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Intratumoral Injection (intratumoral + injection)
Selected AbstractsRegulatory sequences of H19 and IGF2 genes in DNA-based therapy of colorectal rat liver metastasesTHE JOURNAL OF GENE MEDICINE, Issue 3 2005Patricia Ohana Abstract Background Malignant tumors of the liver are among the most common causes of cancer-related death throughout the world. Current therapeutic approaches fail to control the disease in most cases. This study seeks to explore the potential utility of transcriptional regulatory sequences of the H19 and insulin growth factor 2 (IGF2) genes for directing tumor-selective expression of a toxin gene (A fragment of diphtheria toxin), delivered by non-viral vectors. Methods The therapeutic potential of the toxin vectors driven by the H19 and the IGF2-P3 regulatory sequences was tested in a metastatic model of rat CC531 colon carcinoma in liver. Results Intratumoral injection of these vectors into colon tumors implanted in the liver of rats induced an 88% and a 50% decrease respectively in the median tumor volume as compared with the control groups. This therapeutic action was accompanied by increased necrosis of the tumor. Importantly, no signs of toxicity were detected in healthy animals after their treatment by the toxin expression vectors. Conclusions DT-A was preferentially expressed in liver metastases after being transfected with H19 or IGF2-P3 promoter-driven DT-A expression plasmids, causing a very significant inhibition of tumor growth as a result of its cytotoxic effect. Our findings strongly support the feasibility of our proposed therapeutic strategy, which may contribute to open new gene therapeutic options for human liver metastases. Copyright © 2004 John Wiley & Sons, Ltd. [source] Receptor activator of NF-,B ligand, macrophage inflammatory protein-1,, and the proteasomeCANCER, Issue S3 2003Novel therapeutic targets in myeloma Abstract BACKGROUND The bone destruction in myeloma patients is largely responsible for the clinical features of the disease. However, only recently has attention focused on identifying and developing drugs targeted specifically at the osteolysis. Receptor activator of NF-,B ligand (RANKL), macrophage inflammatory protein (MIP)-1,, and proteasomal function have been implicated in the pathogenesis of myeloma and associated bone disease. We provide "proof of principle" in preclinical myeloma models that these are indeed valid molecular targets in development of novel therapeutics. METHODS The efficacy of antagonists of RANKL and MIP-1, bioactivities (RANK.Fc and neutralizing monoclonal anti-MIP-1, antibody) in ameliorating osteolysis and reducing tumor burden was evaluated in a mouse model in which murine myeloma 5TGM1 cells are injected intravenously into syngeneic mice. In addition, the activity of a petidyl aldehyde proteasome inhibitor (proteasome inhibitor-1 [PSI]) on tumor growth was tested in a murine 5TGM1 plasmacytoma model and in mice intravenously inoculated with 5TGM1 cells. RESULTS RANK.Fc and anti-MIP-1, antibody inhibited the development and progression of osteolytic lesions and significantly reduced tumor load assessed by serum monoclonal paraprotein titers. Intratumoral injections of PSI inhibited growth of 5TGM1 plasmacytomas and induced tumor regression in some cases. In addition, systemic administration of PSI significantly prolonged time to onset of paraplegia in tumor-bearing mice. CONCLUSIONS The results highlight the critical roles of RANKL and MIP-1, in the development and progression of myeloma and provide a basis for future evaluation in myeloma patients of novel therapeutics that disrupt interactions of RANKL and MIP-1, with their cognate receptors. The data also suggest that further studies in preclincal myeloma models aimed at identifying other proteasome inhibitors with antitumor efficacy would be worthwhile. Cancer 2003;97(3 Suppl):813,7. © 2003 American Cancer Society. DOI 10.1002/cncr.11133 [source] Inhibitory effect of the polyinosinic-polycytidylic acid/cationic liposome on the progression of murine B16F10 melanomaEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2006Taku Fujimura Abstract Cellular proteins, retinoic acid inducible gene-I and Toll-like receptor 3, sense dsRNA including polyinosinic-polycytidylic acid (PIC) to stimulate innate immune response. The local administration of PIC has been demonstrated to be effective in anti-tumor