Conditionally Replication-competent Adenovirus Research Articles

Chemoprevention Gene Therapy (CGT): Novel Combinatorial Approach for Preventing and Treating Pancreatic Cancer

Pancreatic cancer remains one of the deadliest of all cancers despite aggressive surgical treatment combined with adjuvant radiotherapy and chemotherapy. Chemoresistance and radioresistance are the principal causes of failure of pancreatic cancer patients to respond to therapy. Conditionally replication competent adenovirus (CRCA)-based cancer gene therapy is an innovative strategy for treating cancers displaying inherent resistance to treatment. Limitations of current adenovirus (Ad)-based gene therapies for malignant tumors include lack of cancer-specificity, and effective and targeted delivery. To remedy this situation, CRCAs have been designed that express E1A, necessary for Ad replication, under the control of a cancer-specific progression elevated gene-3 promoter (PEG-Prom) with concomitant expression of an immunomodulatory cytokine, such as mda-7/IL-24 or interferon-γ (IFN-γ), under the control of a ubiquitous and strong cytomegalovirus promoter (CMV-Prom) from the E3 region. These bipartite CRCAs, when armed with a transgene, are called cancer terminator viruses (CTVs), i.e., Ad.PEG-E1A-CMV-mda-7 (CTV-M7) and Ad.PEG-E1A-CMV-IFN-γ (CTV-γ), because of their universal effectiveness in cancer treatment irrespective of p53/pRb/p16 or other genetic alterations in tumor cells. In addition to their selective oncolytic effects in tumor cells, the potent 'bystander antitumor' properties of MDA-7/IL-24 and IFN-γ embody the CTVs with expanded treatment properties for both primary and distant cancers. Pancreatic cancer cells display a "translational block" of mda-7/IL-24 mRNA, limiting production of MDA-7/IL-24 protein and cancer-specific apoptosis. Specific chemopreventive agents abrogate this "translational block" resulting in pancreatic cancer-specific killing. This novel chemoprevention gene therapy (CGT) strategy holds promise for both prevention and treatment of pancreatic cancers where all other strategies have proven ineffective.

Oncolytic Adenovirus Expressing Soluble TGFβ Receptor II-Fc-mediated Inhibition of Established Bone Metastases: A Safe and Effective Systemic Therapeutic Approach for Breast Cancer

In recent years, oncolytic adenoviruses have shown some promise as a novel class of antitumor agents. However, their utility in targeting bone metastases is relatively less studied. We have examined whether the systemic therapy of oncolytic adenoviruses expressing the soluble form of transforming growth factor-β (TGFβ) receptor II fused with human immunoglobulin G1 can be developed for the treatment of established breast cancer bone metastases. MDA-MB-231-luc2 human breast cancer cells were injected in the left heart ventricle of nude mice to establish bone metastasis. Mice with hind limb tumors were administered (on days 8 and 11) oncolytic adenoviruses-Ad.sTβRFc or mhTERTAd.sTβRFc. Skeletal tumor growth was monitored weekly by bioluminescence imaging (BLI) and radiography. At the termination time on day 28, hind limb bones were analyzed for tumor burden, synchrotron micro-computed tomography, and osteoclast activation. Intravenous delivery of Ad.sTβRFc and mhTERTAd.sTβRFc induced significant inhibition of tumor growth, reduction of tumor burden, osteoclast activation, and increased animals' survival. Oncolytic adenoviruses were safer than dl309, a wild-type virus. A slight elevation of liver enzyme activity was observed after Ad.sTβRFc administration; this subsided with time. Based on these studies, we believe that Ad.sTβRFc and mhTERTAd.sTβRFc can be developed as a safe and effective approach for the treatment of established bone metastasis.

