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Biomedical subjects

R G Vile

Publications and source records attributed to R G Vile.

At least 19 recordsLinked to original sources
PubMed2001

Macrophages orchestrate the immune response to tumor cell death.

The mechanisms by which the immune system distinguishes normal developmental cell death from pathological immunogenic cell killing are central to effective cancer immunotherapy. Using HSVtk suicide gene therapy, we showed that macrophages can distinguish between tumor cells dying through classical apoptosis and tumor cells engineered to die through nonapoptotic mechanisms, resulting in secretion of either immunosuppressive cytokines (interleukin 10 and transforming growth factor beta) or inflammatory cytokines (tumor necrosis factor alpha or interleukin 1beta), respectively. Additionally heat shock protein 70 acts as one component of a bimodal alarm signal that activates macrophages in the presence of stressful, immunogenic tumor cell killing. These differential responses of macrophages can also be used to vaccinate mice against tumor challenge, using adoptive transfer, as well as to cure mice of established tumors.

Animals↗
PubMed2001

The effect of irradiation on the biodistribution of radiolabeled pegylated liposomes.

PURPOSE: The effect of total-body irradiation (TBI) on the biodistribution and pharmacokinetics of (111)In-DTPA-labeled pegylated liposomes (IDLPL) was evaluated in tumor-bearing nude mice as part of an ongoing effort to develop liposome-targeted radiosensitizers. METHODS AND MATERIALS: Mice received TBI (2 Gy or 5 Gy) according to two protocols: (1) to test the effect of radiation delivered 30 min before liposome injection on the time course of IDLPL biodistribution to tumor and normal tissues over 96 h; (2) to test the effect of radiation at times ranging from 72 h to 1 h before liposome injection on tumor and normal tissue uptake of IDLPL at 24 h. Tumor and tissue/organ levels of liposome uptake were measured by dissection and quantitation in a gamma counter. RESULTS: For most tissues (tumor, liver, kidney, lung, skin, heart, and central nervous system), irradiation did not alter IDLPL biodistribution. Splenic uptake appeared to be increased by TBI, but further analysis revealed that this effect was due to reduced splenic weight in irradiated mice. IDLPL uptake was increased in the small intestine, stomach, musculoskeletal system, female reproductive tract, and adrenal glands in irradiated mice. CONCLUSION: These findings suggest that concomitant administration of liposomal radiosensitizers during radical radiotherapy is likely to be safe. However, caution should be exercised in situations in which significant volumes of small intestine or hemopoietic tissue will be irradiated.

Animals↗
PubMed2001

Single-fraction irradiation has no effect on uptake of radiolabeled pegylated liposomes in a tumor xenograft model.

PURPOSE: These studies were performed with the intention of examining the effect of single-fraction doses of radiotherapy (RT) on the tumor deposition of radiolabeled pegylated liposomes in an animal xenograft tumor model. METHODS AND MATERIALS: Human KB head-and-neck xenograft tumors were established in female nude mice. The effect of single fraction tumor RT doses (5, 10, 15, and 20 Gy) on the tumor uptake of intravenously administered (111)In-DTPA-labeled pegylated liposomes (IDLPL) was examined using two protocols: (1) to test the effect of RT delivered 30 min before liposome injection on the time course of tumor uptake over a 96-h period; (2) to test the effect of RT at times ranging from 72-h to 1-h before liposome injection on the levels of liposome uptake at 24 h. Tumor and normal tissue/organ (blood, liver, spleen, lung, and kidney) liposome uptake was determined by dissection and quantitation in a gamma counter. RESULTS: There was no demonstrable effect of RT on tumor uptake of IDLPL (p > 0.1 for all comparisons). Reassuringly, neither was there an effect of RT on the pharmacokinetics and biodistribution of radiolabeled liposomes to normal tissues. CONCLUSIONS: Single fraction doses of RT appear to have no effect on tumor or normal tissue biodistribution and pharmacokinetics of radiolabeled pegylated liposomes in this animal model.

Animals↗
PubMed2001

Gene therapy for prostate cancer: current status and future prospects.