immunotherapy. However, the effects of PIC delivered cross the cell membrane have not yet been examined. To address this issue, we used a complex of PIC and cationic liposome (PIC liposome) and examined its anti-tumor effects in vitro and in vivo. PIC liposome could directly suppress the growth of B16F10 melanoma in vitro and repeated peritumoral injections of PIC liposome inhibited melanoma growth in a dose-dependent manner. This treatment induced tyrosinase-related protein-2 (TRP-2)-tetramer+ CD8+ cells in the lymph nodes. As the mechanism for its anti-tumor immune response, we showed that the intradermal injection of PIC liposome induced the maturation of dendritic cells (DC). Moreover, the intratumoral injection of immature DC after treatment with PIC liposome significantly increased the number of TRP-2-specific IFN-,-producing cells in the lymph nodes as well as spleen, which resulted in an augmentation of the anti-tumor immune response. These studies demonstrate the potential of peritumoral injection of PIC liposome as immunotherapy for malignant melanoma. [source] Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4, gene,HEPATOLOGY, Issue 5 2008Chuan Yin Previous studies have shown that hepatocyte nuclear factor-4, (HNF4,) is a central regulator of differentiated hepatocyte phenotype and forced expression of HNF4, could promote reversion of tumors toward a less invasive phenotype. However, the effect of HNF4, on cancer stem cells (CSCs) and the treatment of hepatocellular carcinoma (HCC) with HNF4, have not been reported. In this study, an adenovirus-mediated gene delivery system, which could efficiently transfer and express HNF4,, was generated to determine its effect on hepatoma cells (Hep3B and HepG2) in vitro and investigate the anti-tumor effect of HNF4, in mice. Our results demonstrated that forced re-expression of HNF4, induced the differentiation of hepatoma cells into hepatocytes, dramatically decreased "stemness" gene expression and the percentage of CD133+ and CD90+ cells, which are considered as cancer stem cells in HCC. Meanwhile, HNF4, reduced cell viability through inducing apparent apoptosis in Hep3B, while it induced cell cycle arrest and cellular senescence in HepG2. Moreover, infection of hepatoma cells by HNF4, abolished their tumorigenesis in mice. Most interestingly, systemic administration of adenovirus carrying the HNF4, gene protected mice from liver metastatic tumor formation, and intratumoral injection of HNF4, also displayed significant antitumor effects on transplanted tumor models. Conclusion: The striking suppression effect of HNF4, on tumorigenesis and tumor development is attained by inducing the differentiation of hepatoma cells,especially CSCs,into mature hepatocytes, suggesting that differentiation therapy with HNF4, may be an effective treatment for HCC patients. Our study also implies that differentiation therapy may present as one of the best strategies for cancer treatment through the induction of cell differentiation by key transcription factors. (HEPATOLOGY 2008.) [source] Antitumor effects of a recombinant pseudotype baculovirus expressing Apoptin in vitro and in vivoINTERNATIONAL JOURNAL OF CANCER, Issue 11 2010Yongfei Pan Abstract Apoptin, a chicken anemia virus-derived, p53-independent, bcl-2-insenstive apoptotic protein with the ability to specifically induce apoptosis in tumor or transformed cells, is a promising tool for cancer gene therapy. In this study, pseudotype baculovirus, a recently developed alternative gene delivery system, was used as a vector to express Apoptin. The resultant recombinant baculovirus (BV-Apoptin) efficiently expressed the Apoptin protein and induced apoptosis in HepG2 and H22 cells. Studies in vivo showed that intratumoral injection of BV-Apoptin into a xenogeneic tumor (derived from H22 murine hepatoma cells in C57BL/6 mice) significantly suppressed tumor growth, and significantly prolonged the survival of tumor-bearing mice compared to a control pseudotype baculovirus that expressed EGFP. Taken together, these results suggest that Apoptin, expressed from the pseudotype baculovirus vector, has the potential to become a therapeutic agent for the treatment of solid tumors. [source] Therapeutic efficacy of 5-fluorouracil-loaded microspheres on rat glioma: a magnetic resonance imaging studyNMR IN BIOMEDICINE, Issue 6 2001L. Lemaire Abstract The aim of this work was to assess the therapeutic efficacy