GTMB 7 - Gene Therapy & Molecular Biology

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Sanlioglu et al: Adenovirus mediated gene therapy for prostate carcinomaexpression via adenovirus constructs sensitizes prostatecancer cells to chemotherapeutics and androgenwithdrawal. Another tumor suppressor protein, p27, alsoknown as cyclin-dependent kinase inhibitor (CDKI), isnormally expressed in human prostate. However, themajority of human prostate cancers have reduced levels ofp27. The down regulation of this putative tumorsuppressor gene through proteolysis is mediated bySCFSKP2 ubiquitin ligase complex. Adenovirus-mediatedoverexpression of SKP2 induced ectopic down-regulationof p27 in LNCaP prostate carcinoma cells (Lu et al, 2002).This observation confirmed that SKP2 activity was themajor determinant of p27 levels in human prostate cancercells. Based on in vitro studies, it is believed that theoverexpression of SKP2 might be one of the mechanismsallowing prostate cancer cells to escape growth controlmediated by p27. Therefore, knocking out SKP2 functionwould be a logical novel approach to fight prostate cancer.In another study, an adenovirus construct carrying p27coding sequences Adp27(Kip1) was generated to assesswhether the overexpression of p27 has any affect on theprostatic tumor growth in vivo (Katner et al, 2002).Injection of Adp27(Kip1) vector reduced the growth ofLNCaP tumor xenografts in mice. This study supportedthe idea that Adp27(Kip1) can serve as a potentialtherapeutic vector for the treatment of prostate carcinoma.p14(ARF), encoded by the human INK4a gene locus,is another tumor suppressor protein which is frequentlyinactivated in human cancer. p14(ARF) has recently beenimplicated in p53-independent cell cycle regulation andapoptosis. A replication-deficient adenoviral constructcarrying p14(ARF) coding sequence (Ad-p14(ARF)) wasgenerated in order to explore the pro-apoptotic function ofp14(ARF) in relationship to p53 function (Hemmati et al,2002). Ad-p14(ARF) construct induced apoptosis inp53/Bax-mutated DU145 prostate cancer cells andHCT116 cells lacking functional Bax expression. Thisstudy demonstrated that overexpression of p14 throughadenovirus vectors is sufficient to induce apoptosis in p53-and bax-deficient prostate cancer cells. Prostate carcinomawith p53 mutant phenotype represents a clear obstacle forirradiation therapy. Ionizing radiation (IR) and adenoviralp53 gene therapy (Ad5CMV-p53) were utilizedindividually as well as in combination in order to assessthe effectiveness of combined therapy for prostate cancer(Sasaki et al, 2001). In this study, IR alone did not inducesignificant levels of apoptotic cell death in DU145 andPC-3 cells. However, after combined therapy, theproportion of apoptotic cells was greatly amplified in bothof the cell lines tested. Therefore, it was concluded that theobserved synergistic effect might be useful for thetreatment of radio-resistant prostate carcinoma.The loss of MMAC/PTEN tumor suppressor geneexpression is frequently detected in human tumors.Survival signaling through the phosphatidylinositol-3kinase/Akt pathway is constitutively activated in cellslacking functional PTEN expression. Therefore, thefunctional effect of MMAC/PTEN expression wasexamined in LNCaP cells, which are devoid of afunctional PTEN product (Davies et al, 1999). Infectionwith an adenovirus construct driving the expression ofMMAC/PTEN resulted in a specific inhibition of Akt/PKBactivation. This is consistent with the phosphatidylinositolphosphatase activity of MMAC/PTEN. Compared toadenovirus delivered p53 expression, MMAC/PTENexpression induced apoptosis in LNCaP cells to a lesserextent. Interestingly, the growth suppression properties ofMMAC/PTEN were significantly greater than thoseaccomplished with p53. Moreover, Bcl-2 overexpressionin LNCaP cells blocked both the adenovirus mediatedMMAC/PTEN- and p53-induced apoptosis, but it did notaffect the growth-suppressive properties of MMAC/PTEN. This is consistent with the fact that MMAC/PTENmay play multiple roles in the cell. Prostate cells wereinfected with adenovirus vector carrying PTEN codingsequence in order to