Opinion statement
Cervical carcinoma is associated with human papillomavirus infection. Proliferation of cancer cells depends on the continual expression of the E6 and E7 viral oncogenes. This article includes treatment strategies that can interfere with expression or function of the proteins and immunotherapeutic approaches that can eliminate cells that express E6 and E7 proteins.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References and Recommended Reading
Alani RM, Munger K: Human papillomaviruses and associated malignancies. J Clin Oncol 1998, 16:330–337. A review of the mechanism by which the human papillomavirus exerts its transformation effect on the cervical epethilium. The article also provides the background to understand the therapeutic strategies that are described in the review.
Kirnbauer R, Booy F, Cheng N, et al.: Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci U S A 1992, 89:12180–12184.
Dvoretzky I, Shober R, Chattopadhyay SK, Lowy DR: A quantitative in vitro focus assay for bovine papilloma virus. Virology 1980, 103:369–375.
Lowy DR, Schiller JT: Papillomaviruses: prophylactic vaccine prospects. Biochim Biophys Acta 1999, 1423:M1-M8.
Volpers C, Schirmacher P, Streeck RE, Sapp M: Assembly of the major and the minor capsid protein of human papillomavirus type 33 into virus-like particles and tubular structures in insect cells. Virology 1994, 200:504–512.
Roden RB, Hubbert NL, Kirnbauer R, et al.: Assessment of the serological relatedness of genital human papillomaviruses by hemagglutination inhibition. J Virol 1996, 70:3298–3301.
Kirnbauer R, Taub J, Greenstone H, et al.: Efficient self-assembly of human papillomavirus type 16 L1 and L1-L2 into virus-like particles. J Virol 1993, 67:6929–6936.
Suzich JA, Ghim SJ, Palmer-Hill FJ, et al.: Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas. Proc Natl Acad Sci U S A 1995, 92:11553–11557.
Jansen KU, Rosolowsky M, Schultz LD, et al.: Vaccination with yeast-expressed cottontail rabbit papillomavirus (CRPV) virus-like particles protects rabbits from CRPV-induced papilloma formation. Vaccine 1995, 13:1509–1514.
Breitburd F, Kirnbauer R, Hubbert NL, et al.: Immunization with virus-like particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection. J Virol 1995, 69:3959–3963.
Schiller JT, Lowy DR: Papillomavirus-like particle based vaccines: cervical cancer and beyond. Expert Opin Biol Ther 2001, 1:571–581. An important review that presents the concept of virus-like particles and its use for the prevention of human papillomavirus (HPV) infection, the main strategy that is used for this purpose.
Da Silva DM, Velders MP, Nieland JD, et al.: Physical interaction of human papillomavirus virus-like particles with immune cells. Int Immunol 2001, 13:633–641.
Harro CD, Pang YY, Roden RB, et al.: Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst 2001, 93:284–292.
Schiller J, Lowy D: Papillomavirus-like particle vaccines. J Natl Cancer Inst Monogr 2001:50-54.
Koutsky LA, Ault KA, Wheeler CM, et al.: A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002, 347:1645–1651. The first controlled trial that shows efficacy of HPV prevention in humans. The importance of this paper is that it is a proof of principle that this strategy may be able to prevent an infection of an oncogenic agent.
Nardelli-Haefliger D, Roden R, Balmelli C, et al.: Mucosal but not parenteral immunization with purified human papillomavirus type 16 virus-like particles induces neutralizing titers of antibodies throughout the estrous cycle of mice. J Virol 1999, 73:9609–9613.
Dupuy C, Buzoni-Gatel D, Touze A, et al.: Nasal immunization of mice with human papillomavirus type 16 (HPV-16) virus-like particles or with the HPV-16 L1 gene elicits specific cytotoxic T lymphocytes in vaginal draining lymph nodes. J Virol 1999, 73:9063–9071.
Schreckenbergerab C, Sethupathia P, Kanjanahaluethaia A, et al.: Induction of an HPV 6bL1-specific mucosal IgA response by DNA immunization. Vaccine 2000, 19:227–233.
Valdez Graham V, Sutter G, Jose MV, et al.: Human tumor growth is inhibited by a vaccinia virus carrying the E2 gene of bovine papillomavirus. Cancer 2000, 88:1650–1662.
Rosales C, Graham VV, Rosas GA, et al.: A recombinant vaccinia virus containing the papilloma E2 protein promotes tumor regression by stimulating macrophage antibody-dependent cytotoxicity. Cancer Immunol Immunother 2000, 49:347–360. The paper exhibits an example of how to use the pathway of cell cycle inhibition of the HPV and the integration of the virus into the human cell genome for therapy. The paper includes an example of using gene therapy effectively in the down-regulation of E6 and E7 transcription.
Jin L, Qi M, Chen DZ, et al.: Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res 1999, 59:3991–3997.
Kamradt MC, Mohideen N, Vaughan AT: RU486 increases radiosensitivity and restores apoptosis through modulation of HPV E6/E7 in dexamethasone-treated cervical carcinoma cells. Gynecol Oncol 2000, 77:177–182.