PURPOSE: Locally advanced, relapsed and metastatic prostate cancer has a dismal prognosis with conventional therapies offering no more than palliation. In recent years advances achieved in understanding the molecular biology of cancer have afforded clinicians and scientists the opportunity to develop a range of novel genetic therapies for this disease. MATERIALS AND METHODS: We performed a detailed review of published reports of gene therapy for prostate cancer. Particular emphasis was placed on recent developments in the arena of nonviral (plasmid DNA, DNA coated gold particles, liposomes and polymer DNA complexes) and viral (adenovirus, retrovirus, adeno-associated virus, herpes virus and pox virus) vectors. Therapeutic strategies were categorized as corrective, cytoreductive and immunomodulatory gene therapy for the purpose of data analysis and comparison. RESULTS: Locoregional administration of nonviral and viral vectors can yield impressive local gene expression and therapeutic effects but to our knowledge no efficient systemically delivered vector is available to date. Corrective gene therapy to restore normal patterns of tumor suppressor gene (p53, Rb, p21 and p16) expression or negate the effect of mutated tumor promoting oncogenes (ras, myc, erbB2 and bcl-2) have efficacy in animal models but this approach suffers from the fact that each cancer cell must be targeted. A wide variety of cytoreductive strategies are under development, including suicide, anti-angiogenic, radioisotopic and pro-apoptotic gene therapies. Each approach has strengths and weaknesses, and may best be suited for use in combination. Immunomodulatory gene therapy seeks to generate an effective local immune response that translates to systemic antitumor activity. Currently most studies involve immunostimulatory cytokine genes, such as granulocyte-macrophage colony-stimulating factor, or interleukin-2 or 12. CONCLUSIONS: Various therapeutic genes have proved activity against prostate cancer in vitro and in vivo. However, the chief challenge facing clinical gene therapy strategies is the lack of efficient gene delivery by local and systemic routes. For the foreseeable future vector development may remain a major focus of ongoing research. Despite this caveat it is anticipated that gene therapy approaches may significantly contribute to the management of prostate cancer in the future.

Adjuvants, Immunologic↗
PubMed2001

Phase II study of pegylated liposomal doxorubicin (Caelyx) as induction chemotherapy for patients with squamous cell cancer of the head and neck.

A phase II trial of pegylated liposomal doxorubicin (Caelyx) as induction chemotherapy was conducted in 20 patients with treatment-naïve squamous cell cancer of the head and neck (SCCHN). 10 patients received two cycles of Caelyx (40 mg/m(2)) every 3 weeks before starting radical radiotherapy (RT). Subsequently, consecutive groups of 3 patients received a third escalating dose of Caelyx (10, 15 and 20 mg/m(2)) 3 days before RT. 9 of 18 (50%, 95% confidence intervals (CI): 26-74%) evaluable patients responded to Caelyx, with 11 responses in 26 (42%, 95% CI: 24-62%) evaluable sites (three complete responses (12%), eight partial responses (31%)). There was no grade 3/4 haematological, mucosal or cardiac toxicity. Nausea and vomiting were minimal. There were no drug-related RT delays. Local RT-induced toxicity was not increased. Caelyx has significant activity against SCCHN and warrants further investigation in this disease. In view of its tumour targeting properties and activity at moderate doses, it may be useful in concomitant chemoradiotherapy strategies for SCCHN.

Aged↗
PubMed2001

Phase I-II study of pegylated liposomal cisplatin (SPI-077) in patients with inoperable head and neck cancer.

