GTMB 7 - Gene Therapy & Molecular Biology

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Sanlioglu et al: Adenovirus mediated gene therapy for prostate carcinomadisease, treating patients with prostate cancer still remainsa formidable task. In addition, the molecular mechanismresponsible for the onset of the disease is poorlyunderstood. However, earlier detection of prostate cancerhas been associated with an improved outcome (Perrotti etal, 1998). Thus, the detection of prostate cancer at anearlier stage remains to be the most realistic chance fortherapy.For this purpose, different molecular screeningmethods (Ross et al, 2002a, 2002b) have been employed,but the most effective method is yet to be established. Themost commonly used screening assays are based on thedetection of up-regulated prostate specific markers such asprostate specific antigen (PSA). Currently, prostatespecific antigen, (Farkas et al, 1998) when it is used inconjunction with other markers such as Gleason Scoring(Koksal et al, 2000) and TNM grading (Schroder et al,1992), is considered to be a valuable tool to evaluate thehistological grade of prostate carcinomas (Xess et al,2001). As a result, patients were provided with varioustreatment options based on the results obtained with theseparameters. These treatment options included but were notlimited to operation, (Klotz, 2000b) radiotherapy, (Do etal, 2002) chemotherapy (Wang and Waxman, 2001) andhormone therapy (Klotz, 2000a; Smith et al, 2002).Regrettably, these conventional treatment modalities couldnot decrease the casualties from prostate cancer (Hsiehand Chung, 2001). Hence, there is a great need fordevelopment of novel treatment modalities to fight againstprostate cancer. These remorseful facts ignited theinitiation of gene therapy trials for prostate carcinoma(Sanda, 1997). So far, various viral vectors includinglentivirus (Yu et al, 2001a), herpes simplex virus(Jorgensen et al, 2001), adeno-associated virus (Vieweg etal, 1995) and adenovirus (Loimas et al, 2001) were testedas carriers for therapeutic genes against prostate cancer.Other types of viruses such as Semliki Forest virus andSindbis virus were also tested for gene delivery to prostatecancer cells (Loimas et al, 2001), but these viruses wereunable to transduce prostate cells efficiently. Due to itsantigenic properties and tissue transduction characteristics,adenovirus arose as a favored transporter vector. Theexploitation of the tissue specific promoter in gene therapyespecially eased adenovirus use in clinical trials (Lu andSteiner, 2000). In this review, we mainly highlighted theprogress in adenovirus mediated prostate cancer genetherapy within the last three years with a particularemphasis in death ligand mediated gene therapy approach.II. ImmunomodulationTumors exhibit some degree of immunogenicity andthe human immune system responds to these tumorspecific antigens by mounting humoral and cellularresponses, which are essential for the eradication oftumors. Adenovirus is commonly used for the delivery ofgenes encoding tumor-associated antigens in order toaugment tumor-specific immune responses. However,antiviral immunity against adenovirus is a big concern,challenging its application in gene therapy. Variousmethods were employed in order to get around theantiviral immunity barrier to increase the efficacy ofadenovirus mediated gene delivery. One of these methodsinvolves the testing of a collagen-based matrix (Gelfoam)(Siemens et al, 2001). Coinjection of Gelfoam withadenovirus vectors carrying prostate-specific antigen(Ad5-PSA) into mice naive to PSA but immune toadenovirus, relinquished the inhibitory effects ofadenoviral immunity on CTL activation. Viral vectors arealso being tested to deliver tumor specific peptides intodendritic cells (DCs) to evoke an immune response. Thedegree of immune response generated relies on thefunctionality of DCs following viral transduction. Toprove this, adenovirus and retrovirus vectors werecompared on the basis of their influence on thefunctionality of DCs (Lundqvist et al, 2002a). Adenovirustransducedmonocyte-derived DCs (MO-DCs) stimulatedallogenic lymphocytes and produced high levels of TNFand IL12. In addition, the expression of NF-κB andantiapoptotic molecules such as Bcl-X(L) and Bcl-2(Lundqvist et al, 