Papers by William Mcbride
Journal of Leukocyte Biology
IL-3 gene expression within tumors leads to host-cell infiltration, particularly by macrophages, ... more IL-3 gene expression within tumors leads to host-cell infiltration, particularly by macrophages, slower tumor growth, and enhanced immunogenicity. Surprisingly, tumor-associated macrophages (TAMs) from within FSAN-JmIL3 tumors had decreased expression of TNF-α and iNOS. On short-term culture, TAMs from FSAN-JmIL3 tumors regained their capacity to produce TNF-α and NO, indicating that they were primedin vivo. In vitro experiments were unable to demonstrate differences between FSAN-JmIL3 and FSAN tumor cells in their ability to stimulate TNF-α production by TAMs. In the absence of evidence that TAM activation was responsible for the slower growth of FSAN-JmIL3 tumors, the response of tumor cells to these effector molecules was studied. TNF-α and NO were cytotoxic for FSAN-JmIL3 cells but growth stimulatory for FSAN. These tumor-related phenotypic changes may contribute as much if not more than functional changes in host infiltrating cells to the slower growth of FSAN-JmIL3 tumorsin vivo.
Frontiers in Bioscience
ABSTRACT
Anticancer research
New strategies are becoming available that promise to revolutionize cancer immunotherapy. Althoug... more New strategies are becoming available that promise to revolutionize cancer immunotherapy. Although the task of generating what is in essence a pathogenic autoimmune anti-tumor response in the face of local and systemic immune suppression is likely to remain a formidable one, advances in molecular strategies for enhancing tumor immunity have been made that show considerable promise, in particular those based on gene transfer technology. For example, introduction of certain cytokine genes into murine tumor cells have been shown to enhance tumor immunogenicity and induce regression. Caution is needed in properly interpreting the relevance of observations derived from murine models for human cancer, but clinical trials are underway that will test the utility of cytokine gene therapy for cancer and that will generate data that will be useful for the design of future strategies. Because of the magnitude of the problem of inducing tumor regression, it is argued that, even if genetically en...
Folia biologica, 1994
Retroviral Jzen vectors were used to introduce cytokine genes into cell lines established from a ... more Retroviral Jzen vectors were used to introduce cytokine genes into cell lines established from a "moderately immunogenic" FSAR and a "non-immunogenic" FSAN murine fibrosarcoma. The effects of cytokine gene expression on tumour behaviour and host responses have been studied in vitro and in vivo. In this paper we report that, in comparison to other cytokines, interleukin-3 (IL-3) was surprisingly effective at enhancing the immunogenicity of irradiated tumour cell vaccines as seen by the development of protective immunity to parental tumour growth. Protection was tumour-specific and spleen cells from immunized mice could adoptively transfer immunity causing established parental tumours to regress in SCID mice. IL-3 acted through paracrine and endocrine pathways to induce largely a granulocyte infiltrate into tumours and through an autocrine pathway to increase major histocompatibility complex class I expression on both tumour types and CD44 expression on one. IL-3 g...
Frontiers in Oncology, 2012
There is compelling evidence that lymphocytes are a recurring feature in radiation damaged normal... more There is compelling evidence that lymphocytes are a recurring feature in radiation damaged normal tissues, but assessing their functional significance has proven difficult. Contradictory roles have been postulated in both tissue pathogenesis and protection, although these are not necessarily mutually exclusive as the immune system can display what may seem to be opposing faces at any one time. While the exact role of T lymphocytes in irradiated normal tissue responses may still be obscure, their accumulation after tissue damage suggests they may be critical targets for radiotherapeutic intervention and worthy of further study. This is accentuated by recent findings that pathologically damaged "self," such as occurs after exposure to ionizing radiation, can generate danger signals with the ability to activate pathways similar to those that activate adoptive immunity to pathogens. In addition, the demonstration of T cell subsets with their recognition radars tuned to "self" moieties has revolutionized our ideas on how all immune responses are controlled and regulated. New concepts of autoimmunity have resulted based on the dissociation of immune functions between different subsets of immune cells. It is becoming axiomatic that the immune system has the power to regulate radiation-induced tissue damage, from failure of regeneration to fibrosis, to acute and chronic late effects, and even to carcinogenesis. Our understanding of the interplay between T lymphocytes and radiation-damaged tissue may still be rudimentary but this is a good time to reexamine their potential roles, their radiobiological and microenvironmental influences, and the possibilities for therapeutic manipulation. This review will discuss the yin and yang of T cell responses within the context of radiation exposures, how they might drive or protect against normal tissue side effects and what we may be able do about it.
