01. Gene therapy Boulikas.pdf - Gene therapy & Molecular Biology

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tested for its ability to eliminate bcl-2 expression from hormone-refractory prostate cancer cells. When this hammerhead ribozyme was directly transfected into cultured prostate cancer cells (LNCaP derivatives), it significantly reduced bcl-2 mRNA and protein levels within 18 hr of treatment and induced apoptosis in a lowbcl-2-expressing variant of LNCaP, but not in a high-bcl- 2-expressing LNCaP line (Dorai et al, 1997). B. Bcl-xs Many cancers overexpress a member of the Bcl-2 family of inhibitors of apoptosis, such as Bcl-2 and BclxL. Members of the Bcl-2 family were found to be essential for survival of cancer cells derived from solid tissues including breast, colon, stomach, and neuroblasts (Clarke et al, 1995). On the contrary, Bcl-xs is a dominant negative repressor of Bcl-2 and Bcl-xL; thus, Bcl-xs induces apoptosis. Transient overexpression of Bcl-xs in MCF-7 human breast cancer cells, which overexpress BclxL, with a replication-deficient adenoviral vector induced apoptosis in vitro; intratumoral injection of the bcl-xs adenovirus on solid MCF-7 tumors in nude mice showed a 50% reduction in size with evident apoptotic cells at sites of injection (Ealovega et al, 1996). An adenovirus vector expressing bcl-xs specifically and efficiently killed carcinoma cells arising from multiple organs including breast, colon, stomach, and neuroblasts even in the absence of an exogenous apoptotic signal such as x-irradiation. In contrast, normal hematopoietic progenitor cells and primitive cells capable of repopulating SCID mice were not killed by the bcl-xs adenovirus. Thus, transfer of the bcl-xs gene could be used in killing cancer cells contaminating the bone marrow of patients undergoing autologous bone marrow transplantation (Clarke et al, 1995). C. E2F-1 and TNF-α gene transfer E2F cooperates with p53 to induce apoptosis; high levels of wild-type p53 potentiate E2F-induced apoptosis in fibroblasts. The physiological relevance of E2F in the apoptotic mechanism is thought to arise from the ability of E2F to act as a functional link between p53 and RB; p53 levels increased in response to high levels of E2F. Targeted disruption of the E2F-1 gene yields transgenic animals with an excess of mature T cells due to a defect in lymphocyte apoptosis (Field et al, 1996). Overexpression of the transcription factor E2F-1 could induce apoptosis in quiescent rat embryo fibroblasts in a p53-dependent manner; however, Hunt et al (1997) have shown that overexpression of the E2F-1 gene after adenoviral transfer can mediate apoptosis in the absence of wild-type p53: adenovirus-mediated transfer of the E2F-1 gene under control of the CMV promoter to human breast and ovarian carcinoma cell lines resulted in the induction Boulikas: An overview on gene therapy 70 of significant morphological changes in four of the five cell lines that had mutations in the p53 gene within 48 h of transduction characteristic of apoptosis. Retroviral vector-mediated transfer of the TNF-α gene into the DNA of human tumor cells induced apoptosis in high- TNF-α-producing clones generated from a human lymphoma T-cell line (ST4); the apoptotic death of the cells was associated with a downregulation of the apoptosis-preventing gene, bcl-2, while the expression of bax and p53 genes persisted (Gillio et al, 1996). D. E6, E7 of human papillomavirus (HPV) E6 and E7 of HPV possess transforming ability, have been shown to interact with the cellular tumor suppressors p53 and RB (Werness et al, 1990; Dyson et al., 1989) and are believed to play a central role in HPV-induction of cervical carcinogenesis as well as in the maintenance of the malignant phenotype. Viruses have developed strategies to shut down protein synthesis in the host and subdue its protein synthesizing machinery to produce progeny virus when infecting cells. Because virus-infected cells commit suicide to protect the organism from further infection viruses have evolved mechanisms to prevent apoptosis of the host cell ensuring their propagation; E6 protein interacts with p53 to exclude p53 molecules from their apoptotic functions and to inhibit apoptosis in HPVinfected cells thus giving to HPV a proliferation advantage. 27-mer phosphorothioate oligodeoxynucleotides (oligos) targeting the ATG translational start region of HPV-16 E6 and E7 sequences showed antiproliferative effects in all HPV-16-positive cell lines tested and in primary cervical tumor explants while the endometrial and two ovarian primary tumors as well as the HPV-negative C33-A cell line and HPV-18-positive cell line HeLa were relatively insensitive to the HPV-16 oligos (Madrigal et al, 1997). E. Prevention of apoptosis for gene therapy of heart disease and for ex vivo manipulations of therapeutic cells As induction of apoptosis is the desired effect for the gene therapy of cancer, prevention of apoptosis by gene therapy can fight heart disease. Cardiomyocyte death results from heart ischemia proceeding via necrosis and from reperfusion which induces additional cardiomyocyte death by apoptosis; prevention of apoptosis would constitute an important target for fighting heart disease. Prevention of apoptosis should also solve a major problem in cell culture cells which are subject to oxidation damage during their manipulation for ex vivo gene transfer and most important during the step of reimplantation, encapsulation in biopolymer membranes for surgical