Maehama T, Patzelt A, Lengert M, et al.: Selective downregulation of human papillomavirus transcription by 2-deoxyglucose. Int J Cancer 1998, 76:639–646.
Narayanan BA, Holladay EB, Nixon DW, Mauro CT: The effect of all-trans and 9-cis retinoic acid on the steady state level of HPV16 E6/E7 mRNA and cell cycle in cervical carcinoma cells. Life Sci 1998, 63:565–573.
Hietanen S, Lain S, Krausz E, et al.: Activation of p53 in cervical carcinoma cells by small molecules. Proc Natl Acad Sci U S A 2000, 97:8501–8506.
Scribner DR Jr, Benbrook DM: Retinoids enhance cisplatin-based chemoradiation in cervical cancer cells in vitro. Gynecol Oncol 2002, 85:223–225.
Follen M, Atkinson EN, Schottenfeld D, et al.: A randomized clinical trial of 4-hydroxyphenylretinamide for high-grade squamous intraepithelial lesions of the cervix. Clin Cancer Res 2001, 7:3356–3365.
Wadler S, Schwartz EL, Anderson P, et al.: Preliminary phase II clinical and pharmacokinetic study of 9-cis retinoic acid in advanced cervical cancer. New York Gynecologic Oncology Group. Cancer J Sci Am 1999, 5:165–170.
DeLong R, Nolting A, Fisher M, et al.: Comparative pharmakokinetics, tissue distribution, and tumor accumulation of phosphorothioate, phosphorodithioate, and methylphosphonate oligonucleatide in nude mice. Antisense Nucleic Acid Drug Dev 1997, 7:71–77.
Crook T, Tidy JA, Vousden KH: Degradation of p53 can be targeted by HPV E6 sequences distinct from those required for p53 binding and trans-activation. Cell 1991, 67:547–556.
Green DW, Roh H, Pippin J, Drebin JA: Antisense oligonucleotides: an evolving technology for the modulation of gene expression in human disease. J Am Coll Surg 2000, 191:93–105.
Hamada K, Sakaue M, Alemany R, et al.: Adenovirusmediated transfer of HPV 16 E6/E7 antisense RNA to human cervical cancer cells. Gynecol Oncol 1996, 63:219–227.
He Z, Wlazlo AP, Kowalczyk DW, et al.: Viral recombinant vaccines to the E6 and E7 antigens of HPV-16. Virology 2000, 270:146–161.
Alvarez-Salas LM, Arpawong TE, DiPaolo JA: Growth inhibition of cervical tumor cells by antisense oligodeoxynucleotides directed to the human papillomavirus type 16 E6 gene. Antisense Nucleic Acid Drug Dev 1999, 9:441–450. The article provides an example of the strategy that is directed at the inhibition of the translation of E6/E7 mRNA by antisense technology.
Cotten M, Birnstiel ML: Ribozyme mediated destruction of RNA in vivo. Embo J 1989, 8:3861–3866.
Shippy R, Lockner R, Farnsworth M, Hampel A: The hairpin ribozyme. Discovery, mechanism, and development for gene therapy. Mol Biotechnol 1999, 12:117–129.
Alvarez-Salas LM, Cullinan AE, Siwkowski A, et al.: Inhibition of HPV-16 E6/E7 immortalization of normal keratinocytes by hairpin ribozymes. Proc Natl Acad Sci U S A 1998, 95:1189–1194.
Chen PW, Wang M, Bronte V, et al.: Therapeutic antitumor response after immunization with a recombinant adenovirus encoding a model tumor-associated antigen. J Immunol 1996, 156:224–231.
Phelps WC, Barnes JA, Lobe DC: Molecular targets for human papillomaviruses: prospects for antiviral therapy. Antivir Chem Chemother 1998, 9:359–377.
Butz K, Denk C, Ullmann A, et al.: Induction of apoptosis in human papillomavirus-positive cancer cells by peptide aptamers targeting the viral E6 oncoprotein. Proc Natl Acad Sci U S A 2000, 97:6693–6697.
Beerheide W, Bernard HU, Tan YJ, et al.: Potential drugs against cervical cancer: zinc-ejecting inhibitors of the human papillomavirus type 16 E6 oncoprotein. J Natl Cancer Inst 1999, 91:1211–1220.
Hamada K, Alemany R, Zhang WW, et al.: Adenovirusmediated transfer of a wild-type p53 gene and induction of apoptosis in cervical cancer. Cancer Res 1996, 56:3047–3054.
Bischoff JR, Kirn DH, Williams A, et al.: An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996, 274:373–376.
Lane DP: Killing tumor cells with viruses: a question of specificity. Nat Med 1998, 4:1012–1013.
Heise C, Sampson-Johannes A, Williams A, et al.: ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nat Med 1997, 3:639–645.
Kirn D, Hermiston T, McCormick F: ONYX-015: clinical data are encouraging. Nat Med 1998, 4:1341–1342.
