Long non-coding RNA LINP1 promotes the malignant progression of prostate cancer by regulating p53.

We detected some serious inaccuracies and mistakes. Therefore, the article "Long non-coding RNA LINP1 promotes the malignant progression of prostate cancer by regulating p53, by H.-F. Wu, L.-G. Ren, J.-Q. Xiao, Y. Zhang, X.-W. Mao, L.-F. Zhou, published in Eur Rev Med Pharmacol Sci 2018; 22 (14): 4467-4476-DOI: 10.26355/eurrev_201807_15498-PMID: 30058678" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/15498.

Combined Effects of Low-Dose Proton Radiation and Simulated Microgravity on the Mouse Retina and the Hematopoietic System.

The purpose of the current study was to characterize the effects of simulated microgravity and radiation-induced changes in retina and retinal vasculature, and to assess the accompanying early changes in immune cells and hematological parameters. To better understand the effects of spaceflight, we used a combination of treatments designed to simulate both the radiation and low-gravity aspects of space conditions. To simulate the broad energy spectrum of a large solar particle event (SPE) and galactic cosmic ray (GCR) radiation, male C57BL/6J mice were exposed to whole-body irradiation using fully modulated beams of 150-MeV protons containing particles of energy from 0 to 150 MeV and a uniform dose-vs.-depth profile. The mice were also hindlimb-unloaded (HLU) by tail suspension. Mice were unloaded for 7 days, exposed to 50 cGy, unloaded for an additional 7 days and then sacrificed for tissue isolation at days 4 and 30 after the combined treatments. Increases in the number of apoptotic cells were observed in the endothelial cells of mice that received radiation alone or with HLU compared to controls at both days 4 and 30 (P < 0.05). Endothelial nitric oxide synthase (eNOS) levels were significantly elevated in the retina after irradiation only or combined with HLU compared to controls at the 30-day time point (P < 0.05). The most robust changes were observed in the combination group, suggesting a synergistic response to radiation and unloading. For hematopoietic parameters, our analysis indicated the main effects for time and radiation at day 4 after treatments (day 11 postirradiation) (P < 0.05), but a smaller influence of HLU for both white blood cell and lymphocyte counts. The group treated with both radiation and HLU showed greater than 50% reduction in lymphocyte counts compared to controls. Radiation-dependent differences were also noted in specific lymphocyte subpopulations (T, B, natural killer cells). This study shows indications of an early effect of low-dose radiation and spaceflight conditions on retina and immune populations.

Circular RNA ciRS-7 correlates with advance disease and poor prognosis, and its down-regulation inhibits cells proliferation while induces cells apoptosis in non-small cell lung cancer.

OBJECTIVE: This study aimed to assess the association of circular RNA (circRNA) ciRS-7 expression with clinicopathological characteristics and prognosis of non-small cell lung cancer (NSCLC) patients, and to investigate its effect on cells proliferation as well as apoptosis in NSCLC. PATIENTS AND METHODS: 132 patients with primary NSCLC who received surgical resection were recruited in this retrospective study. All patients' tumor tissue and paired adjacent tissue were collected for circRNA ciRS-7 expression detection by RT-qPCR. Disease-free survival (DFS) and overall survival (OS) were calculated. CCK-8 and Annexin-V/propidium iodide (AV/PI) assays were performed to detect cells proliferation and apoptosis in A549 cells after circRNA ciRS-7 inhibition plasmid transfection. RESULTS: CircRNA ciRS-7 expression in tumor tissue was elevated compared to paired adjacent tissue, and positively correlated with tumor size, lymph node metastasis and tumor node metastasis (TNM) stages. K-M curves illustrated that circRNA ciRS-7 high expression was correlated with both shorter DFS and OS, and multivariate Cox's proportional hazards regression analysis showed that circRNA ciRS-7 high expression was an independent factor for predicting unfavorable DFS and OS. Cells methods revealed that circRNA ciRS-7 expression was elevated in NSCLC cell lines (A549, PC9, NCI-H1299 and NCI-H1650) compared to normal lung epithelial cells (DEAS-2B), and the inhibition of circRNA ciRS-7 expression reduced cells proliferation and promoted cells apoptosis in A549 cells. CONCLUSIONS: CircRNA ciRS-7 overexpression is associated with advanced disease and poor prognosis in NSCLC patients, and the down-regulation of circRNA ciRS-7 inhibits tumor cells proliferation as well as improves cells apoptosis.