of an intratumoral bolus injection of 5-fluorouracil (FU) compared to that of drug loaded in biodegradable microspheres, for the treatment of brain tumour. Experiments were carried out using a fast-growing C6-glioma rat model. The therapeutic protocols were performed 12 days after the injection of glioma cells. At this stage, the tumours were installed and the mean volume was 13,±,2,µl as measured by proton magnetic resonance (MR) imaging. This technique was used for the follow-up of the tumour volume with respect to time and therapy. In terms of rat survival, both therapies induced a significant 50% increase in animal life span (p,<,0.05) compared to animals receiving no drug or unloaded microspheres. Whilst no cure was observed, analysis of the MR images showed that the local and sustained delivery of FU slowed the tumour development in the vicinity of the microspheres by a factor of 3, compared with the bolus intratumoral injection. Copyright © 2001 John Wiley & Sons, Ltd. [source] Comparative analysis of antitumor activity of CD40L, RANKL, and 4-1BBL in vivo following intratumoral administration of viral vectors or transduced dendritic cellsTHE JOURNAL OF GENE MEDICINE, Issue 2 2006Zoya R. Yurkovetsky Abstract The tumor necrosis factor (TNF) family comprises a group of ligands that regulate cell proliferation, differentiation, activation, maturation and apoptosis through interaction with the corresponding TNF receptor family members. In this study, we have evaluated whether adenovirus-mediated intratumoral gene transfer of CD40L, RANKL, or 4-1BBL elicits an immune response to established murine MC38 and TS/A tumors. Intratumoral administration of the recombinant adenoviral vectors expressing CD40L, RANKL or 4-1BBL 7 days post-tumor cell inoculation resulted in significant inhibition of MC38 tumor growth for all three ligands when compared with control groups treated with either saline or control adenovirus. However, intratumoral injection of Ad-4-1BBL or Ad-CD40L resulted in a significantly stronger inhibition of TS/A tumor progression than did Ad-RANKL treatment. We also demonstrated that intratumoral administration of dendritic cells (DC) transduced with adenoviral vectors encoding the TNF-related ligands resulted in a significant inhibition of MC38 tumor growth as compared with control groups treated with Ad-LacZ-transduced DC or saline-treated DC. In addition, DC overexpressing CD40L secreted considerably more IL-12 and expressed higher levels of the co-stimulatory molecules, CD80, CD86 and CD40, than did DC overexpressing LacZ, 4-1BBL or RANKL. We have also demonstrated that DC/CD40L, DC/4-1BBL, and DC/RANKL survived significantly longer than control DC or DC infected with the LacZ vector. Taken together, these results demonstrate that adenoviral gene transfer of CD40L, RANKL or 4-1BBL elicit a significant antitumor effect in two different tumor models, with CD40L gene transfer inducing the strongest antitumor effect. Copyright © 2005 John Wiley & Sons, Ltd. [source] Combined radiation therapy and dendritic cell vaccine for treating solid tumors with liver micro-metastasisTHE JOURNAL OF GENE MEDICINE, Issue 4 2005Zhuang Chen Abstract Background Tumor metastasis and relapse are major obstacles in combating human malignant diseases. Neither radiotherapy alone nor injection of dendritic cells (DCs) can successfully overcome this problem. Radiation induces tumor cell apoptosis and necrosis, resulting in the release of tumor antigen and danger signals, which are favorable for DC capturing antigens and maturation. Hence, the strategy of combined irradiation and DC vaccine may be a novel approach for treating human malignancies and early metastasis. Methods To develop an effective combined therapeutic approach, we established a novel concomitant local tumor and liver metastases model through subcutaneous (s.c.) and intravenous (i.v.) injection. We selected the optimal time for DC injection after irradiation and investigated the antitumor effect of combining irradiation with DC intratumoral injection and the related mechanism. Results Combined treatment with radiotherapy and DC vaccine could induce a potent antitumor immune response, resulting in a significant decrease in the rate of local tumor relapse and the numbers of liver metastases. The related mechanisms for this strong antitumor immunity of this combined therapy might be associated with the production of apoptotic and