Sandalon, Z
(Department of Oral Biology and Pathology, SUNY at Stony Brook, Stony Brook, NY, USA)
,
Fusenig, N E
(German Cancer Research Center, Division of Differentiation and Carcinogenesis, Heidelberg, Germany)
,
McCutcheon, J
(New York University, School of Dentistry, New York, NY, USA)
,
Taichman, L B
(Department of Oral Biology and Pathology, SUNY at Stony Brook, Stony Brook, NY, USA)
,
Garlick, J A
(Department of Oral Biology and Pathology, SUNY at Stony Brook, Stony Brook, NY, USA)
The potential of gene therapy to treat premalignant disease or recurrent cancer has not been investigated. The goal of the present investigation was to explore the efficacy of pro-drug-mediated, suicide gene therapy as a strategy to treat incipient neoplasia in stratified squamous epithelium. To tes...
The potential of gene therapy to treat premalignant disease or recurrent cancer has not been investigated. The goal of the present investigation was to explore the efficacy of pro-drug-mediated, suicide gene therapy as a strategy to treat incipient neoplasia in stratified squamous epithelium. To test this strategy, a tissue model of premalignancy was generated by mixing normal human keratinocytes (NHK) that express the bacterial cytosine deaminase gene (CD) with premalignant keratinocytes which have been genetically marked with the bacterial gene for &bgr;-galactosidase (II-4-&bgr;-gal) in skin-like organotypic cultures. Preliminary studies in monolayer cultures demonstrated that CD-transduced NHK (NHK/CD) efficiently expressed the transgene and deaminated the pro-drug 5-fluorocytosine (5FC) to the toxic product 5-fluorouracil (5FU). The capacity of NHK/CD to kill II-4-&bgr;-gal cells through bystander effect was assayed in both submerged culture and in the organotypic model of premalignancy. In submerged cultures, it was found that CD-mediated killing of II-4-&bgr;-gal cells did not require cell–cell contact and that the LD50 of 5FC for efficient bystander killing of II-4-&bgr;-gal was 0.5 mM. When this concentration of pro-drug was used in organotypic cultures, a significant number of dysplastic II-4-&bgr;-gal cells were eliminated from the tissue. Bystander killing of II-4-&bgr;-gal cells was related to the number of NHK/CD present. These findings demonstrated that potentially malignant keratinocytes could be eliminated from a dysplastic tissue through activation of pro-drug and killing of adjacent cells through the bystander effect. By establishing an in vitro model to eliminate premalignant cells using suicide gene therapy, these studies provide a new approach for the treatment of incipient cancer as it develops, thereby preventing invasive disease.
The potential of gene therapy to treat premalignant disease or recurrent cancer has not been investigated. The goal of the present investigation was to explore the efficacy of pro-drug-mediated, suicide gene therapy as a strategy to treat incipient neoplasia in stratified squamous epithelium. To test this strategy, a tissue model of premalignancy was generated by mixing normal human keratinocytes (NHK) that express the bacterial cytosine deaminase gene (CD) with premalignant keratinocytes which have been genetically marked with the bacterial gene for &bgr;-galactosidase (II-4-&bgr;-gal) in skin-like organotypic cultures. Preliminary studies in monolayer cultures demonstrated that CD-transduced NHK (NHK/CD) efficiently expressed the transgene and deaminated the pro-drug 5-fluorocytosine (5FC) to the toxic product 5-fluorouracil (5FU). The capacity of NHK/CD to kill II-4-&bgr;-gal cells through bystander effect was assayed in both submerged culture and in the organotypic model of premalignancy. In submerged cultures, it was found that CD-mediated killing of II-4-&bgr;-gal cells did not require cell–cell contact and that the LD50 of 5FC for efficient bystander killing of II-4-&bgr;-gal was 0.5 mM. When this concentration of pro-drug was used in organotypic cultures, a significant number of dysplastic II-4-&bgr;-gal cells were eliminated from the tissue. Bystander killing of II-4-&bgr;-gal cells was related to the number of NHK/CD present. These findings demonstrated that potentially malignant keratinocytes could be eliminated from a dysplastic tissue through activation of pro-drug and killing of adjacent cells through the bystander effect. By establishing an in vitro model to eliminate premalignant cells using suicide gene therapy, these studies provide a new approach for the treatment of incipient cancer as it develops, thereby preventing invasive disease.