Long non-coding RNA LINP1 promotes the malignant progression of prostate cancer by regulating p53.

OBJECTIVE: We aim to investigate the expression of long non-coding RNA-LINP1 (lncRNA LINP1) in prostate cancer (PCa) and its potential mechanism. PATIENTS AND METHODS: The expression of lncRNA LINP1 in 74 pairs of PCa and normal tissues were detected by quantitative Real-time polymerase chain reaction (qRT-PCR); the relationship between its expression and the pathological features and prognosis of PCa was also analyzed. The expression of lncRNA LINP1 in the PCa cell line was verified by qRT-PCR. Knockdown of LINP1 was constructed by transfection of small interfering RNA (siRNA) in two PCa cell lines (Lncap and PC-3). The biological function of LINP1 was evaluated by cell counting kit-8 (CCK-8) assay, colony formation assay, migration and invasion assay, respectively. Finally, the potential mechanism of LINP1 was explored by Western blot and qRT-PCR. RESULTS: qRT-PCR results showed a higher expression of LINP1 in PCa than that of normal tissues. Compared with PCa patients with a lower expression of LINP1, those with higher expression had a higher tumor stage, lymphatic metastasis and distant metastasis rate, and lower overall survival rate. Proliferation, invasion and metastasis in cells transfected with si-LINP1 were remarkably decreased than those transfected with negative control (si-NC). Moreover, the expressions of the key proteins in the p53 signaling pathway, including p53, PTEN, Akt and CDK2 were remarkably decreased in cells after knockdown of LINP1. In addition, a negative correlation between LINP1 and p53 was confirmed by rescue experiments. CONCLUSIONS: Up-regulated LINP1 in PCa was correlated with a higher PCa stage, lymphatic metastasis, distant metastasis, and worse prognosis. Furthermore, LINP1 could promote the proliferative, migratory and invasive abilities of PCa by regulating the p53-signaling pathway.

Acute Effect of Low-Dose Space Radiation on Mouse Retina and Retinal Endothelial Cells.

There is concern that degradation of vision as a result of space flight may compromise both mission goals and long-term quality of life after space travel. The visual disturbances may be due to a combination of intracerebral pressure changes and exposure to ionizing radiation. The retina and the retinal vasculature play important roles in vision, yet have not been studied extensively in relationship to space travel and space radiation. The goal of the current study was to characterize oxidative damage and apoptosis in retinal endothelial cells after whole-body gamma-ray, proton and oxygen (16O) ion radiation exposure at 0.1 to 1 Gy. Six-month-old male C57Bl/6J mice were whole-body irradiated with 600 MeV/n 16O ions (0, 0.1, 0.25, 1 Gy), solar particle event (SPE)-like protons (0, 0.1, 0.25, 0.5 Gy) or 60Co gamma rays (0, 0.1, 0.25, 0.5 Gy). Eyes were isolated for examining endothelial nitric oxide synthase (eNOS) expression and characterization of apoptosis in retina and retinal endothelial cells at two weeks postirradiation. The expression of eNOS was significantly increased in the retina after proton and 16O ion exposure. 16O ions induced over twofold increase in eNOS expression compared to proton exposure at two weeks postirradiation ( P < 0.05). TUNEL assays showed dose-dependent increases in apoptosis in the retina after irradiation. Low doses of 16O ions elicited apoptosis in the mouse retinal endothelial cells with the most robust changes observed after 0.1 Gy irradiation ( P < 0.05) compared to controls. Data also showed that 16O ions induced a higher frequency of apoptosis in retinal endothelial cells compared to protons ( P < 0.05). In summary, our study revealed that exposure to low-dose ionizing radiation induced oxidative damage and apoptosis in the retina. Significant changes in retinal endothelial cells occur at doses as low as 0.1 Gy. There were significant differences in the responses of endothelial cells among the radiation types examined here.

[Comparison of two quantitative methods of endobronchial ultrasound real-time elastography for evaluating intrathoracic lymph nodes].