determine if supplying PTENfunction would sensitize these cells to various apoptoticstimuli (Yuan and Whang, 2002). As predicted,adenovirus-mediated PTEN delivery sensitized LNCaPprostate cancer cells to apoptosis through the inhibition ofconstitutive Akt activation. Since PTEN G129E mutantlacking lipid phosphatase activity was unable to sensitizecells to apoptosis, it was concluded that the lipidphosphatase activity of PTEN was required for apoptosis.The therapeutic effect of adenoviral delivery ofMMAC/PTEN was tested on both the in vitro and in vivogrowth of PC3 human prostate cancer cells (Davies et al,2002). The in vitro growth of PC3 cells was repressed byadenovirus expression of MMAC/PTEN via blocking ofcell cycle progression. Although this approach did notinhibit the tumor progression of orthotopically implantedPC3 cells, a significant reduction was observed in thetumor size in vivo, in addition to complete inhibition ofmetastases. Therefore, it was suggested thatMMAC/PTEN might play a role mostly in the regulationof the metastatic potential of prostate cancer.A considerable fraction of prostate tumors display analteration of Mxi1 expression, an antagonist to c-Myc.This was confirmed by transgenic approaches in whichprostatic hyperplasia was observed in mice deficient forMxi1. Mxi1-expressing adenovirus (AdMxi1) wasgenerated to study the ability of Mxi1 to act as a growthsuppressor in prostate tumor cells (Taj et al, 2001).Overexpression of Mxi1 using adenovirus vectors in theDU145 prostate carcinoma cell line resulted in growtharrest and decreased colony formation on soft agar. Allthese studies emphasize that the modulation of tumorsuppressor gene function might be necessary for anoptimum therapeutic response to fight against prostatecancer.VIII. Cell adhesion molecules and antiangiogenicapproachesCell adhesion molecules play major roles especiallyin metastasis of cancer cells. Therefore, aberrantexpression patterns of cell adhesion molecules arefrequently associated with poor prognosis. For instance,the expression of a well-known cell adhesion molecule, C-CAM1, is downregulated during the early stages ofprostate carcinoma in an animal model (TRAMP) (Pu etal, 1999). C-CAM1 was cloned into an adenovirus122
Gene Therapy and Molecular Biology Vol 7, page 123construct and its efficacy was tested both in vitro and invivo using PC3 xenograft murine model (Lin et al, 1999).AdC-CAM1 construct manifested a strong antitumoralactivity on PC3 tumor cells grown in nude mice.Therefore, selective use of cell adhesion molecules mightbe beneficial for the treatment of prostate carcinoma.Moreover, combining C-CAM1-based therapy with TNP-470, a potent angiogenesis inhibitor, induced greatergrowth suppression on DU145 tumor xenografts than byeither Ad-C-CAM1 or TNP-470 application alone (Pu etal, 2002).Vascularization of a solid tumor is required forcancer growth. Recently, preventing vascularizationthrough inhibition of angiogenesis was a popular target forcancer gene therapy. For example, a 16-kDa prolactinprotein (PRL) has previously been shown to possess anantiangiogenic activity (Galfione et al, 2003). Notsurprisingly, adenovirus delivery of PRL proteinmanifested a significant antitumoral activity in vivo (Kimet al, 2003). In addition, vascular endothelial growth factor(VEGF) receptor signaling is another relevant pathway,which modulates the vascularization of newly growingtumors. Interfering with such a signaling pathway mightbe valuable in controlling the tumor growth. In fact, whenfused to an Fc domain and cloned into the recombinantadenovirus construct, the ligand-binding ectodomain ofVEGF receptor 2 (Flk1) manifested a considerablereduction in tumor growth induced by a drastic decline inthe microvessel density in SCID mice carrying humanLNCaP xenografts (Becker et al, 2002).Growth factors are needed for survival of cancer cellsand molecular chaperones are required for functionalproduction of these molecules. A new member of the heatshock protein family functioning as a molecular chaperonein the endoplasmic reticulum was recently discovered andnamed as 150-kDa oxygen-regulated protein (ORP150).Since prostate