BACKGROUND: Concomitant chemoradiotherapy (CCRT) for squamous cancers of the head and neck (SCCHN) improves survival but increases toxicity. Pegylated liposomes localise to solid cancers and may deliver radiosensitizing agents preferentially to tumour tissue, potentially improving the therapeutic ratio of CCRT. PATIENTS AND METHODS: A phase I-II trial of pegylated liposome encapsulated cisplatin (SPI-077) was conducted in 18 patients with treatment-naive locally advanced, inoperable SCCHN. The first 10 patients received 2 cycles of 200 mg/m2, and the next 8 received 260 mg/m2, every 3 weeks before commencing radical radiotherapy (RT). RESULTS: Only 2 of 18 (11%) patients had partial responses to SPI-077 with 2 responses in 29 (6.9%) evaluable sites. SPI-077 was tolerated well with no haematological, renal, hepatic or neurological toxicities. Nausea and vomiting were minimal. There were no drug-related delays in the delivery of RT. RT-induced mucosal and cutaneous toxicity were not significantly increased. CONCLUSIONS: SPI-077 is essentially inactive against SCCHN and, in its present formulation, does not merit further evaluation as induction chemotherapy or as part of a CCRT approach.

Aged↗
PubMed2001

Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes.

The biodistribution and pharmacokinetics of (111)In-DTPA-labeled pegylated liposomes (IDLPL) were studied in 17 patients with locally advanced cancers. The patients received 65-107 MBq of IDLPL, and nuclear medicine whole body gamma camera imaging was used to study liposome biodistribution. The t(1/2beta) of IDLPL was 76.1 h. Positive tumor images were obtained in 15 of 17 studies (4 of 5 breast, 5 of 5 head and neck, 3 of 4 bronchus, 2 of 2 glioma, and 1 of 1 cervix cancer). The levels of tumor liposome uptake estimated from regions of interest on gamma camera images were approximately 0.5-3.5% of the injected dose at 72 h. The greatest levels of uptake were seen in the patients with head and neck cancers [33.0 +/- 15.8% ID/kg (percentage of injected dose/kg)]. The uptake in the lung tumors was at an intermediate level (18.3 +/- 5.7% ID/kg), and the breast cancers showed relatively low levels of uptake (5.3 +/- 2.6% ID/kg). These liposome uptake values mirrored the estimated tumor volumes of the various tumor types (36.2 +/- 18.0 cm3 for squamous cell cancer of the head and neck, 114.5 +/- 42.0 cm3 for lung tumors, and 234.7 +/- 101.4 cm3 for breast tumors). In addition, significant localization of the liposomes was seen in the tissues of the reticuloendothelial system (liver, spleen, and bone marrow). One patient with extensive mucocutaneous AIDS-related Kaposi sarcoma was also studied according to a modified protocol, and prominent deposition of the radiolabeled liposomes was demonstrated in these lesions. An additional two patients with resectable head and neck cancer received 26 MBq of IDLPL 48 h before undergoing surgical excision of their tumors. Samples of the tumor, adjacent normal mucosa, muscle, fat, skin, and salivary tissue were obtained at operation. The levels of tumor uptake were 8.8 and 15.9% ID/kg, respectively, with tumor uptake exceeding that in normal mucosa by a mean ratio of 2.3:1, in skin by 3.6:1, in salivary gland by 5.6:1, in muscle by 8.3:1, and in fat by 10.8:1. These data strongly support the development of pegylated liposomal agents for the treatment of solid tumors, particularly those of the head and neck.

Adult↗
PubMed2000

Transcriptional control: an essential component of cancer gene therapy strategies?

The therapeutic index of cancer gene therapy approaches will, at least in part, be dictated by the spatial and temporal control of expression of the therapeutic transgenes. Strategies which allow precise control of gene transcription are likely to play a crucial role in the future pre-clinical and clinical development of gene therapy. In this review, we discuss these issues as they relate to tissue and tumor specific promoters. In addition, the exciting opportunities offered by the development of regulated gene expression systems using small molecules, radiation and heat are reviewed. It is realistic to expect that the future offers the prospect of amalgamating elements of a number of these different systems in a co-ordinated gene delivery approach with the potential to increase the efficacy and reduce the toxicity of treatment.

Allosteric Regulation↗
PubMed2000

Viral fusogenic membrane glycoprotein expression causes syncytia formation with bioenergetic cell death: implications for gene therapy.