Objective: To compare the clinical value of two quantitative methods in analyzing endobronchial ultrasound real-time elastography (EBUS-RTE) images for evaluating intrathoracic lymph nodes. Methods: From January 2014 to April 2014, EBUS-RTE examination was performed in patients who received EBUS-TBNA examination in Shanghai Chest Hospital. Each intrathoracic lymph node had a selected EBUS-RTE image. Stiff area ratio and mean hue value of region of interest (ROI) in each image were calculated respectively. The final diagnosis of lymph node was based on the pathologic/microbiologic results of EBUS-TBNA, pathologic/microbiologic results of other examinations and clinical following-up. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were evaluated for distinguishing malignant and benign lesions. Results: Fifty-six patients and 68 lymph nodes were enrolled in this study, of which 35 lymph nodes were malignant and 33 lymph nodes were benign. The stiff area ratio and mean hue value of benign and malignant lesions were 0.32±0.29, 0.62±0.20 and 109.99±28.13, 141.62±17.52, respectively, and statistical differences were found in both of those two methods (t=-5.14, P<0.01; t=-5.53, P<0.01). The area under curves was 0.813, 0.814 in stiff area ratio and mean hue value, respectively. The optimal diagnostic cut-off value of stiff area ratio was 0.48, and the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 82.86%, 81.82%, 82.86%, 81.82% and 82.35%, respectively. The optimal diagnostic cut-off value of mean hue value was 126.28, and the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 85.71%, 75.76%, 78.95%, 83.33% and 80.88%, respectively. Conclusion: Both the stiff area ratio and mean hue value methods can be used for analyzing EBUS-RTE images quantitatively, having the value of differentiating benign and malignant intrathoracic lymph nodes, and the stiff area ratio is better than the mean hue value between the two methods.

Biological and metabolic response in STS-135 space-flown mouse skin.

There is evidence that space flight condition-induced biological damage is associated with increased oxidative stress and extracellular matrix (ECM) remodeling. To explore possible mechanisms, changes in gene expression profiles implicated in oxidative stress and in ECM remodeling in mouse skin were examined after space flight. The metabolic effects of space flight in skin tissues were also characterized. Space Shuttle Atlantis (STS-135) was launched at the Kennedy Space Center on a 13-day mission. Female C57BL/6 mice were flown in the STS-135 using animal enclosure modules (AEMs). Within 3-5 h after landing, the mice were euthanized and skin samples were harvested for gene array analysis and metabolic biochemical assays. Many genes responsible for regulating production and metabolism of reactive oxygen species (ROS) were significantly (p < 0.05) altered in the flight group, with fold changes >1.5 compared to AEM control. For ECM profile, several genes encoding matrix and metalloproteinases involved in ECM remodeling were significantly up-/down-regulated following space flight. To characterize the metabolic effects of space flight, global biochemical profiles were evaluated. Of 332 named biochemicals, 19 differed significantly (p < 0.05) between space flight skin samples and AEM ground controls, with 12 up-regulated and 7 down-regulated including altered amino acid, carbohydrate metabolism, cell signaling, and transmethylation pathways. Collectively, the data demonstrated that space flight condition leads to a shift in biological and metabolic homeostasis as the consequence of increased regulation in cellular antioxidants, ROS production, and tissue remodeling. This indicates that astronauts may be at increased risk for pathophysiologic damage or carcinogenesis in cutaneous tissue.

Protracted low-dose radiation priming and response of liver to acute gamma and proton radiation.

This study evaluated liver from C57BL/6 mice irradiated with low-dose/low-dose-rate (LDR) γ-rays (0.01 Gy, 0.03 cGy/h), with and without subsequent exposure to acute 2 Gy gamma or proton radiation. Analyses were performed on day 56 post-exposure. Expression patterns of apoptosis-related genes were strikingly different among irradiated groups compared with 0 Gy (p < 0.05). Two genes were affected in the Gamma group, whereas 10 were modified in the LDR + Gamma group. In Proton and LDR + Proton groups, there were six and 12 affected genes, respectively. Expression of genes in the Gamma (Traf3) and Proton (Bak1, Birc2, Birc3, Mcl1) groups was no longer different from 0 Gy control group when mice were pre-exposed to LDR γ-rays. When each combined regimen was compared with the corresponding group that received acute radiation alone, two genes in the LDR + Gamma group and 17 genes in the LDR + Proton group were modified; greatest effect was on Birc2 and Nol3 (> 5-fold up-regulated by LDR + Protons). Oxygen radical production in livers from the LDR + Proton group was higher in LDR, Gamma, and LDR + Gamma groups (p < 0.05 vs. 0 Gy), but there were no differences in phagocytosis of E. coli. Sections stained with hematoxylin and eosin (H&E) suggested more inflammation, with and without necrosis, in some irradiated groups. The data demonstrate that response to acute radiation is dependent on radiation quality and regimen and that some LDR γ-ray-induced modifications in liver response were still evident nearly 2 months after exposure.