implantation, and similar processes. Prevention of apoptosis could be effected by transfer and overexpression of the bcl-2 gene. Also prevention of oxidative damage during reimplantation of ex vivo-modified cells could be reduced by transfer and overexpression of the Cu/Zn superoxide dismutase gene (Nakao et al, 1995). Overexpression of bcl-2 delayed onset of motor neuron disease and prolonged survival in a transgenic mouse model of familial amyotrophic lateral sclerosis (Kostic et al, 1997). XXII. E1A and HER-2/neu (c-erbB-2) in cancer gene therapy A. HER-2/neu The human epidermal growth factor receptor-2 (HER2), a membrane tyrosine kinase highly expressed in many epithelial tumors, could be a target for cancer gene therapy. The HER-2/neu (also called c-erbB-2) protooncogene is overexpressed in many human cancer cells, including those of breast cancer and ovarian cancer correlating with lower survival rate in ovarian cancer patients; amplification or overexpression of HER-2/neu has also been observed in human lung cancer and has been correlated with poor prognosis and chemoresistance. A reversible transformation of NIH3T3 fibroblasts by overexpression of the HER2/c-erbB2 receptor tyrosine kinase under control of a tetracycline-responsive promoter has been demonstrated in tissue culture; induction of HER2 expression resulted in cellular transformation in vitro and treatment of transformed cells with the effector anhydrotetracyline switched-off HER2 expression and induced morphological and functional changes characteristic for non-transformed cells (Baasner et al, 1996). B. E1A-based gene therapy E1A-based gene therapy approaches are now in clinical trials (see below); the molecular mechanism behind this approach is that the E1A protein of Adenovirus 5 represses HER-2/neu transcription and functions as a tumor suppressor gene in HER-2/neuoverexpressing cancer cells. Breast cancer cells that overexpress HER-2/neu are more resistant to chemotherapeutic agents such as paclitaxel (Taxol) and docetaxel (Taxotere) than those that do not overexpress HER-2/neu; paclitaxel sensitivity correlated with HER- 2/neu expression level in a panel of mouse fibroblasts expressing different levels of HER-2/neu; downregulation of HER-2/neu expression by E1A sensitized the cells to paclitaxel. Transfer the E1A gene into two human breast cancer cell lines that overexpress HER-2/neu and E1A Gene Therapy and Molecular Biology Vol 1, page 71 71 gene transfer sensitized these cells to the drug by repressing HER-2/neu expression (Ueno NT et al, 1997). Increased HER-2/neu expression led to more severe ovarian malignancy and increased metastatic potential in animal models; the adenovirus 5 E1A gene repressed HER-2/neu gene expression and suppressed growth of human ovarian cancer SKOV-3 cells, which overexpress HER-2/neu, in cell culture (Yu et al, 1995). Intraperitoneal injection of SKOV-3 cells into female nu/nu mice elicited tumors and the animals died within 160 days of severe tumor symptoms; cationic liposome-mediated delivery of the E1A gene into adenocarcinomas that developed in the peritoneal cavity and on the mesentery of the mice significantly inhibited growth and dissemination of ovarian cancer cells; about 70% of the treated mice survived at least for 365 days (Yu et al, 1995). Regulatory regions derived from the 5' flank of the human prostate-specific antigen (PSA) gene were inserted into adenovirus type 5 DNA to drive the expression of the E1A gene; infection of cells in culture with this recombinant adenovirus was able to drive the expression of the E1A gene only in cell lines which expressed PSA such as the human LNCaP cells but not in human DU145 cells which do not express PSA; the recombinant adenovirus destroyed large LNCaP tumors (1x10 9 cells) and abolished PSA production in nu/nu mouse xenograft models after a single intratumoral injection (Rodriguez et al, 1997). A replication-deficient adenovirus containing the E1A gene, Ad.E1A + , was used to transduce E1A into HER- 2/neu-overexpressing and low expressing human lung cancer cell lines and shown a better therapeutic efficacy in HER-2/neu-overexpressing cells. The cell culture studies were then extended to animal studies: tumor-bearing mice established by intratracheal injection of lung cancer cells overexpressing HER-2/neu and treated by i.v. tail injections of Ad.E1A + showed suppression of the intratracheal lung cancer growth. However, no significant tumor suppression effect was observed in mice bearing a low HER-2/neu−expressing cell line with the same regimen (Chang et al, 1996). C. Clinical trials with E1A and c-Erb-B2 Liposome-mediated E1A gene transfer suppressed tumor development and prolonged survival of mice bearing human breast cancer cells overexpressing HER- 2/neu. These studies resulted in the initiation of a phase I clinical trial using an E1A-liposome complex administered to patients with HER-2/neu-overexpressing breast or ovarian cancer (Protocol 205 in Table 4 of following article, pages 203-206). The principal investigators are Drs. Hortobagyi, Lopez-Berstein, and Hung at MD Anderson Cancer Center, Houston, Texas). The safety of this regimen was shown by intraperitoneal injection of