The development of the conditionally replication‐competent adenovirus: replacement of E4 orf1‐4 region by exogenous gene

Tumor or tissue specific replicative adenovirus armed with a therapeutic gene has shown a promising anti-cancer therapeutic modality. However, because the genomic packaging capacity is constrained, only a few places inside it are available for transgene insertion. In the present study, we introduce a novel strategy utilizing the early E4 region for the insertion of therapeutic gene(s). We constructed the conditionally replication-competent adenovirus (CRAd), Ad5E4(mRFP) by: (i) replacing the E4/E1a promoter by the prostate-specific enhancer element; (ii) inserting mRFP inside the E4orf1-4 deletion region; and (iii) sub-cloning enhanced green fluorescent protein controlled by cytomegalovirus promoter in the left end of the viral genome. Subsequently, we evaluated its replication abilities and killing activities in vitro, as well as its in vivo anti-tumor efficacy in CWR22rv xenografts. When infected with Ad5E4(mRFP), the number and intensity of the mRFP gene products increased in a prostate cancer cell-specific manner as designed, suggesting that the mRFP gene and E4orfs other than E4orf1-4 were well synthesized from one transcript via alternative splicing as the recombinant adenovirus replicated. As expected from the confirmed virus replication capability, Ad5E4(mRFP) induced cell lysis as potent as the wild-type adenovirus and effectively suppressed tumor growth when tested in the CWR22rv xenografts in nude mice. Furthermore, Ad5E4(endo/angio) harboring an endostatin-angiostatin gene in E4orf1-4 was able to enhance CRAd by replacing mRFP with a therapeutic gene. The approach employed in the present study for the insertion of a therapeutic transgene in CRAd should facilitate the construction of CRAd containing multiple therapeutic genes in the viral genome that may have the potential to serve as highly potent cancer therapeutic reagents.

A Phase I Study of Telomerase-specific Replication Competent Oncolytic Adenovirus (Telomelysin) for Various Solid Tumors

A phase I clinical trial was conducted to determine the clinical safety of Telomelysin, a human telomerase reverse transcriptase (hTERT) promoter driven modified oncolytic adenovirus, in patients with advanced solid tumors. A single intratumoral injection (IT) of Telomelysin was administered to three cohorts of patients (1 x 10(10), 1 x 10(11), 1 x 10(12) viral particles). Safety, response and pharmacodynamics were evaluated. Sixteen patients with a variety of solid tumors were enrolled. IT of Telomelysin was well tolerated at all dose levels. Common grade 1 and 2 toxicities included injection site reactions (pain, induration) and systemic reactions (fever, chills). hTERT expression was demonstrated at biopsy in 9 of 12 patients. Viral DNA was transiently detected in plasma in 13 of 16 patients. Viral DNA was detectable in four patients in plasma or sputum at day 7 and 14 post-treatment despite below detectable levels at 24 h, suggesting viral replication. One patient had a partial response of the injected malignant lesion. Seven patients fulfilled Response Evaluation Criteria in Solid Tumors (RECIST) definition for stable disease at day 56 after treatment. Telomelysin was well tolerated. Evidence of antitumor activity was suggested.

Potent anti-tumor effects of a dual specific oncolytic adenovirus expressing apoptin in vitro and in vivo

BackgroundOncolytic virotherapy is an attractive drug platform of cancer gene therapy, but efficacy and specificity are important prerequisites for success of such strategies. Previous studies determined that Apoptin is a p53 independent, bcl-2 insensitive apoptotic protein with the ability to specifically induce apoptosis in tumor cells. Here, we generated a conditional replication-competent adenovirus (CRCA), designated Ad-hTERT-E1a-Apoptin, and investigated the effectiveness of the CRCA a gene therapy agent for further clinical trials.ResultsThe observation that infection with Ad-hTERT-E1a-Apoptin significantly inhibited growth of the melanoma cells, protecting normal human epidermal melanocytes from growth inhibition confirmed cancer cell selective adenoviral replication, growth inhibition, and apoptosis induction of this therapeutic approach. The in vivo assays performed by using C57BL/6 mice containing established primary or metastatic tumors expanded the in vitro studies. When treated with Ad-hTERT-E1a-Apoptin, the subcutaneous primary tumor volume reduction was not only observed in intratumoral injection group but in systemic delivery mice. In the lung metastasis model, Ad-hTERT-E1a-Apoptin effectively suppressed pulmonary metastatic lesions. Furthermore, treatment of primary and metastatic models with Ad-hTERT-E1a-Apoptin increased mice survival.ConclusionsThese data further reinforce the previously research showing that an adenovirus expressing Apoptin is more effective and advocate the potential applications of Ad-hTERT-E1a-Apoptin in the treatment of neoplastic diseases in future clinical trials.

