Adenovirus-mediated expression of HSV1-TK or Fas ligand induces cell death in primary human glioma-derived cell cultures that are resistant to the chemotherapeutic agent CCNU

Maleniak, Tricia C.; Darling, John L.; Löwenstein, Pedro R.; Castro, María G.

doi:10.1038/sj.cgt.7700348

Cited by 36 publications

(27 citation statements)

References 39 publications

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“…This could be due to, at least in part, different responsiveness of different tumor types to (i) the gene paradigm used (eg prodrug therapy), and also (ii) to the interindividual variability of cells within the same tumor to vector infectivity. Maleniak et al 17 exposed five human glioblastoma cell cultures from surgical biopsies to different gene therapy approaches and found noticeable differences in their responsiveness toward therapy. These intercellular differences in malignant brain tumors have not been adequately addressed in current clinical gene therapy protocols.…”

Section: Introductionmentioning

confidence: 99%

Variability in infectivity of primary cell cultures of human brain tumors with HSV-1 amplicon vectors

et al. 2005

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We investigated the variability in infectivity of cells in primary brain tumor samples from different patients using an HSV-1 amplicon vector. We studied the infectivity of HSV-1 amplicon vectors in tumor samples derived from neurosurgical resections of 20 patients. Cells were infected with a definite amount of HSV-1 amplicon vector HSV-GFP. Transduction efficiency in primary tumor cell cultures was compared to an established human glioma line. Moreover, duration of transgene expression was monitored in different tumor cell types. All primary cell cultures were infectable with HSV-GFP with variable transduction efficiencies ranging between 3.0 and 42.4% from reference human Gli36DEGFR glioma cells. Transduction efficiency was significantly greater in anaplastic gliomas and meningiomas (26.7717.4%) compared to more malignant tumor types (glioblastomas, metastases; 11.278.5%; P ¼ 0.05). To further investigate the possible underlying mechanism of this variability, nectin-1/HevC expression was analyzed and was found to contribute, at least in part, to this variability in infectability. The tumor cells expressed the exogenous gene for 7 to 61 days with significant shorter expression in glioblastomas (18713 d) compared to anaplastic gliomas (42724 d; Po0.05). Interindividual variability of infectivity by HSV-1 virions might explain, at least in part, why some patients enrolled in gene therapy for glioblastoma in the past exhibited a sustained response to HSV-1-based gene-and virus therapy. Infectivity of primary tumor samples from respective patients should be tested to enable the development of efficient and safe herpes vector-based gene and virus therapy for clinical application. Gene Therapy (2005) 12, 588-596.

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Section: Introductionmentioning

confidence: 99%

Variability in infectivity of primary cell cultures of human brain tumors with HSV-1 amplicon vectors

et al. 2005

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“…First-generation adenoviral vectors are powerful vectors for gene transfer and gene therapy in the CNS (Bilang-Bleuel et al, 1997;Bemelmans et al, 1999;Dewey et al, 1999;Bjorklund et al, 2000;Mittoux et al, 2000;Sandmair et al, 2000;Maleniak et al, 2001;Mittoux et al, 2002;Biglari et al, 2004;Chiocca et al, 2004;Do Thi et al, 2004;Gondi et al, 2004;HurtadoLorenzo et al, 2004;Immonen et al, 2004). As a result, recent trials have shown adenoviral vectors encoding HSV1-TK to be effective in randomized clinical trials for brain glioblastoma multiforme, compared to patients treated with standard treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Experimentally, they are successful in gene therapy models of many brain diseases, including Parkinson's disease (Bilang-Bleuel et al, 1997;Bjorklund et al, 2000;Do Thi et al, 2004;), Huntington's disease (Bemelmans et al, 1999;Mittoux et al, 2000;Mittoux et al, 2002), brain tumors (Dewey et al, 1999;Sandmair et al, 2000;Maleniak et al, 2001;Biglari et al, 2004;Chiocca et al, 2004;Gondi et al, 2004;Immonen et al, 2004) and various pain syndromes (Cope et al, 2006). In comparative clinical trials of gene therapy for malignant brain tumors, first-generation adenoviral vectors are significantly more effective than retroviral vectors, utilizing the conditional cytotoxic gene HSV 1 -TK and ganciclovir (Immonen et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells

