GTMB 7 - Gene Therapy & Molecular Biology

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Sanlioglu et al: Adenovirus mediated gene therapy for prostate carcinomaHowever, it was known that the promoter of choice mightinfluence the level of toxicity. In order to study thepromoter effect on adenovirus mediated toxicity the mousecaveolin 1 promoter was cloned into the adenovirus HSVtkvector (Adcav-1tk) because this promoter was highlyactive in metastatic and androgen-resistant prostate cancercells (Pramudji et al, 2001). The efficacy of this vector forsuicide gene therapy was compared to those of AdHSV-tkvectors carrying either cytomegalovirus (AdCMV-tk) orrous sarcoma virus (AdRSV-tk) promoters in micetransplanted with mouse prostate cancer cells. FollowingGCV administration, all the HSV-tk expressing vectorsregressed the tumor growth in situ. Interestingly, theefficacy of Adcav-1tk vector was much greater in terms ofinducing necrosis and microvessel density. In order toevaluate the toxicity profile of adenovirus vectors carryingCMV, RSV or mouse caveolin promoter-driven HSV-tktransgenes, these vectors were also injected systemicallyinto mice (Ebara et al, 2002). Adenovirus vectors withCMV and RSV promoters, but not caveolin promoter,exhibited significant levels of liver damage. These resultssuggested that the promoter selection greatly influencesthe toxicity profile of adenovirus-mediated suicide genetherapy approach. In order to increase the number ofpromoters available for prostate specific gene expression,transgenic mice were generated expressing a reporter gene(SV40 Tag) directed by prostate secretory protein of 94amino acids (PSP94) (Gabril et al, 2002). PSP94 genepromoter/enhancer region directed SV40 Tag expressionexclusively in prostate leading to prostatic intraepithelialneoplasia and eventually to high-grade prostate carcinoma.These studies suggested that this PSP94 genepromoter/enhancer strategy could be employed for thetreatment of prostate carcinoma.One conventional way to limit the toxicity of virusmediated suicide gene therapy is to use cell type specificpromoters as suggested above. Although adenovirusvectors with the native PSA enhancer and promoter(PSAP) provided prostate-specific expression, lowertranscriptional activity observed in prostate challenged itsuse in prostate-targeted gene therapy. To improve theactivity and specificity of the prostate-specific PSAenhancer for gene therapy, various studies were carried outby exploring the properties of the natural PSA controlregions. Chimeric PSA enhancer constructs weregenerated with tandem copies of the proximal AREelements and then inserted into adenovirus constructs (Ad-PSE-BC-luc) (Wu et al, 2001). This construct was highlyinducible with androgens as shown by systemicadministration into SCID mice carrying LAPC-9 humanprostate cancer xenografts while retaining prostate specificgene expression. Furthermore, the CreLoxP system wasalso utilized to enhance the activity of PSAP. CD suicidegene therapy approach using adenoviral vectors withCRELoxP augmented PSAP activity effectively inhibitedsubcutaneous LNCaP tumor growth in nude mice(Yoshimura et al, 2002). In addition, hormone refractoryprostate cancer cells retain the expression of prostatespecificmembrane antigen (PSMA) and prostate-specificantigen (PSA). An adenovirus construct with an artificialchimeric enhancer (PSES) composed of two modifiedregulatory elements of PSA and PSMA genes (Ad-PSESluc)was generated and tested for its promoter activity forthe treatment of prostate cancer (Lee et al, 2002a).Systemic injection of Ad-PSES-luc construct into miceproduced very low levels of reporter gene expression inmajor organs. However, when injected directly intoprostate, only the prostate but not other tissues producedhigh levels of reporter gene expression. These resultsencouraged the use of PSES for the treatment of androgenindependentprostate carcinoma. Even though prostatespecificantigen (PSA/hK3) provided prostate specificgene expression, its expression displayed an inversecorrelation with prostate cancer grade and stage, givingreason to doubt its effectiveness for advanced stage ofprostate carcinoma. A new approach was developed inorder to generate gene therapy vectors targeting highergrades especially of prostate carcinoma. The humanglandular kallikrein 2 (hK2) is upregulated in