참고문헌 (41)
J Am Dent Assoc GL Hays 126 47 1995 10.14219/jada.archive.1995.0023 Hays GL et al. Co-carcinogenesis and field cancerization: oral lesions offer first signs J Am Dent Assoc 1995 126: 47-51
Ann Med TE Carey 28 183 1996 10.3109/07853899609033118 Carey TE . Field cancerization: are multiple primary cancers monoclonal or polyclonal Ann Med 1996 28: 183-188
(ed) Farber E 21 1996 Advances in Cancer Research Farber E (ed.) . The step-by-step development of epithelial cancer: from phenotype to genotype Advances in Cancer Research Academic Press: London 1996 pp 21-48
RA Weinberg 1 1991 Origin of Human Cancer: A Comprehensive Review Weinberg RA . Oncogenes, tumor suppressor genes and cell transformation: trying to put it all together. In: Brugge J, Curran T, Harlow E, McCormick F (eds) Origin of Human Cancer: A Comprehensive Review Cold Spring Harbor Laboratory: Cold Spring Harbor, NY 1991 pp 1-16
Cancer Res A Javaherian 58 2200 1998 Javaherian A, Vaccariello M, Fusenig NE, Garlick JA . Normal keratinocytes suppress early stages of neoplastic progression in stratified epithelium Cancer Res 1998 58: 2200-2208
Proc Natl Acad Sci USA BE Huber 91 8302 1994 10.1073/pnas.91.17.8302 Huber BE et al. Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small precentage ofvtumor cells express cytosine deaminase Proc Natl Acad Sci USA 1994 91: 8302-8306
Cancer Gene Ther FL Moolten 1 279 1994 Moolten FL . Drug sensitivity (‘suicide’) genes for selective cancer chemotherapy Cancer Gene Ther 1994 1: 279-287
Hum Gene Ther SO Freytag 9 1323 1998 10.1089/hum.1998.9.9-1323 Freytag SO et al. A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene and radiotherapy Hum Gene Ther 1998 9: 1323-1333
Hum Gene Ther RG Crystal 8 985 1997 10.1089/hum.1997.8.8-985 Crystal RG, Hirschowitz MD, Lieberman MD . Phase I study of direct administration of a replication-deficient adenovirus vector containing the E. Coli cytosine deaminase gene to metastatic colon carcinoma of the liver in association with the oral administration of the pro-drug 5-fluorocytosine Hum Gene Ther 1997 8: 985-1001
Biochem Pharmacol K Ghoshal 53 1569 1997 10.1016/S0006-2952(97)00040-3 Ghoshal K, Jacob ST . An alternative molecular mechanism of action of 5-flurouracil, a potent anticancer drug Biochem Pharmacol 1997 53: 1569-1575
Chemotherapy A Polak 21 113 1975 10.1159/000221854 Polak A, Scholer HJ . Mode of action of 5-fluorocytosine and mechanisms of resistance Chemotherapy 1975 21: 113-130
Cancer Res BE Huber 53 4619 1993 Huber BE et al. In vivo antitumor activity of 5-fluorocytosine on human colorectal carcinoma cells genetically modified to express cytosine deaminase Cancer Res 1993 53: 4619-4626
Cancer Res CA Mullen 54 1503 1994 Mullen CA, Coale MM, Lowe R, Blease RM . Tumor expressing the cytosine deaminase suicide gene can be eliminated in vivo with 5-fluorocytosine and induce protective immunity to wild type tumor Cancer Res 1994 54: 1503-1506
Hum Gene Ther EA Hirschowitz 6 1055 1995 10.1089/hum.1995.6.8-1055 Hirschowitz EA et al. In vivo adenovirus-mediated gene transfer of the escherichia coli cytosine deaminase gene to human colon carcinoma-derived tumors induces chemosensitivity to 5-fluorocytosine Hum Gene Ther 1995 6: 1055-1063
Proc Natl Acad Sci USA AC Mullen 89 33 1992 10.1073/pnas.89.1.33 Mullen AC, Kilstrup M, Blaese M . Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-flurocytosine: a negative selection system Proc Natl Acad Sci USA 1992 89: 33-37
Hum Gene Ther K Haack 8 1395 1997 10.1089/hum.1997.8.11-1395 Haack K et al. Detection of cytosine deaminase in genetically modified tumor cells by specific antibodies Hum Gene Ther 1997 8: 1395-1401
Cancer Res BW O'Malley 55 1080 1995 O'Malley BW, Chen SH, Schwartz MR, Woo SL . Adenovirus-mediated gene therapy for human head and neck squamous cell cancer in nude mouse model Cancer Res 1995 55: 1080-1085