HTERT-promoter-dependent oncolytic adenovirus enhances the transduction and therapeutic efficacy of replication-defective adenovirus vectors in pancreatic cancer cells

Adenovirus-mediated gene therapy shows promise for cancer therapy, but transgene expression of replication-defective adenovirus may be low and transient in clinical settings. Recent reports have shown that the use of a conditionally replication-competent adenovirus (CRAd) enhanced the gene transduction of a replication-defective adenovirus vector. The control of tumor-stromal interactions has also been determined to be important in cancer therapy. In this study, we investigated the effect of the human telomerase reverse transcriptase (hTERT)-CRAd, Ad5/3hTERTE1, which possesses the tumor-specific hTERT promoter with the chimeric fiber 5/3, on the transgene expression and therapeutic efficacy of a replication-defective adenovirus vector expressing NK4 under the control of the CMV promoter, Ad-NK4. In addition, we established a new strategy to target both cancer cells and cancer-stromal interactions. Human pancreatic cancer cells were infected with Ad-NK4 and either Ad5/3hTERTE1 (CRAd-combination group) or Ad5/3hTERTLuc (control-combination group). In the CRAd-combination group, Ad-NK4-delivered transgene expression was increased, leading to an enhanced inhibitory effect on the invasion of cancer cells. In in vivo experiments, NK4 expression within tumors and its inhibitory effect on tumor growth, angiogenesis, and metastasis were enhanced in the CRAd-combination group. These results suggest that hTERT-CRAd enhances the transgene expression and therapeutic efficacies of Ad-NK4, possibly through the in-trans replication of Ad-NK4 induced by adenovirus E1 derived from co-infected hTERT-CRAd. This approach may be a promising combination therapy against advanced pancreatic cancer.

812. Addressing the Limitations of Adenoviral-Mediated Gene Delivery through Coating the Viral Surface in Lipid Bilayers

Recombinant adenovirus (Ad) is a powerful tool in gene therapy. However, the ability to deliver Ad to target tissues and cells following systemic administration is limited due to rapid clearance from blood circulation by the mononuclear phagocyte system (MPS), leading to transfection of non-target tissues (primarily liver), vector related toxicity and immunogenicity. The aim of this work was to engineer synthetic lipid envelopes around adenovirus in order to develop a novel gene therapy vector based on a hybrid viral/non-viral vector platform that would address some of the limitations of Ad. The interaction between the virions and phospholipid bilayers was systematically studied in order to develop a protocol for constructing this vector by using self-assembly principles without any alteration of the Ad genome or application of surface conjugation chemistry The hypothesis that envelopment of Ad using different lipid bilayers would produce nanoparticles with characteristics determined by the type of lipid used was tested using a variety of structural, physicochemical, and biological assays. Vector physicochemical characteristics such as size, degree of aggregation, stability in suspension, and surface charge were linked to biological function in vitro and in vivo. The results indicated several key parameters toward the development of stable, non-flocculated suspensions of lipid enveloped Ad, and how such characteristics affected the gene transfer efficiency, organ distribution, and pharmacokinetics of the resulting vectors. Further, these results demonstrated that it was possible to overcome problems of inherent viral tissue affinities and to reduce immunogenicity by introduction of the synthetic envelope. Next, the lipid components of the envelope were altered to optimize the vector for cancer therapy. Inclusion of stealth components like poly(ethylene glycol) (PEG)-lipids in the envelope extended blood circulation time. It was also found that enveloped Ad vectors could be tailored to preferentially accumulate in tumor tissue with little interaction with non-target tissue in vivo. Further, these vectors were demonstrated to possess enhanced tumor-penetration capability in vitro. Finally, the possibility of enhancing the therapeutic effect and reducing the toxicity of conditionally replication competent adenovirus (CRAd) used for cancer therapy was evaluated using both in vitro and in vivo models of human tumors. Although no improvements were observed in cancer therapy, the enveloped CRAd was far less toxic than the unmodified virus. This may lead to the development of cancer targeting vectors with low systemic toxicity, which will greatly broaden the horizon for oncolytic virotherapy of cancer. In summary, the studies in this thesis provide a new paradigm for modification of non-enveloped virions (such as Ad) by application of self-assembly principles and have contributed to a greater understanding of the importance of characterizing and manipulating Ad's physicochemical characteristics to enhance its biological activity. As such, this thesis provides the basis for development of a novel vector platform that may be used for the systemic treatment of primary or broadly disseminated cancer.