an advancedform of prostate cancer with a higher grade. Therefore thehK2 promoter was cloned into adenovirus construct incombination with EGFP reporter gene (ADV.hK2-E3/P-EGFP) in order to obtain preferential expression of EGFPin prostate cancer (Xie et al, 2001a). Indeed ADV.hK2-E3/P-EGFP injection led to a robust but tumor-restrictedEGFP expression in subcutaneously generated LNCaPtumors. These results showed that adenovirus constructswith the hk2 multienhancer/promoter driven therapeuticgenes might be a powerful tool for gene therapy ofadvanced prostate cancer.Previous studies have shown that the bone matrixprotein osteocalcin is predominantly expressed in prostatecancer epithelial cells, fibromuscular stromal cells andosteoblasts. A conditional replication competentadenovirus vector carrying the osteocalcin promoterdriven early E1A gene (AdOCE1A) was generated to cotargetboth prostate cancer cells and their surroundingstromal cells (Matsubara et al, 2001). Both PSA-producing(LNCaP) and non-producing (DU145 and PC3) humanprostate cancer cell lines as well as human stromal cellsand osteoblasts were effectively killed by this recombinantvirus in vitro. In addition a single systemic intravenousinjection of the AdOCE1A construct significantlydestroyed prostate tumor cells transplanted in SCID mice.This co-targeting strategy appeared to have a broadereffect compared to other recombinant constructs tested onthe preclinical models of human prostate cancer. Thesepromising results initiated first gene therapy trial (phase I)in which adenoviruses carrying the osteocalcin promoterdriven HSV-tk gene (AdOCHSVTK) were directlyinjected into prostate cancer lymph node and bonemetastasis (Kubo et al, 2003). The results of this trialsuggested that adenoviruses did not display any adverseeffects and the treatment was well tolerated in all patients.In addition, 63 % of the patients had local cell death intreated lesions. Further studies are suggested in order toassess the efficacy of this approach for androgenindependentprostate carcinoma. A new treatmentmodality to enhance adenoviral replication by vitamin D 3in androgen-independent human prostate cancer cells andtumors was tested using a novel replication-competentadenoviral vector, Ad-hOC-E1, carrying the human124
Gene Therapy and Molecular Biology Vol 7, page 125osteocalcin (hOC) promoter to drive both the early viralE1A and E1B genes (Hsieh et al, 2002). While thereplication properties of Ad-hOC-E1 vector wererestricted to OC-expressing cells, vitamin D 3 exposurefurther enhanced viral replication by 10 fold. The growthof both androgen-dependent and androgen-independentprostate cancer cells was suppressed by Ad-hOC-E1infection, irrespective of the cells’ androgenresponsiveness and PSA status. This is in contrast to AdsPSA-E1vector, which only replicated in PSA-expressingcells with androgen receptor (AR). Ad-hOC-E1 injectioninhibited the growth of DU145 (an AR and PSA-negativecell line) tumor xenografts in mice. Consequently, vitaminD 3 -enhanced Ad-hOC-E1 viral replication represented analternative for the treatment of localized or osseousmetastatic prostate cancer. Prostate specific antigenpromoter (PSAP) and rat probasin (rPB) promoter arecurrently employed to drive the therapeutic transgeneexpression in prostate cancer cells. However, since thesepromoters require the binding of androgen to androgenreceptor for activation, they were only functional inandrogen-dependent prostate carcinoma cells. Becauseandrogen refractory prostate carcinoma cells lose theexpression of androgen receptor along the way, constructswith PSAP or rPB promoters are not useful for treatingpatients with androgen-independent prostate carcinoma. Inorder to circurment this problem, prostate specificpromoters were modified so that they were activated inresponse to the retinoids-retinoid receptor complex inplace of the androgen-AR complex. As a result, retinoidtreated androgen-independent prostate cancer cells weresensitized to HSVTK-ganciclovir gene therapy usingpromoters responding to retinoids (Furuhata et al, 2003).Apart from promoters providing tissue specific geneexpression, expression inducible promoters were clonedinto adenovirus constructs to control the onset and theduration of gene expression. Tetracycline-inducibleadenovirus vectors expressing the cytokine interleukin-12were successfully