Ann Otology EA Goebel 105 562 1996 Goebel EA et al. Adenovirus-mediated gene therapy for head and neck squamous cell carcinomas Ann Otology 1996 105: 562-567
Mol Endocrinol BWJ O'Malley 11 667 1997 10.1210/me.11.6.667 O'Malley BWJ et al. The role of interleukin-2 in combination adenovirus gene therapy for head and neck cancer Mol Endocrinol 1997 11: 667-673
Cancer Res SM Freeman 53 5274 1993 Freeman SM et al. The ‘bystander effect’: tumor regression when a fraction of the tumor mass is genetically modified Cancer Res 1993 53: 5274-5283
Proc Natl Acad Sci USA M Mesnil 93 1831 1996 10.1073/pnas.93.5.1831 Mesnil M et al. Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins Proc Natl Acad Sci USA 1996 93: 1831-1835
Gene Therapy AA Elshami 3 85 1996 Elshami AA et al. Gap junctions play a role in the bystander effect of the herpes simplex virus thymidine kinase/ganciclovir system in vitro Gene Therapy 1996 3: 85-92
Cancer Res DK Hoganson 56 1315 1996 Hoganson DK, Batra RK, Olsen JC, Boucher RC . Comparison of the effects of three different toxin genes and their level of expression on cell growth and bystander effect in lung adenocarcinoma Cancer Res 1996 56: 1315-1323
Cancer Res QT Trinh 55 4808 1995 Trinh QT et al. Enzyme/prodrug gene therapy: comparison of cytosine deaminase/5-fluorocytosine versus thymidine kinase/ganciclovir enzyme/prodrug systems in human colorectal carcinoma cell line Cancer Res 1995 55: 4808-4812
Hum Gene Ther W Uckert 9 855 1998 10.1089/hum.1998.9.6-855 Uckert W et al. Double suicide gene (cytosine deaminase and herpes simplex virus thymidine kinase) but not single gene transfer allows reliable elimination of tumor cells in vivo Hum Gene Ther 1998 9: 855-865
Cancer Res J Karen 59 474 1999 Karen J et al. 12-O-tetradecanoylphorbol-13-acetate induces clonal expansion of potentially malignant keratinocytes in a tissue model of early neoplastic progression Cancer Res 1999 59: 474-481
J Invest Dermatol M Vaccariello 113 384 1999 10.1046/j.1523-1747.1999.00701.x Vaccariello M et al. Cell interactions control the fate of malignant keratinocytes in an organotypic model of early neoplasia J Invest Dermatol 1999 113: 384-391
Cell JG Rheinwald 6 331 1975 10.1016/S0092-8674(75)80001-8 Rheinwald JG, Green H . Serial cultivation of strains of human epidermal keratinocytes: the formation of keratonocyte colonies from single cells Cell 1975 6: 331-344
Cell Y-J Wu 31 693 1982 10.1016/0092-8674(82)90324-5 Wu Y-J et al. The mesothelial keratins: a new family of cytoskeletal proteins identified in cultured mesothelial cells nonkeratinizing epithelia Cell 1982 31: 693-703
J Cell Biol Boukamp 106 761 1988 10.1083/jcb.106.3.761 Boukamp et al. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line J Cell Biol 1988 106: 761-771
Cancer Res P Boukamp 50 2840 1990 Boukamp P et al. c-Ha-ras oncogene expression in immortalized human keratinocytes (HaCat) alters growth potential in vivo but lacks correlation with malignancy Cancer Res 1990 50: 2840-2847
NL Parenteau 45 1994 The Keratinocyte Handbook Parenteau NL . Skin equivalents. In: Leigh IM, Watt FM (eds) The Keratinocyte Handbook Cambridge University Press: Cambridge, UK 1994 pp 45-56
Proc Natl Acad Sci USA JC Burns 90 8033 1993 10.1073/pnas.90.17.8033 Burns JC et al. Vasicular somatitis virus G glycoprotein pseudotyped retroviral vectors: concentration to very high titer and efficient gene transfer into mammalian and non-mammalian cells Proc Natl Acad Sci USA 1993 90: 8033-8037
JA Garlick 181 1994 Keratinocyte Methods Garlick JA . Keratinocyte methods. In: Leigh IM, Lane EB, Watt FM (eds) Keratinocyte Methods Cambridge University Press: Cambridge, UK 1994 181-183
이 논문을 인용한 문헌
활용도 분석정보
상세보기
다운로드
내보내기
활용도 Top5 논문
해당 논문의 주제분야에서 활용도가 높은 상위 5개 콘텐츠를 보여줍니다. 더보기 버튼을 클릭하시면 더 많은 관련자료를 살펴볼 수 있습니다.
※ AI-Helper는 부적절한 답변을 할 수 있습니다.