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Gene Ther Mol Biol Vol 1, 1-172. Ma
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I. Introduction Monumental progress
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The use of retroviral vectors in hu
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displaying the cleavable EGF domain
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molecules in the nucleus (Lowe and
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sensitive mutations which allow pro
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processed as described in panel A s
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On the contrary, the payload capaci
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in K562 human erythroleukemia cells
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Page 21 and 22: complex into the cytosol from the e
Page 23 and 24: Gene Therapy and Molecular Biology
Page 25 and 26: delivered by Sendai virus-liposome
Page 27 and 28: plasmids with the cell surface, tra
Page 29 and 30: infected by adenovirus alone; infec
Page 33 and 34: B. Transcription factor binding sit
Page 35 and 36: A closely related family of ubiquit
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Page 41 and 42: C. Considerations of chromatin stru
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Page 57 and 58: Prives, 1994). Whereas the wild-typ
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Page 63 and 64: Work from several groups has shown
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Page 81 and 82: C. Antisense ras gene transfer for
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Page 111 and 112: (Prehn et al, 1996); this implies a
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However, CsA also inhibits the acti
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The peptide kinin, after binding to
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intake when administered to adrenal
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Introgen Therapeutics (Austin and H
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When a subfragment of only 513 bp o
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Armentano D, Zabner J, Sacks C, Soo
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Brady HJM, Miles CG, Pennington DJ,
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Chen J, Stickles RJ, Daichendt KA (
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Day ML, Wu S, Basler JW (1993) Pros
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Farmer G, Bargonetti J, Zhu H, Frie
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Giovannangeli C, Perrouault L, Escu
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the neoplastic phenotype by replace
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integrate in a site-specific fashio
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Li R, Waga S, Hannon GJ, Beach D, S
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adiation-induced apoptosis in the g
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Nakaya T, Iwai S, Fujinaga K, Sato
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Polyak K, Xia Y, Zweier JL, Kinzler
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macrophages from simian immunodefic
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intimal hyperplasia in a rat caroti
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Trono D, Feinberg MB, Baltimore D (
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Wattiaux R, Jadot M, Warnier-Pirott
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similar to mammalian interleukin-1
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Gene Therapy and Molecular Biology
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24. Gene Marking /Infectious Diseas
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Drug 50. Gene Therapy /Phase I /Can
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76. Gene Therapy /Phase I /Cancer /
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99. Gene Therapy /Phase II /Cancer
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120. Gene Therapy /Phase I /Monogen
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Gene Therapy and Molecular Biology
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cancer not specified) /Immunotherap
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