tested in an immunotherapy model forprostate cancer (Nakagawa et al, 2001). Thus, recombinantadenovirus vectors with tetracycline-inducible geneexpression opened up new avenues while improving thesafety of viral vector administration for cancer genetherapy. Limitation of cytotoxic gene expression only totumor cells is very much desired in adenovirus-mediatedgene therapy approach for cancer. Unfortunately, theexpression levels of many tumor and tissue-specificpromoters are much lower than the constitutively activepromoters. A complex adenoviral vector was generated byfusing the tetracycline transactivator gene to a prostatespecificARR2PB promoter while placing a mouse FASL-GFP fusion gene under the control of the tetracyclineresponsive promoter. This allowed the joining of cell-typespecificity with high-level regulation of transgeneexpression (Rubinchik et al, 2001). The doxycyclineregulated, ARR2PB driven FASL-GFP vector generatedhigher levels of prostate-specific FASL-GFP expressionthan FASL-GFP expression directed with ARR2PB alone,leading to apoptosis in LNCaP cells. Systemic delivery ofboth the prostate-specific and the prostate-specific/tetregulatedvectors was well tolerated in animals at dosesthat were lethal for adenovirus vectors with CMV-drivenFASL-GFP expression. This approach improved the safetyand efficacy of adenovirus-mediated cytotoxic genedelivery for the treatment of prostate carcinoma.The prostate-specific adenovirus gene expressiontechnology can also be used for the identification ofmetastatic lesions of prostate cancer through the use ofnon-invasive imaging. A prostate-specific adenovirusvector expressing a luciferase reporter gene (AdPSE-BCluc)and a charge-coupled device-imaging system wereemployed for this purpose (Adams et al, 2002). A robustexpression from AdPSE-BC-luc construct was found inthe prostate, especially in the androgen-independenttumors. Furthermore, metastatic lesions in the lung andspine with prostatic origin were identified successfullythrough repetitive imaging over a three-week period afterAdPSE-BC-luc injection into tumor-bearing mice. Theseresults demonstrate that adenovirus gene delivery specificto the prostate can be coupled to a non-invasive imagingmodality for therapeutic and diagnostic strategies forprostate cancer.XII. Adenovirus vectors forvaccination and adjuvant gene therapyCAR receptors and MHC class I heavy chains areimportant mediators of adenovirus entry into tumor cells.Contrary to the cell lines derived from other malignancies,down regulation of CAR or MHC class I expression isrelatively rare in both human and murine prostatecarcinoma cells. This brought the possibility of developingvaccine strategies for prostate cancer based on themodification of prostate cancer cells using recombinantadenovirus vectors (Pandha et al, 2003). The expression ofprostate-specific antigen (PSA) is highly restricted toprostatic epithelial cells. In fact, 95 % of patients withprostate carcinoma express PSA, making this antigen agood candidate for targeted immunotherapy. Arecombinant PSA adenovirus type 5 (Ad5-PSA) wasgenerated in order to activate PSA-specific T-cell responsewith the potential of eliminating prostate cancer cells(Elzey et al, 2001). Ad5-PSA immunized mice displayed aPSA-specific cellular immunity involving CD8 + Tlymphocytes. This approach deterred subcutaneous tumorformation with RM11 prostate cancer cells expressingPSA (RM11psa). However, this did not affect the growthof existing RM11psa tumors. On the contrary, Ad5-PSAadministration followed by intratumoral injection ofrecombinant canarypox viruses (ALVAC) encodinginterleukin-12 (IL-12), IL-2, and tumor necrosis factor-αeffectively eliminated established RM11psa tumors.Surgery is one of the conventional treatmentmodalities used against solid tumors. Due to the fact thatminor residual tumors following surgical operation mayresult in local recurrence, surgery is neither efficient norplausible for the treatment of metastatic disease. AlthoughAdHSV-tk gene therapy followed by gancicloviradministration has been evaluated extensively as apotential treatment modality for numerous tumors, it hasnot yet been proven to achieve a complete cure on its own.125
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GTMB 7 - Gene Therapy & Molecular Biology

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