2002b) were also increased inadenovirus-transduced MO-DCs. Consequently, thesecells became more resistant to spontaneous as well as Fasmediatedcell death. In contrast, retroviruses failed even totransduce MO-DCs. Although CD34(+) cell-derived DCswere transducable with retroviruses to a lesser extent, theywere less potent in their ability to stimulate allogeniclymphocytes in comparison to nontransduced DCs. Theseresults suggest that adenovirus transduction of DCsincreased the survival and the potency of DC mediatedactivation of the immune system. This might be importantfor prolonging the antigen presentation to generate agreater degree of immune response.Cytokine stimulated tumor infiltrating macrophagesalso play a major role in the generation of the cellularimmune response against the tumor. The role of tumorinfiltratingmacrophages in IFN-β-induced host defenseagainst prostate cancer was revealed using xenograft micemodels injected with adenovirus carrying IFN-β gene(Zhang et al, 2002a). Injection of an adenoviral vectorencoding murine IFN-β (AdIFN-β) directly into the tumorsuppressed the growth of PC-3MM2 tumors as well asprevented metastasis and prolonged the survival of tumorbearingmice. Based on immunohistochemical staining,AdIFN-β infection resulted in the reduction of microvesseldensity of the tumor and increased apoptotic cell death(Cao et al, 2001). On the contrary, macrophage-selectiveanti-Mac-1 and anti-Mac-2 antibodies significantlyreduced the antitumor effect of AdIFN-β induced therapy.Therefore, it was concluded that tumor-infiltratingmacrophages must be involved in IFN-β inducedsuppression of tumor growth and metastasis.III. Suicide Gene TherapySuicide strategy is a combined treatment modalityinvolving chemotherapy and the gene transfer technology.The underlying principle is to limit the cytotoxicity of adrug to the local area of the tumor. To achieve this, thecDNA of a prodrug-converting enzyme is delivered intothe tumor using viral vectors followed by regional orsystemic application of the corresponding prodrug. As114
Gene Therapy and Molecular Biology Vol 7, page 115soon as the prodrug reaches the tumor, it is taken up andconverted to a cytotoxic drug by tumor cells expressingthe prodrug-converting enzyme. For example, 5-Fluorouracil (5-FU) is widely used as a chemotherapeuticagent for the treatment of various malignancies. Althoughclinical trials have been conducted, so far 5-FU manifesteda poor therapeutic index, which drastically limited itsclinical use for cancer therapy. It is still not knownwhether the lack of success was due to problemsassociated with drug delivery or inherent insensitivity ofcancer cells to this metabolite. However, adenovirus (Ad)vector-mediated cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy had the potential toovercome pharmacokinetic issues associated with systemic5-FU administration. Escherichia coli cytosine deaminaseconverts the prodrug 5-FC to the cytotoxic product 5-FU.Adenovirus encoding cytosine deaminase (AdCD) genewas injected into the prostate cancer cells transplantedorthotopically on mice followed by the systemic use of 5-FC in order to investigate the antitumor and antimetastaticeffects of this approach (Zhang et al, 2002c).An effective inhibition on tumor growth and metastasiswas observed through in situ injection of AdCD followedby systemic use of 5-FC in the xenograft mouse model ofprostate cancer. The use of E. coli uracilphosphoribosyltransferase (UPRT), a pyrimidine salvageenzyme, which modifies 5-FU into 5-fluorouridinemonophosphate, improved the activity of AdCD throughenhancing the anti-tumoral effect of 5-FU. In order toassess the efficacy of the combined suicide gene therapyapproach, two separate adenovirus constructs expressingeither the E. coli CD or E. coli UPRT genes were infectedinto androgen refractory prostate cancer cell line DU145bearing mice. This combined gene therapy approachdrastically regressed the growth of tumors in these animalsbetter than what was achieved with AdCD alone (Miyagiet al, 2003).The most commonly used prodrug-convertingenzyme for clinical approaches is the herpes simplex virusthymidine kinase gene (HSV-tk). The enzyme thymidinekinase phosphorylates the prodrug ganciclovir (GCV) toganciclovir monophosphate, which is then furtherphosphorylated