Radiotherapy and Oncology, 1993
The goals of this study were to quantify myelin-associated changes in the brain following single ... more The goals of this study were to quantify myelin-associated changes in the brain following single doses of radiation and to determine their relationship to the dose limits that this tissue can tolerate. Mice developed a transient loss of balance 1 month after 60 Gy doses 250 kVp X-rays to the brain and 3-4 months after 30-45 Gy radiation, but not after lower doses. The symptoms were transient and lasted-1 month. The EDs0/300 for radiation-induced brain death, which occurred largely between 200 and 240 days, was 32.4 Gy (29.1, 35.5 Gy, 95% confidence limit of mean). At the time that animals developed neurological symptoms, 3-4 months after irradiation with doses of 30-45 Gy, biochemical assays of myelin-associated proteins showed decreases in 2',3'-cyclic nucleotide phosphohydrolase (CNPase) and myelin basic protein (MBP) levels that were not seen with lower radiation doses. By 120-180 days, further dose-dependent decreases in both CNPase and MBP levels were found after 20-45 Gy irradiation that preceded and correlated with death. The correlation of the decrease in CNPase and MBP levels with the incidence of transient neurological malfunction and animal death, together with histological evidence, suggests that demyelination is responsible for these phenomena.
Radiation Research, 1994
Cells from patients with ataxia telangiectasia (AT) are abnormal in their response to irradiation... more Cells from patients with ataxia telangiectasia (AT) are abnormal in their response to irradiation as judged by clonogenic survival and accumulation in G2 phase. The relationship of the results of these two assays, however, is still a matter of controversy. Flow cytometry was used to measure the distribution of cells in the phases of the cell cycle after 2 Gy irradiation in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) and SV40-transformed fibroblasts. AT cells showed increased and prolonged accumulation in G2/M phase regardless of the cell type (lymphoblastoid or fibroblast) or complementation group (A, C or D). To test the hypothesis that prolonged accumulation of AT cells in G2 phase after irradiation was not simply a reflection of their radiosensitivity, we gave iso-survival radiation doses to SV40-transformed fibroblasts of two AT and one control cell lines. The two AT cell lines exited from the G2/M-phase block more slowly than control cells after each dose tested. This implies that prolonged accumulation in G2/M phase in AT cells is not directly related to radiosensitivity as measured by clonogenic survival, but that factors involved in the exit from G2 phase after irradiation may be abnormally regulated. We found that G2-phase arrest of AT cells did not necessarily result in a fatal consequence in the first cell cycle after irradiation. Furthermore, G2-phase arrest did not lead to detectable DNA fragmentation characteristic of apoptosis as judged by gel electrophoresis.