Viral fusogenic membrane glycoproteins (FMGs) are candidates for gene therapy of solid tumors because they cause cell fusion, leading to formation of lethal multinucleated syncytia. However, the cellular mechanisms mediating cell death after FMG-induced cell fusion remain unclear. The present study was designed to examine the mechanisms by which FMG expression in hepatocellular carcinoma cells lead to cell death. Transfection of Hep3B cells with the Gibbon Ape leukemia virus hyperfusogenic envelope protein (GALV-FMG) resulted in the formation of multinucleated syncytia that reached a maximum 5 days after transfection (100 nuclei/syncytia). The syncytia were viable for a period of 2 days and then rapidly lost viability by day 5. Mitochondrial dysfunction occurred in GALV-FMG-induced syncytia prior to loss of viability with loss of the mitochondrial membrane potential, cellular ATP depletion, and release of mitochondrial cytochrome c-GFP into the cytosol. The pan-caspase inhibitor, Z-VAD-fmk, did not prevent cell death. However, glycolytic generation of ATP with fructose effectively increased cellular ATP and preserved syncytial viability. These data suggest that expression of FMG in hepatoma cells results in the formation of multinucleated syncytia, causing mitochondrial failure with ATP depletion, a bioenergetic form of cell death with necrosis. This form of cell death should be effective in vivo and enhance the bystander effect, suggesting that FMG-based gene therapy deserves further study for the treatment of hepatocellular and other cancers.

Adenosine Triphosphate↗
PubMed2000

Fusogenic membrane glycoproteins as a novel class of genes for the local and immune-mediated control of tumor growth.

We report here the use of viral fusogenic membrane glycoproteins (FMGs) as a new class of therapeutic genes for the control of tumor growth. FMGs kill cells by fusing them into large multinucleated syncytia, which die by sequestration of cell nuclei and subsequent nuclear fusion by a mechanism that is nonapoptotic, as assessed by multiple criteria. Direct and bystander killing of three different FMGs were at least one log more potent than that of herpes simplex virus thymidine kinase or cytosine deaminase suicide genes. Transduction of human tumor xenografts with plasmid DNA prevented tumor outgrowth in vivo, and cytotoxicity could be regulated through transcriptional targeting. Syncytial formation is accompanied by the induction of immunostimulatory heat shock proteins, and tumor-associated FMG expression in immunocompetent animals generated specific antitumor immunity.

Animals↗
PubMed2000

Cancer gene therapy: hard lessons and new courses.

Gene therapy for the treatment of cancer was initiated with high levels of optimism and enthusiasm. Recently, this perception has had to be tempered by the realisation that efficiency and accuracy of gene delivery remain the most significant barriers to its success. So far, there has been a disappointing inability to reach target cells with sufficient efficacy to generate high enough levels of direct killing and this has necessitated the invocation of bystander effects in order for any potential strategy to be convincing. At least in the foreseeable future, clinical advance will come from co-operation with other more established disciplines - such as chemotherapy, radiotherapy and immunotherapy. This is inevitable - and necessary - in order to prove that gene therapy can have efficacy as part of a combinatorial therapy, before hoping to move clinical mountains alone. In addition, there will have to be a thorough understanding of the clinical situations in which gene therapy will be used in order both to understand its own limitations, and to exploit its full potential. This will enable it to find the appropriate clinical niche in which its abilities will be optimally useful. Finally, anyone wishing to practise clinical cancer gene therapy will rapidly have to learn the ways of the free market and be able to juggle commercial necessities with ideological purity. Gene Therapy (2000) 7, 2-8.

Gene Targeting↗
PubMed2000

Feeding dendritic cells with tumor antigens: self-service buffet or à la carte?

Adoptive transfer of autologous dendritic cells (DC) presenting tumor-associated antigens initiate and sustain an immune response which eradicate murine malignancies. Based on these observations, several clinical trials are in progress testing safety and efficacy with encouraging preliminary reports. In these approaches, ex vivo incubation of DC with a source of tumor antigens is required to load the relevant antigenic epitopes on the adequate antigen presenting molecules. Recent data show that in some instances exogenous DC artificially injected into malignant tissue or endogenous DC attracted to the tumor nodule by means of gene transfer of GM-CSF and CD40L into malignant cells result in efficacious antitumor immunity. In the case of intratumoral injection of DC the procedure is curative only if DC had been genetically engineered to produce IL-12, IL-6 or to express CD40L. Evidence has been obtained showing that intratumoral DC can capture and process tumor antigens to be presented to T-lymphocytes. Although the exact mechanisms of tumor antigen acquisition by DC are still unclear, available data suggest a role for heat shock proteins released from dying malignant cells and for the internalization of tumor-derived apoptotic bodies. Roles for tumor necrosis versus apoptosis are discussed in light of the 'danger theory'. Gene Therapy (2000) 7, 1167-1170.