636. Development of Prostate-Specific Conditional Replication-Competent Adenovirus for Prostate Cancer Gene Therapy

636. Development of Prostate-Specific Conditional Replication-Competent Adenovirus for Prostate Cancer Gene Therapy

Vascular endothelial growth factor promoter-based conditionally replicative adenoviruses for pan-carcinoma application

Treatment of advanced lung cancer is one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and has an extremely poor prognosis. Thus, new therapeutic approaches are needed. Lung tumor formation depends on angiogenesis in which the vascular endothelial growth factor (VEGF) produced by cancer cells plays a pivotal role. Neutralizing VEGF with a soluble VEGF receptor suppresses tumor growth; however, the anticancer effect with this therapy is weakened after the intratumoral vascular network is completed. In this study, we turned the expression of VEGF by tumors to therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 is controlled by the human VEGF promoter. This virus achieved good levels of viral replication in lung cancer cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with tropism modification of the virus to express the knob domain of Ad3, which improved infectivity for cancer cells. These VEGF promoter-based CRAds also showed a significant cell killing effect for various types of cancer lines other than lung cancer. Conversely, the VEGF promoter has low activity in normal tissues, and the CRAd caused no damage to normal bronchial epithelial cells. Since tumor-associated angiogenesis via VEGF signalling is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that VEGF promoter-based CRAds have the potential to be an effective strategy for cancer treatment.

Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice.

Limitations of current viral-based gene therapies for malignant tumors include lack of cancer-specific targeting and insufficient tumor delivery. To ameliorate these problems and develop a truly effective adenovirus gene-based therapy for cancer, we constructed a conditionally replication competent adenovirus (CRCA) manifesting the unique properties of tumor-specific virus replication in combination with production of a cancer-selective cytotoxic cytokine, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), which embodies potent bystander antitumor activity. Cancer cell selective tropism was ensured by engineering the expression of the adenoviral E1A protein, necessary for viral replication, under the control of a minimal promoter region of progression elevated gene-3 (PEG-3), which functions selectively in diverse cancer cells with minimal activity in normal cells. In the E3 region of this CRCA, we introduced the mda-7/IL-24 gene, thereby mediating robust production of this cytokine as a function of adenovirus replication. Infection of this CRCA (designated Ad.PEG-E1A-mda-7) in normal mammary epithelial cells and breast cancer cells confirmed cancer cell selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 into human breast cancer xenografts in athymic nude mice completely eradicated not only the primary tumor but also distant tumors (established on the opposite flank of the animal) thereby implementing a cure. This dual cancer-specific targeting strategy provides an effective approach for treating breast and other human neoplasms with the potential for eradicating both primary tumors and metastatic disease. Additionally, these studies support the potential use of mda-7/IL-24 in the therapy of malignant cancers.

Infectivity enhanced, hTERT promoter-based conditionally replicative adenoviruses are useful for SCLC treatment

Treatment of advanced small-cell lung cancer (SCLC) remains one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and it also has an extremely poor prognosis. As a result, new therapeutic approaches are needed. Telomere maintenance to the regulation of replicative lifespan strongly implies that alterations in telomere biology play an important role during malignant transformation. Cancers that exhibit high levels of telomerase activity, such as all of the SCLC, were examined in a previous study. In this study, we turned the expression of human telomerase reverse transcriptase (hTERT) by tumors to a therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 (early region 1) is controlled by the hTERT promoter. This virus achieved good levels of viral replication in SCLC cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with a tropism modification of the virus to express the knob domain of Ad3 (serotype 3 adenovirus), and this improved infectivity for cancer cells. Conversely, the hTERT promoter has low activity in normal tissues, and the CRAd caused no damage to normal lung fibroblast cells. Since the telomerase activity is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that the use of hTERT promoter-based CRAds may be a potentially effective strategy for cancer treatment.