Radiation Research, 2012
Cytokines function in many roles that are highly relevant to radiation research. This review focu... more Cytokines function in many roles that are highly relevant to radiation research. This review focuses on how cytokines are structurally organized, how they are induced by radiation, and how they orchestrate mesenchymal, epithelial and immune cell interactions in irradiated tissues. Pro-inflammatory cytokines are the major components of immediate early gene programs and as such can be rapidly activated after tissue irradiation. They converge with the effects of ionizing radiation in that both generate free radicals including reactive oxygen and nitrogen species (ROS/ RNS). "Self" molecules secreted or released from cells after irradiation feed the same paradigm by signaling for ROS and cytokine production. As a result, multilayered feedback control circuits can be generated that perpetuate the radiation tissue damage response. The pro-inflammatory phase persists until such times as perceived challenges to host integrity are eliminated. Antioxidant, antiinflammatory cytokines then act to restore homeostasis. The balance between pro-inflammatory and anti-inflammatory forces may shift to and fro for a long time after radiation exposure, creating waves as the host tries to deal with persisting pathogenesis. Individual cytokines function within socially interconnected groups to direct these integrated cellular responses. They hunt in packs and form complex cytokine networks that are nested within each other so as to form mutually reinforcing or antagonistic forces. This yin-yang balance appears to have redox as a fulcrum. Because of their social organization, cytokines appear to have a considerable degree of redundancy and it follows that an elevated level of a specific cytokine in a disease situation or after irradiation does not necessarily implicate it causally in pathogenesis. In spite of this, "driver" cytokines are emerging in pathogenic situations that can clearly be targeted for therapeutic benefit, including in radiation settings. Cytokines can greatly affect intrinsic cellular radiosensitivity, the incidence and type of radiation tissue complications, bystander effects, genomic instability and cancer. Minor and not so minor, polymorphisms in cytokine genes give considerable diversity within populations and are relevant to causation of disease. Therapeutic intervention is made difficult by such complexity; but the potential prize is great.
Neoplasia, 2006
INTRODUCTION: Transient hypoxia and subsequent reoxygenation are common phenomena in solid tumors... more INTRODUCTION: Transient hypoxia and subsequent reoxygenation are common phenomena in solid tumors that greatly influence the outcome of radiation therapy. This study was designed to determine how varying cycles of hypoxia/reoxygenation affect the response of cervical carcinoma cells irradiated under oxic and hypoxic conditions and whether this could be modulated by proteasome inhibition. MATERIALS AND METHODS: Plateau-phase SiHa cervical carcinoma cells in culture were exposed to varying numbers of 30-minute cycles of hypoxia/reoxygenation directly before irradiation under oxic or hypoxic conditions. 26S Proteasome activity was blocked by addition of MG-132. Clonogenic survival was measured by a colonyforming assay. RESULTS: Under oxic conditions, repeated cycles of hypoxia/reoxygenation decreased the clonogenic survival of SiHa cells. This effect was even more pronounced after the inhibition of 26S proteasome complex. In contrast, under hypoxic conditions, SiHa cells were radioresistant, as expected, but this was increased by proteasome inhibition. CONCLUSIONS: Proteasome inhibition radiosensitizes oxygenated tumor cells but may also protect tumor cells from ionizing radiation under certain hypoxic conditions.
Molecular Diagnosis, 1998
Background: Being able to predict the response of tumors to radiation therapy would improve the d... more Background: Being able to predict the response of tumors to radiation therapy would improve the decision-making process involved in choosing treatment options for cancer. Expression of certain oncogenes and/or inactivation of tumor suppressor genes has been shown to alter cellular radiation responses; however, it is still not clear what marker or combination of markers would best indicate a radioresistant tumor, or whether such screening would be clinically useful. Current choices of markers are derived mainly from in vitro studies on cell survival after irradiation. In general, expression of transforming oncogenes increases cellular radioresistance. This was also demonstrated in this study for v-abl, bcr abl, v-Ha-ras, v-mos, and v-fes expressed in rat-1 cells. There are, however, conflicting data. Some of the discrepancies may in part be due to interactions between the oncogene-activated signals and other intrinsic or activated pathways. One downstream pathway that is required for oncogene-induced transformation involves c-myc. There is evidence that in some systems myc expression can potentiate ras-induced radiation resistance. Myc may therefore play an important role in determining tumor radioresistancy in the context of other oncogenes. Methods and Results: In this study, the role of c-myc in modulating intrinsic and oncogene-induced cellular radiation responses was investigated in more detail. Retroviral vectors were used to express c-myc and dominant negative mutant c-myc genes in rat 1 cells, with and without ca-transfection of v-abl as measured by clonogenic assay, rat 1. Cells infected with c-myc or v-abl were more resistant to irradiation than neo-transfected cells or control cells; however, cells doubly infected were not resistant, even though they had an increased transformation index. This indicates that transformation-related events per se do not necessarily lead to radiation resistance. It also suggests that the effects of c-myc on radioresistance may depend on what other pathways are activated. This conclusion was strengthened by the finding that expression of a dominant negative c-myc (dn-myc) mutant gene blocked v-abl-induced radiation resistance, but on its own made rat-1 cells more resistant to radiation. Conclusions: The apparently contradictory effects of c-myc in either enhancing or reducing radioresponsiveness may be explained by the dualistic roles of c-myc in promoting signal transduction pathways resulting in either cell proliferation or death, depending on what other pathways are activated. The studies indicate that it will be difficult to predict tumor response to radiation purely by examining expression of transforming oncogenes and it is likely that a number of markers will need to be examined to derive a reliable indication of tumor radiation response.