Adenoviridae↗
PubMed2000

A lentiviral vector expressing a fusogenic glycoprotein for cancer gene therapy.

The gibbon ape leukaemia virus envelope fusogenic membrane glycoprotein (GALV FMG) is a highly potent cytotoxic gene with great potential for use in cancer gene therapy. Here, we show that production of a VSV-G pseudotyped lentiviral vector expressing GALV FMG reconciles the requirements of viral production with the cytotoxic effects of GALV in human cells and has high titres on both dividing and quiescent tumour cells. Direct intratumoral injection of these stocks eradicated progressively growing human tumour xenografts. The potent bystander effect of the FMG transgene is a major contributor to the success of this approach but immunological activation may also be a factor. To our knowledge, this is the first demonstration in vivo of the potential both of FMG and lentiviral vectors for cancer gene therapy and highlights the importance of exploring different vector systems to complement the biological properties of the therapeutic transgene.

Animals↗
PubMed2000

Cancer gene therapy: developments to 2000.

Cancer, at the molecular level, continues to be more thoroughly understood. With this understanding comes the opportunity for innovative therapeutic intervention. Gene therapy remains an attractive concept to treat cancer. However, a number of gene therapy clinical trials have now been reported and it is clear that barriers remain before gene therapy gains widespread clinical application. This article outlines current directions and novel developments in the field of cancer gene therapy, which attempt to overcome these obstacles.

Animals↗
PubMed2000

Pegylated liposomes have potential as vehicles for intratumoral and subcutaneous drug delivery.

The potential value of intratumoral or s.c. injections of pegylated liposomes as locoregionally targeted therapy of tumors and their draining lymph nodes was assessed in nude mice as part of an ongoing program aimed at developing pegylated liposomal radiosensitizers for the treatment of head and neck cancers. Animals received (111)In-labeled diethylenetriaminepentaacetic acid (DTPA), either encapsulated in pegylated liposomes (IDLPL) or in the unencapsulated form ((111)In-DTPA), as intratumoral or s.c. injections, and the local retention, locoregional nodal drainage, and systemic biodistribution were measured. After intratumoral injections, IDLPL were effectively retained in the tumor with an area under the curve (AUC) between 1 and 96 h of 2,574.4% injected dose per gram hours (%ID/g x h). The corresponding value for (111)In-DTPA was 204.4%ID/g x h. Accumulation of IDLPL was seen in ipsilateral lymph nodes. The maximal ipsilateral:contralateral node ratios were 8:1 (2.2 versus 0.27%ID/g) for inguinal nodes at 24 h and 19:1 (2.5 versus 0.13%ID/g) for axillary nodes at 48 h. Unencapsulated (111)In-DTPA showed no evidence of accumulation in locoregional nodes. After s.c. injection, IDLPL were cleared slowly from the injection site with an AUC between 1 and 192 h of 24,051.1%ID/g x h. Unencapsulated (111)In-DTPA was cleared rapidly with an AUC between 1 and 192 h of 46.4%ID/g x h. Again, significant levels of IDLPL were detected in the ipsilateral locoregional nodes, with ipsilateral:contralateral ratios of 121:1 (57.9 versus 0.48%ID/g) at 24 h (inguinal nodes) and 17:1 (5.2 versus 0.3%ID/g) at 72 h (axillary nodes). There was no retention of unencapsulated (111)In-DTPA in the draining nodes. Locoregional administration of pegylated liposomal radiosensitizers may be a useful approach for targeted therapy of head and neck tumors and their nodal metastases.

Animals↗