629. VEGF Promoter-Based Conditionally Replicative Adenoviruses Are Useful for the Treatment of Malignant Pleural Mesothelioma

Malignant pleural mesothelioma, MPM is an asbestos-related malignancy characterized by rapidly progressive and diffusely local growth, late metastases, and poor prognosis. Chemotherapy or radiation therapy, alone or in combination, is not effective, and the majority of patients with MPM die within 2 years regardless of treatment. Therefore, new therapeutic approaches are needed. The tumor formation of malingnant mesothelioma depends on angiogenesis in which the VEGF produced by cancer cells plays a pivotal role. In our previous work, we developed a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 is controlled by the human VEGF promoter, AdVEGFE1. This virus achieved good levels of viral replication in lung cancer cells and induced a substantial anti-cancer effect in vitro and in vivo. Since many MPM tumors are known to produce VEGF, VEGF promoter based CRAd has a potential to suppress a VEGF expressing MPM tumor growth. Six MPM cell lines tested showed the significant VEGF mRNA and protein expression. The cancer cell killing effect by AdVEGFE1 was roughly correlated with the extent of VEGF mRNA expression and the results of luciferase assay using AdVEGFLuci. We also investigated the in vivo anticancer effect of AdVEGFE1 to MPM tumor established in the pleural space of the nude mice. In this experiment, only two MPM cell lines were selected by the tumor forming ability after the screening of all six MPM cell lines. When these intact MPM cells were pre-mixed with infected cells by AdVEGFE1 at the ratio of 10%, tumor formation was suppressed significantly. A direct injection of AdVEGFE1 to pleural space of tumor-bearing nude mice at day 15 improved the survival time, and furthermore, repeat injections at day 15, 22, and 29 showed better results. These results suggest the VEGF promoter based CRAd is the promising strategy for the MPM tumors. We are now investigating the viral replication in MPM in vivo.

964. Infectivity Enhanced, hTERT Promoter-Based Conditionally Replicative Adenoviruses Are Useful for the Treatment of Small Cell Lung Cancer

Treatment of advanced small cell lung cancer (SCLC) remains one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and it also has an extremely poor prognosis. As a result, new therapeutic approaches are needed. Telomere maintenance to the regulation of replicative life span strongly implies that alterations in telomere biology play an important role during malignant transformation. Cancers that exhibit high levels of telomerase activity, such as all of the small-cell lung cancers were examined in a previous study. In this study, we turned the expression of hTERT by tumors to a therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 is controlled by the hTERT promoter. This virus achieved good levels of viral replication in SCLC cells and induced a substantial anti-cancer effect in vitro and in vivo. As a further enhancement the cancer cell killing effect was improved with a tropism modification of the virus to express the knob domain of Ad3, and this improved infectivity for cancer cells. Conversely, the hTERT promoter has low activity in normal tissues, and the CRAd caused no damage to normal lung fibroblast cells. Since the telomerase activity is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that the use of hTERT promoter-based CRAds may be a potentially effective strategy for cancer treatment.

441. Conditional Replication Competent Adenovirus Ad-mTERT-Δ19 Driven by Human Telomerase Promoter Replicates and Elicits Cytopathic Effect Specifically in Cancer Cells

Resistance to chemotherapy is responsible for failure of current treatment regimens in cancer patients. We have previously reported that nuclear localization of the Y-box protein YB-1 regulates expression of the P-glycoprotein gene mdr1 which plays a major role in the development of a multidrug resistant tumor phenotype. Recent research has indicated that adenoviruses as oncolytic agents could be used as an alternative therapeutic approach in cancer patient. However, successful therapy crucially requires understanding how viral replication is brought about. Recently we were able to demonstrate that nuclear accumulation of the human transcription factor YB-1 in adenovirus infected cells is a function of the E1-region and we have shown that YB-1 facilitates adenovirus replication. Here we report that in multidrug resistant cancer cells, where YB-1 is located in the nucleus, adenovirus vectors such as Ad312 and dl520 efficiently replicate and induce strong cell lysis in vitro and in vivo. Thus replication defective adenoviruses are a previously unrecognized vector system for a selective elimination of multidrug resistant cancer cells. Our work forms the basis for the development of novel oncolytic adenovirus vectors in the treatment of multidrug resistant malignant diseases in the clinical setting.