Nemunaitis J, Cunningham C, Buchanan A, et al.: Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity. Gene Ther 2001, 8:746–759.
Vasey PA, Shulman LN, Campos S, et al.: Phase I trial of intraperitoneal injection of the E1B-55-kd-genedeleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/ refractory epithelial ovarian cancer. J Clin Oncol 2002, 20:1562–1569.
Nemunaitis J, Ganly I, Khuri F, et al.: Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: a phase II trial. Cancer Res 2000, 60:6359–6366.
Lamont JP, Nemunaitis J, Kuhn JA, et al.: A prospective phase II trial of ONYX-015 adenovirus and chemotherapy in recurrent squamous cell carcinoma of the head and neck (the Baylor experience). Ann Surg Oncol 2000, 7:588–592.
Onyx plans phase III trial of ONYX-015 for head & neck cancer. Oncologist 1999, 4:432.
Kadish AS, Ho GY, Burk RD, et al.: Lymphoproliferative responses to human papillomavirus (HPV) type 16 proteins E6 and E7: outcome of HPV infection and associated neoplasia. J Natl Cancer Inst 1997, 89:1285–1293.
Evans EM, Man S, Evans AS, Borysiewicz LK: Infiltration of cervical cancer tissue with human papillomavirus-specific cytotoxic T-lymphocytes. Cancer Res 1997, 57:2943–2950.
Alexander M, Salgaller ML, Celis E, et al.: Generation of tumor-specific cytolytic T lymphocytes from peripheral blood of cervical cancer patients by in vitro stimulation with a synthetic human papillomavirus type 16 E7 epitope. Am J Obstet Gynecol 1996, 175:1586–1593.
Chu NR, Wu HB, Wu T, et al.: Immunotherapy of a human papillomavirus (HPV) type 16 E7-expressing tumour by administration of fusion protein comprising Mycobacterium bovis bacille Calmette-Guerin (BCG) hsp65 and HPV16 E7. Clin Exp Immunol 2000, 121:216–225.
Chen CH, Wang TL, Hung CF, et al.: Enhancement of DNA vaccine potency by linkage of antigen gene to an HSP70 gene. Cancer Res 2000, 60:1035–1042.
Liu DW, Tsao YP, Kung JT, et al.: Recombinant adenoassociated virus expressing human papillomavirus type 16 E7 peptide DNA fused with heat shock protein DNA as a potential vaccine for cervical cancer. J Virol 2000, 74:2888–2894.
Greenstone HL, Nieland JD, de Visser KE, et al.: Chimeric papillomavirus virus-like particles elicit antitumor immunity against the E7 oncoprotein in an HPV-16 tumor model. Proc Natl Acad Sci U S A 1998, 95:1800–1805.
Mayordomo JI, Zorina T, Storkus WJ, et al.: Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity. Nat Med 1995, 1:1297–1302.
Cheever MA, Chen W: Therapy with cultured T cells: principles revisited. Immunol Rev 1997, 157:177–194.
Boursnell ME, Rutherford E, Hickling JK, et al.: Construction and characterisation of a recombinant vaccinia virus expressing human papillomavirus proteins for immunotherapy of cervical cancer. Vaccine 1996, 14:1485–1494.
Chen CH, Ji H, Suh KW, et al.: Gene gun-mediated DNA vaccination induces antitumor immunity against human papillomavirus type-16 E7-expressing murine tumor metastases in the liver and lungs. Gene Ther 1999, 6:1972–1981.
Borysiewicz LK, Fiander A, Nimako M, et al.: A recombinant vaccinia virus encoding human papillomavirus types 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer. Lancet 1996, 347:1523–1527. The paper includes examples of HPV-vaccine clinical trials and different methods of vaccination and proof of principal of the immunologic efficacy of HPV-E7 vaccination when used in various antigen forms.
Steller MA, Gurski KJ, Murakami M, et al.: Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type-16 E7. Clin Cancer Res 1998, 4:2103–2109. The paper includes examples of HPV-vaccine clinical trials and different methods of vaccination and proof of principal of the immunologic efficacy of HPV-E7 vaccination when used in various antigen forms.
van Driel WJ, Ressing ME, Kenter GG, et al.: Vaccination with HPV-16 peptides of patients with advanced cervical carcinoma: clinical evaluation of a phase I-II trial. Eur J Cancer 1999, 35:946–952. The paper includes examples of HPV-vaccine clinical trials and different methods of vaccination and proof of principal of the immunologic efficacy of HPV-E7 vaccination when used in various antigen forms.
Wojtowicz M, Hamilton JM, Khong H, et al.: Vaccination of Cervical Cancer Patients with Papillomavirus Type-16 E6 and E7 Peptides. Atlanta, GA: American Society of Clinical Oncology; 1999.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Khleif, S.N. Human papillomavirus therapy for the prevention and treatment of cervical cancer. Curr. Treat. Options in Oncol. 4, 111–119 (2003). https://doi.org/10.1007/s11864-003-0012-0
Issue Date:
DOI: https://doi.org/10.1007/s11864-003-0012-0