.
Stephens C, Harlow E . Differential splicing yields novel adenovirus 5 E1A mRNAs that encode 30 kD and 35 kD proteins. EMBO J 1987; 6: 2027–2035.
Doehn C, Jocham D . Technology evaluation: CN-706, Calydon Inc. Curr Opin Mol Ther 2000; 2: 703–708.
Park BJ et al. Augmentation of melanoma-specific gene expression using a tandem melanocyte-specific enhancer results in increased cytotoxicity of the purine nucleoside phosphorylase gene in melanoma. Hum Gene Ther 1999; 10: 889–898.
Diaz RM, Eisen T, Hart IR, Vile RG . Exchange of viral promoter/enhancer elements with heterologous regulatory sequences generates targeted hybrid long terminal repeat vectors for gene therapy of melanoma. J Virol 1998; 72: 789–795.
Siders WM, Halloran PJ, Fenton RG . Transcriptional targeting of recombinant adenoviruses to human and murine melanoma cells. Cancer Res 1996; 56: 5638–5646.
Steinwaerder DS, Lieber A . Insulation from viral transcriptional regulatory elements improves inducible transgene expression from adenovirus vectors in vitro and in vivo. Gene Ther 2000; 7: 556–567.
Jones SN, Tibbetts C . Upstream DNA sequences determine different autoregulatory responses of the adenovirus types 5 and 3 E1A promoters. J Virol 1989; 63: 1833–1838.
Shisler J et al. The adenovirus E3-10.4K/14.5 K complex mediates loss of cell surface Fas (CD95) and resistance to Fas-induced apoptosis. J Virol 1997; 71: 8299–8306.
Gooding LR et al. A 14,700 MW protein from the E3 region of adenovirus inhibits cytolysis by tumor necrosis factor. Cell 1988; 53: 341–346.
Yu DC et al. The addition of adenovirus type 5 region E3 enables calydon virus 787 to eliminate distant prostate tumor xenografts. Cancer Res 1999; 59: 4200–4203.
Tollefson AE et al. The adenovirus death protein (E3-11.6 K) is required at very late stages of infection for efficient cell lysis and release of adenovirus from infected cells. J Virol 1996; 70: 2296–2306.
Haninec P, Vachtenheim J . Tyrosinase protein is expressed also in some neural crest derived cells which are not melanocytes. Pigment Cell Res 1988; 1: 340–343.
Chi DD et al. Molecular detection of tumor-associated antigens shared by human cutaneous melanomas and gliomas. Am J Pathol 1997; 150: 2143–2152.
Chen Y, Yu DC, Charlton D, Henderson DR . Pre-existent adenovirus antibody inhibits systemic toxicity and antitumor activity of CN706 in the nude mouse LNCaP xenograft model: implications and proposals for human therapy. Hum Gene Ther 2000; 11: 1553–1567.
Greber UF . Signalling in viral entry. Cell Mol Life Sci 2002; 59: 608–626.
Russell WC . Update on adenovirus and its vectors. J Gen Virol 2000; 81: 2573–2604.
Trotman LC et al. Import of adenovirus DNA involves the nuclear pore complex receptor CAN/Nup214 and histone H1. Nat Cell Biol 2001; 3: 1092–1100.
Acknowledgements
We thank C Torres-de los Reyes, E Horvath, J Willers and P Selvam for excellent technical assistance and F Ochsenbein for the artwork. Statistical analysis was performed with the help of W Blanckenhorn, Museum of Zoology, University of Zürich. Isabelle Peter was supported by the Julius Klaus Foundation, Silvio Hemmi was supported by the Cancer Society of the Kanton Zürich and the University of Zürich, Reinhard Dummer and Urs Greber were supported by the Swiss National Science Foundation (3200-063704.00/1) and (31-55994.98), respectively.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Peter, I., Graf, C., Dummer, R. et al. A novel attenuated replication-competent adenovirus for melanoma therapy. Gene Ther 10, 530–539 (2003). https://doi.org/10.1038/sj.gt.3301940
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3301940
Keywords
This article is cited by
-
Small-size recombinant adenoviral hexon protein fragments for the production of virus-type specific antibodies
Virology Journal (2017)
-
Analysis of adenovirus trans-complementation-mediated gene expression controlled by melanoma-specific TETP promoter in vitro
Virology Journal (2010)
-
Prodrug converting enzyme gene delivery by L. monocytogenes
BMC Cancer (2008)
-
Cellular genetic tools to control oncolytic adenoviruses for virotherapy of cancer
Journal of Molecular Medicine (2008)
-
Selective replication of E1B55K-deleted adenoviruses depends on enhanced E1A expression in cancer cells
Cancer Gene Therapy (2006)