Ad-mTERT-delta19, a conditional replication-competent adenovirus driven by the human telomerase promoter, selectively replicates in and elicits cytopathic effect in a cancer cell-specific manner.

Human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, functions to stabilize telomere length during chromosomal replication. Previous studies have shown that hTERT promoter is highly active in most tumor and immortal cell lines but inactive in normal somatic cell types. The use of wild-type hTERT promoter, however, may be limited by its inability to direct high level and cancer cell-specific expression necessary for effective targeted gene therapy. To improve cancer cell specificity and the strength of the hTERT promoter, a modified hTERT, m-hTERT promoter was generated in which additional copies of c-Myc and Sp1 binding sites were incorporated adjacent to the promoter. As assessed using relative lacZ expression, hTERT and m-hTERT promoter activity was significantly upregulated in cancer cells but not in normal cells, and within these upregulated cancer cells, m-hTERT promoter strength was substantially higher than that of the wild-type hTERT. Next, to restrict viral replication to tumor cells, a conditional replication-competent adenoviruses, Ad-TERT-Delta19 and Ad-mTERT-delta19 were generated in which the E1A gene, which is essential for viral replication, was placed under the control of the hTERT and m-hTERT promoter, respectively. While the wild-type Ad-TERT-delta19 replicated in and induced cytopathic effect in cancer and in some normal cell lines, Ad-mTERT-delta19 enhanced viral replication and cytopathic effect only in cancer cells. Furthermore, the growth of established human cervical carcinoma in nude mice was significantly suppressed by intratumoral injection of Ad-mTERT-delta19. Taken together, present results strongly suggest that the use of the m-hTERT promoter is not only useful in the regulation of therapeutic gene expression but also that replication-competent oncolytic adenovirus under the control of the m-hTERT promoter may be a new promising tool for the treatment of human malignancies.

Development of a Conditional Replication Competent Adenovirus, Controlled by the Human Telomerase Promoter (hTERT).

This study has been planned to generate a replication-competent adenovirus which replicates in a cancer cell-specific manner, thus minimizing the side effects and toxicity of cancer gene therapy. we have generated an E1B 19 kD attenuated recombinant adenoviruses, Ad-TERT-delta19 and Ad-mTERT-delta19, which encode E1A gene driven by the wild type hTERT and modified m-hTERT promoter containing additional c-myc and Sp1 binding sites in the backbone of Ad-deltaE1B19. The in vitro efficacy and specificity of the hTERT and m-hTERT promoter have been evaluated by the comparison of viral replication and cytopathic effect in cancer cells and normal cell lines. To assess anti-tumor effect and safety of hTERT or m-hTERT promoter driven replication competent adenoviruses, tumor regression after subcutaneous injection in subcutaneous C33A xenografts and lacZ expression after systemic injection in organs were examined. The activation of hTERT or m-hTERT promoter was significantly up-regulated only in hTERT-positive cells, but not in hTERT-negative cells. Moreover, the activity of m-hTERT promoter was substantially increased in hTERT-positive cancer cells, but not in hTERT-negative cells. While Ad-TERT-delta19 replicated in and induced cytopathic effect in cancer and in some normal cell lines, Ad-mTERT-delta19 enhanced viral replication and cytopathic effect in cancer cells only. Furthermore, the growth of established human cervical carcinoma in nude mice was significantly suppressed by intratumoral injection of Ad-mTERT-delta19. S: The use of m-hTERT promoter is not only useful in the regulation of therapeutic gene expression but also that replication-competent oncolytic adenovirus under the control of m-hTERT promoter may be a new promising tool for the treatment of human malignancies.

924. Enhanced Tumor Cell Specificity and Efficacy of Conditional Replication Competent Adenovirus Controlled by Modified Human Telomerase Promoter (m-hTERT)

924. Enhanced Tumor Cell Specificity and Efficacy of Conditional Replication Competent Adenovirus Controlled by Modified Human Telomerase Promoter (m-hTERT)

194. Development of Conditional Replication CompetentAdenovirus Controlled by Human Telomerase Promoter (hTERT)

194. Development of Conditional Replication CompetentAdenovirus Controlled by Human Telomerase Promoter (hTERT)