et al. 2006

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First-generation adenovirus can be engineered with powerful promoters to drive expression of therapeutic transgenes. Numerous clinical trials for glioblastoma multiforme using first generation adenoviral vectors have either been performed or are ongoing, including an ongoing, Phase III, multicenter trial in Europe and Israel (Ark Therapeutics, Inc.). Although in the absence of antiadenovirus immune responses expression in the brain lasts 6-18 months, systemic infection with adenovirus induces immune responses that inhibit dramatically therapeutic transgene expression from first generation adenoviral vectors, thus, potentially compromising therapeutic efficacy. Here, we show evidence of an immunization threshold for the dose that generates an immune response strong enough to eliminate transgene expression from the CNS. For the systemic immunization to eliminate transgene expression from the brain, ≥1 × 10 7 infectious units (iu) of adenovirus need to be used as immunogen. Furthermore, this immune response eliminates >90% of transgene expression from 1 × 10 7 -1 × 10³ iu of vector injected into the striatum 60 days earlier. Importantly, elimination of transgene expression is independent of the nature of the promoter that drives transgene expression and is accompanied by brain infiltration of CD8 + T cells and macrophages. In conclusion, once the threshold for systemic immunization (i.e. 1 × 10 7 iu) is crossed, the immune response eliminates transgene expression by >90% even from brains that receive as little as 1000 iu of adenoviral vectors, independently of the type of promoter that drives expression.

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“…Three different vectors were used: RAd-hCMV-TNF- (Ehtesham et al 2002), RAd-hCMV-FasL (Larregina et al 1998, Morelli et al 1999, Maleniak et al 2001 and RAd-hCMV--Gal (Castro et al 1997). The RAds were grown and purified as previously described (Lowenstein et al 1996, Southgate et al 2000a.…”

Section: Adenoviral Vectorsmentioning

confidence: 99%

Adenoviral vectors encoding tumor necrosis factor-α and FasL induce apoptosis of normal and tumoral anterior pituitary cells

Candolfi

Jaita

Pisera

et al. 2006

Journal of Endocrinology

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Our previous work showed that tumor necrosis factor (TNF)-and FasL induce apoptosis of anterior pituitary cells. To further analyze the effect of these proapoptotic factors, we infected primary cultures from rat anterior pituitary, GH3 and AtT20 cells with first-generation adenoviral vectors encoding TNF-, FasL or, as a control, -galactosidase ( -Gal), under the control of the human cytomegalovirus promoter. Successful expression of the encoded transgenes was determined by immunocytochemistry. Although we observed basal expression of TNF-and FasL in control cultures of anterior pituitary cells, fluorescence-activated cell sorting (FACS) cell cycle analysis showed that the overexpression of TNF-or FasL increases the percentage of hypodiploid lactotropes and somatotropes. Nuclear morphology and TUNEL staining revealed that the cells undergo an apoptotic death process. We detected strong immunoreactivity for TNFR1 and Fas in the somatolactotrope cell line GH3. TNF-, but not FasL, was expressed in control cultures of GH3 cells. The infection of GH3 cells with adenovirus encoding TNF-or FasL increased the percentages of hypodiploid and TUNEL-positive cells. TNF-or FasL immunoreactivity was not observed in the corticotrope cell line AtT20. However, adenovirus encoding TNF-or FasL efficiently transduced these cells and increased the percentages of hypodiploid and TUNEL-positive cells. The expression of -Gal was detected in all these cultures but did not affect cell viability. In conclusion, these results suggest that death signaling cascades triggered by TNF receptor 1 (TNFR1) and Fas are present in both normal and tumoral pituitary cells. Therefore, overexpression of proapoptotic factors could be a useful tool in the therapy of pituitary adenomas.

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Adenovirus-mediated expression of HSV1-TK or Fas ligand induces cell death in primary human glioma-derived cell cultures that are resistant to the chemotherapeutic agent CCNU

Cited by 36 publications

References 39 publications

Variability in infectivity of primary cell cultures of human brain tumors with HSV-1 amplicon vectors

Variability in infectivity of primary cell cultures of human brain tumors with HSV-1 amplicon vectors

Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells

Adenoviral vectors encoding tumor necrosis factor-α and FasL induce apoptosis of normal and tumoral anterior pituitary cells

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