cancer cells exhibited an upregulation ofORP150 protein and VEGF, adenovirus delivery of anantisense ORP150 cDNA approach was used to reduceangiogenicity and tumorigenicity through inhibition ofVEGF secretion. This approach indeed suppressed thegrowth of DU145 prostate carcinoma cell line in axenograft model (Miyagi et al, 2002).IX. Replication competent adenovirusvectorsReplication competent adenoviral vectors providepowerful means to kill cancer cells through cell lysis.Since they only replicate in tumor cells, the therapeuticrange is limited to cancer cells. Two replication-competentadenoviruses, CV706 and CV787, were generated in orderto selectively destroy PSA producing prostate cancer cells.It has been demonstrated earlier that prostate-specificantigen (PSA)-selective replication-competent adenovirusvariant CV706 specifically eliminated tumors in humanprostate cancer xenografts in preclinical models(Rodriguez et al, 1997). Since adenovirus E1A is known tobe a potent inducer of chemosensitivity andradiosensitivity through p53-dependent and independentmechanisms, the potential radiosensitizing effects ofCV706 on prostate cancer cells were evaluated (Chen etal, 2001). The CV706 construct demonstrated a synergisticantitumoral effect both on irradiated human prostatecancer cells and tumor xenografts. Moreover, in order toinvestigate the safety and the functionality of intraprostaticdelivery of CV706 for the treatment of patients withlocally recurrent prostate cancer following radiationtherapy, a Phase I dose-escalation study was conducted(DeWeese et al, 2001). Results from this study suggestedthat even at high doses, intraprostatic delivery of theCV706 was relatively safe for patients and CV706construct demonstrated high therapeutic activity asreflected by the reduction in serum PSA. This was the firstclinical trial of a prostate-specific, replication-restrictedadenovirus for the treatment of prostate cancer. Anotherprostate-specific replication-competent adenoviruscarrying not one, but two, cell type specific promoters(CV787) was constructed. This construct contained E1Bgene driven by the human prostate-specificenhancer/promoter and the adenovirus type 5 (Ad5) theE1A gene under the control of prostate-specific ratprobasin promoter. The Ad5 E3 region was also conservedin the vector to improve the efficacy. A single tail veininjection of CV787 eliminated LNCaP xenografts within 4weeks in nude mice (Yu et al, 1999). When the prostatecancer-specific adenovirus CV787 was combined withchemotherapeutic agents like taxanes (paclitaxel anddocetaxel), a synergistic antitumoral effect was observedin mice carrying human prostate cancer xenografts (Yu etal, 2001b).Heat-inducible gene expression is another approachused in the context of suicide gene therapy. A recombinantadenovirus containing the CD-TK fusion gene controlledby the human inducible heat shock protein 70 promoter(Ad.HS-CDTK) was generated for this purpose. Heatapplication at 41 o C for 1 hour induced therapeutic geneexpression from this vector. Despite the fact that theAd.HS-CDTK construct induced CD-TK expression inhuman prostate cancer cells, a therapeutic benefit was notobserved due to lower transduction efficiency of tumors invivo. Instead, a replication-competent, E1B-attenuatedadenoviral vector containing the hsp70 promoter-drivenCD-TK gene (Ad.E1A + HS-CDTK) was generated toincrease CD-TK gene expression to achieve a therapeuticeffect (Lee et al, 2001). Contrary to replicationincompetent Ad.HS-CDTK, replication competentAd.E1A + HS-CDTK construct yielded severe cytotoxicityand greater levels of therapeutic index in the presence ofprodrugs. This approach revealed the beneficial effects ofusing replication competent virus complemented with aheat inducible suicide gene therapy approach for prostatecarcinoma.X. Adenovirus vectors with cell typespecific and inducible promotersEven though adenovirus-mediated HSVTK suicidegene therapy approach manifested a satisfactory toxicityprofile in Phase I clinical trials, the toxicity studies usingadenovirus vectors were very restricted in numbers.123
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