necrotic tumor antigens and heat shock proteins after irradiation, phagocytosis, migration and maturation of DCs, and induction of more efficient tumor-specific cytotoxic T lymphocyte activity through a cross-presentation pathway. Conclusions Co-administration of local irradiation and intratumoral DC injection may be a promising strategy for treating radiosensitive tumors and eliminating metastasis in the clinic. Copyright © 2004 John Wiley & Sons, Ltd. [source] Gene Therapy for Head and Neck Cancer ,THE LARYNGOSCOPE, Issue 5 2000Lyon L. Gleich MD Abstract Objectives/Hypothesis New treatment methods are needed for head and neck cancer to improve survival without increasing morbidity. Gene therapy is a potential method of improving patient outcome. Progress in gene therapy for cancer is reviewed with emphasis on the limitations of vector technology and treatment strategies. Given the current technological vector limitations in transmitting the therapeutic genes, treatments that require the fewest number of cells to be altered by the new gene are optimal. Therefore an immune-based gene therapy strategy was selected in which the tumors were transfected with the gene for an alloantigen, human leukocyte antigen (HLA),B7, a class I major histocompatibility complex (MHC). This would restore an antigen presentation mechanism in the tumor to induce an antitumor response. This gene therapy strategy was tested in patients with advanced, unresectable head and neck cancer. Study Design Prospective trial. Methods Twenty patients with advanced head and neck cancer who had failed conventional therapy and did not e-press HLA-B7 were treated with gene therapy using a lipid vector by direct intratumoral injection. The gene therapy product contained the HLA-B7 gene and the ,2-microglobulin gene, which permits complete e-pression of the class I MHC at the cell surface. Patients were assessed for any adverse effects, for changes in tumor size, for time to disease progression, and for survival. Biopsy specimens were assessed for pathological response, HLA-B7 e-pression, apoptosis, cellular proliferation, CD-8 cells, granzyme, and p53 status. Results There were no adverse effects from the gene therapy. At 16 weeks after beginning gene therapy, four patients had a partial response and two patients had stable disease. Two of the tumors completely responded clinically, but tumor was still seen on pathological examination. The time to disease progression in the responding patients was 20 to 80 weeks. The median survival in patients who completed gene therapy was 54 weeks, compared with 21 weeks in patients whose tumors progressed after the first cycle of treatment. One patient survived for 106 weeks without any additional therapy. HLA-B7 was demonstrated in the treated tumors, and increased apoptosis was seen in the responding tumors. Conclusion Significant advances have been made in the field of gene therapy for cancer. Alloantigen gene therapy has had efficacy in the treatment of cancer and can induce tumor responses in head and neck tumors. Alloantigen gene therapy has significant potential as an adjunctive treatment of head and neck cancer. [source] Intratumoral cisplatin/epinephrine gel in advanced head and neck cancer: A multicenter, randomized, double-blind, phase III study in North America,HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 9 2003Dan J. Castro MD Abstract Background. The objective was to evaluate the efficacy and safety of a novel intratumoral cisplatin/epinephrine injectable gel (CDDP/epi gel) for local control and palliation of tumor-related symptoms in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Patients and Methods. Eighty-seven patients were randomly assigned to either CDDP/epi or placebo gel in this phase III, double-blind study. Tumors were ,20 cm3; most recurrences (88%) were in a previously irradiated field. The most symptomatic or threatening tumor was designated as the target tumor. Dose: 0.25 mL CDDP/epi gel/cm3 tumor volume. Treatments: ,6 weekly intratumoral injections in an 8-week period. Primary outcomes: target tumor response and symptom relief. Results. During the blinded phase, 34% (21 of 62) of patients achieved an objective response (CR or PR) in the target tumor treated with CDDP/epi gel vs 0% (0 of 24) treated with placebo gel (p < .001). Responses occurred within a median of four treatments (range, 2,6) and were durable (median, 95 days; range, 34,168+ days). More patients treated with CDDP/epi gel achieved palliative benefit than did those treated with placebo gel (37% vs 12%, p = .036). Most frequent side effects were local pain and local cutaneous reactions, which resolved over 3,12 weeks. Renal and hematologic toxicities were rare. Conclusions. This phase III trial showed that CDDP/epi gel significantly reduces tumor burden, palliates tumor-related symptoms, and is an effective local treatment for recurrent tumors. © 2003 Wiley Periodicals, Inc. Head Neck 25: 717,731, 2003 [source] Poor intercellular transport and absence of enhanced antiproliferative activity after non-viral gene transfer of VP22-P53 or P53-VP22 fusions into p53 null cell lines in vitro or in vivoTHE JOURNAL OF GENE MEDICINE, Issue 7 2005David Zavaglia Abstract Background The herpes simplex virus type 1 (HSV-1) VP22 protein has the property to mediate intercellular trafficking of heterologous proteins fused to its C- or N-terminus. We have previously shown improved delivery and enhanced therapeutic effect in vitro and in vivo with a P27-VP22 fusion protein. In this report, we were interested in studying the spread and biological activity of VP22 fused to the P53 tumor suppressor. Methods Expression of the VP22-P53 and P53-VP22 fusion proteins was shown by Western blot and intercellular spreading was monitored by immunofluorescence on transiently transfected cells. In vitro antiproliferative activity of wild-type (wt) P53 and P53-VP22 was assessed by proliferation assays and transactivating ability was studied by a reporter gene test and a gel-shift assay. Antitumor activity was also tested in vivo by intratumoral injections of naked DNA in a model of subcutaneous tumors implanted in nude mice. Results Our results show that the C-terminal fusion or the N-terminal P53-VP22 fusion proteins are not able to spread as efficiently as VP22. Moreover, we demonstrate that VP22-P53 does not possess any transactivating ability. P53-VP22 has an antiproliferative activity, but this activity is not superior to the one of P53 alone, in vitro or in vivo. Conclusions Our study indicates that a gene transfer strategy using VP22 cannot be considered as a universal system to improve the delivery of any protein. Copyright © 2005 John Wiley & Sons, Ltd. [source] A nonreplicating adenoviral vector that contains the wild-type p53 transgene combined with chemotherapy for primary breast cancerCANCER, Issue 5 2006Safety, biologic activity of a novel gene-therapy approach, efficacy Abstract BACKGROUND. Primary systemic therapy (PST) is the standard approach to the management of patients with locally advanced breast cancer (LABC). The authors hypothesized that the intratumoral administration of a nonreplicating adenoviral vector (Ad5) that contains the human wild-type p53, AdCMV- p53, combined with chemotherapy, could increase the efficacy of PST as measured by pathologic complete response. METHODS. In a prospective, open-label, Phase II trial, 13 patients with LABC were treated with 6 3-week cycles of PST, which consisted of intratumoral injections of Ad5CMV- p53 for 2 consecutive days plus docetaxel and doxorubicin followed by surgery. p53 status was determined at baseline and was assessed immediately after the first injection (up to 48 hours). Clinical response was assessed by clinical and radiologic methods. RESULTS. The trial was terminated early, because none of the patients achieved a pathologic complete response. The median age was 56 years (range, 39,71 years), and the median tumor size was 8 cm (range, 5,11 cm). Eight patients (73%) had a p53 mutation. Serial biopsies showed an increase in p53 messenger RNA (mRNA) and p21WAF1/Cip1 mRNA. All 12 evaluable patients achieved an objective clinical response. The surgical specimens revealed scattered tumor cells with extensive tumor-infiltrate leukocytes (predominantly T-lymphocytes). At a median follow-up of 37 months (range, 30,41 months), 4 patients (30%) developed systemic recurrence, and 2 patients died. The estimate breast cancer-specific survival rate at 3 years was 84% (95% confidence interval, 65.7,100%). There was no increase in systemic toxicity. CONCLUSIONS. Ad5CMV- p53 combined with PST is safe, active, and associated with local immunomodulatory effects. The promising clinical activity of this combination deserves further investigation in randomized studies. Cancer 2006. © 2006 American Cancer Society. [source] | ||||||||||