Molecular Cancer Therapeutics, 2005
JNCI: Journal of the National Cancer Institute, 2006
2Gy ] = 0.2, versus mammospheres, mean SF 2Gy = 0.46, difference = 0.26, 95% confi dence interval... more 2Gy ] = 0.2, versus mammospheres, mean SF 2Gy = 0.46, difference = 0.26, 95% confi dence interval [CI] = 0.05 to 0.47; P = .026; MDA-MB-231: monolayer cultures, mean SF 2Gy = 0.5, versus mammospheres, mean SF 2Gy = 0.69, difference = 0.19, 95% CI = − 0.07 to 0.45; P = .09). Levels of ROS increased in both mammospheres and monolayer cultures after irradiation with a single dose of 10 Gy but were lower in mammospheres than in monolayer cultures (MCF-7 monolayer cultures: 0 Gy, mean = 1.0, versus 10 Gy, mean = 3.32, difference = 2.32, 95% CI = 0.67 to 3.98; P = .026; mammospheres: 0 Gy, mean = 0.58, versus 10 Gy, mean = 1.46, difference = 0.88, 95% CI = 0.20 to 1.56; P = .031); phosphorylation of H2AX increased in irradiated monolayer cultures, but no change was observed in mammospheres. Fractionated doses of irradiation increased activation of Notch-1 (untreated, mean = 10.7, versus treated, mean = 15.1, difference = 4.4, 95% CI = 2.7 to 6.1, P = .002) and the percentage of the cancer stem/initiating cells in the nonadherent cell population of MCF-7 monolayer cultures (untreated, mean = 3.52%, versus treated, mean = 7.5%, difference = 3.98%, 95% CI = 1.67% to 6.25%, P = .009). Conclusions: Breast cancer-initiating cells are a relatively radioresistant subpopulation of breast cancer cells and increase in numbers after short courses of fractionated irradiation. These fi ndings offer a possible mechanism for the accelerated repopulation of tumor cells observed during gaps in radiotherapy. [J Natl Cancer Inst 2006;98: 1777-85 ] One view of cancer is that it may arise from a single cell that has the ability to self-renew and thus to maintain the growth of a tumor, whereas the majority of its cellular progeny does not. There is increasing evidence that such a cell population exists and that these cells can be prospectively identifi ed in brain tumors (1) , breast cancer (2) , prostate cancer (3) , and melanoma
The Journal of Immunology, 2006
Proteasome inhibition results in proapoptotic changes in cancer cells, which may make them more s... more Proteasome inhibition results in proapoptotic changes in cancer cells, which may make them more sensitive to immune effector cells. We established a murine model to test whether the proteasome inhibitor bortezomib could sensitize established B16 melanoma tumors to dendritic cell (DC)-activated immune effector cells. Day 3-established s.c. B16 tumors had significantly decreased tumor outgrowth when treated with a combination of bortezomib and DC, regardless of whether the DC were loaded or not with a tumor Ag. In vivo Ab-depletion studies demonstrated that the effector cells were NK and CD8+ cells, but not CD4+ cells. NF-κB nuclear transcription factor assay and gene-expression profiling of B16 treated with bortezomib was consistent with inhibition of NF-κB target genes leading to a proapoptotic phenotype. In vitro lytic assays demonstrated that TNF-α, but not perforin, Fas-ligand, or TRAIL, was responsible for bortezomib-sensitized B16 cytotoxicity. In conclusion, the proteasome inh...
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Papers by William Mcbride