by cellular enzymes to ganciclovirtriphosphate, a toxic metabolite and inhibitor of DNApolymerase. The efficacy of this approach was evaluatedin an extended phase I/II study involving 36 prostatecancer patients with local recurrence after radiotherapy.These patients received single or repeated cycles ofreplication-deficient adenoviral mediated HSV-tk plusGCV in situ gene therapy (Miles et al, 2001). The studyconcluded that the repeated cycles of in situ HSV-tk plusGCV gene therapy can safely be administered to patientswith prostate cancer who failed radiotherapy and have alocalized recurrence. The therapeutic parameters such asPSA doubling time (PSADT), the mean PSA reduction(PSAR), and return to initial PSA (TR-PSA) values wereall increased as a response to the treatment, indicating atherapeutic effect. A combined gene therapy approachusing a recombinant adenovirus containing a fusion geneof CD and HSV-tk controlled by a cytomegalovirus(CMV) enhancer-promoter was designed to explore newfrontiers in prostate cancer gene therapy (Lee et al,2002b). Both of the prostate carcinoma cell lines tested(DU-145 or PC-3 cells) were effectively transduced andkilled by this replication-incompetent adenovirus encodingCD-TK fusion protein in the presence of prodrugs. Theeffect of radiation and heat treatment was also tested usingthis vector system. Interestingly, heat treatment not onlyincreased the expression of CD-TK but sensitized prostatecancer cells to radiation as well. These results suggestedthat combining heat treatment with radiation therapyimproved the efficacy of the adenovirus mediated suicidegene therapy approach for prostate carcinoma. The CD-TK fusion fragment was also cloned into a lytic,replication-competent adenovirus (Ad5-CD/TKrep) andadministered into patients with prostate carcinoma in aPhase I trial. This was the first gene therapy study inwhich a replication-competent virus was used to deliver atherapeutic gene to humans (Freytag et al, 2002a). Thisstudy demonstrated that intraprostatic administration ofthe replication-competent Ad5-CD/TKrep virus followedby 2 weeks of 5-fluorocytosine and ganciclovir prodrugtherapy led to the destruction of tumor cells in patientswithout safety concerns. In addition, the efficacy and thetoxicity of replication-competent adenovirus-mediateddouble suicide gene therapy (AdCD-TK) combined withan external beam radiation therapy (EBRT) approach wastested as a trimodal treatment modality in a preclinicalstudy (Freytag et al, 2002b). Animals bearing prostatetumors were first injected with the lytic, replicationcompetentAd5-CD/TKrep virus, then received 1 week of5-fluorocytosine + ganciclovir (GCV) prodrug therapysupplemented with EBRT. The results from this studysuggested that replication-competent adenovirus-mediateddouble suicide gene therapy combined with EBRT is veryeffective in eliminating tumors and reducing metastasis inan orthotropic mouse model of prostate carcinoma.The efficacy of another gene-directed enzyme prodrugtherapy based on the Escherichia coli enzyme purinenucleoside phosphorylase (PNP) was tested in androgenindependentprostate cancer cells. PNP modifies theprodrug fludarabine to 2-fluoroadenine (Voeks et al,2002). In this study, a recombinant ovine adenovirusvector (OAdV220) with a different receptor choice thanthat of human adenovirus type 5 carrying the PNP geneunder the control of RSV promoter was used for functionalstudies. OAdV220 manifested a higher transgeneexpression compared to human Ad5 vector in infectedmurine RM1 prostate cancer cells during in vitro studies.Furthermore, the OAdV220 construct dramaticallyinhibited subcutaneous tumor growth when fludarabinephosphate was administered systemically inimmunocompetent mice. Similar results were obtainedusing human PC3 xenografts in mice. PNP is also knownto convert the prodrug 6MPDR to a toxic purine (6MP)causing cell death. In order to assess the efficacy of thisapproach for prostate cancer, replication-deficient humantype-5 adenovirus (Ad5) carrying the PNP gene (Ad5-SVPb-PNP) was directly injected into PC3 tumors(Martiniello-Wilks et al, 2002). The specificity and thelevel of transgene expression from this recombinantadenoviral vector were controlled by the promoter from115
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