Radioprotective effect of a metalloporphyrin compound in rat eye model.

PURPOSE: The purpose of this study was to evaluate the efficacy of the antioxidant Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP) in protecting ocular tissue and retinal microvasculature from radiation damage. MATERIALS AND METHODS: 75 rats were treated with Mn TE-2-PyP at 2.5 micro g/injection into one eye an hour before proton irradiation. The radiation was delivered in a single fraction to total doses of 8 Gray (Gy) or 28 Gy; Rats were sacrificed 3 days and 3, 6, 9, and 12 months thereafter for histology and quantification of photoreceptor cell populations and retinal capillary changes. RESULTS: By 6 months following radiation, there was significant loss of retinal outer and inner nuclear layers in eyes receiving radiation only (8 and 28 Gy) (p < 0.05) compared to their controls and to the eyes of rats treated with radiation plus metalloporphyrin. Retinal microvessel length density decreased significantly 6 months following 28 Gy (p < 0.05) compared to their controls and to MnTE-2-PyP treated rats. By 12 months following irradiation, irradiated eyes showed extensive damage to the photoreceptor layer, whereas the eyes of animals receiving radiation plus MnTE-2-PyP showed almost no morphological damage. MnTE-2-PyP treatment also suppressed radiation-induced apoptosis in our study. CONCLUSIONS: These results demonstrated that MnTE-2-PyP protected both photoreceptors and retinal capillaries from radiation damage, suggesting that this metalloporphyrin antioxidant is effective in regulating the damage induced by proton radiation.

Evaluation of polysaccharopeptide effects against C6 glioma in combination with radiation.

Long-term control of high-grade brain tumors is rarely achieved with current therapeutic regimens. The major goal of this study was to determine whether polysaccharopeptide (PSP), a crude polysaccharide peptide extract derived from Coriolus versicolor, a fungus, could enhance the effects of radiation against glioma cells in culture and in xenografted tumors in vivo. PSP significantly augmented radiation-induced damage to C6 rat glioma cells in vitro. Nude mice injected subcutaneously with the C6 cells were treated with PSP (injected intraperitoneally at 2 mg/injection) and radiation (2 Gy/fraction, 8 Gy in total) using three different time-dose protocols. Tumor volumes were consistently smaller in all treated groups compared to the non-treated tumor-bearing controls except in one group which received PSP prior to tumor implantation. The administration of radiation alone resulted in the slowest tumor progression, whereas PSP alone had no effect. Furthermore, PSP in combination with radiation treatment did not increase radiation efficacy. Natural killer cell, lymphocyte and granulocyte counts in blood and spleen were significantly higher in PSP-treated animals, demonstrating that PSP has protective effects on immunological function. Collectively, these results warrant further investigation to determine if PSP can be effectively utilized to upregulate immune responsiveness in case of neoplasia and other diseases in which immunosuppression is a prominent feature.

Dose response of rat retinal microvessels to proton dose schedules used clinically: a pilot study.

PURPOSE: This preclinical rat pilot study quantifies retinal microvessel, endothelial, and pericyte population changes produced by proton irradiation METHODS AND MATERIALS: The left eyes of rats were irradiated with single doses of 8, 14, 20, and 28 Gy protons; right eyes, with two fractions. Animals were euthanized, and eyes were removed; elastase digests were prepared, and cell populations were counted in sample fields. Results were compared with unirradiated controls. RESULTS: Progressive time- and dose-dependent endothelial cell loss occurred following all schedules. Cell loss was significantly different from control values (p < 0.001) following 28 Gy and following 20 Gy (p < 0.05) in a single dose. Endothelial cell loss was the same for single- and split-dose schedules. Progressive endothelial cell loss produced vessel collapse and acellular vessel strands. Endothelial cells were in the G(0) phase of the mitotic cycle. 28 Gy produced photoreceptor cell loss. CONCLUSION: The retinal digest is an elegant bioassay to quantify the microvessel population response. Single- and split-dose schedules appear to yield similar outcomes, in terms of endothelial cell density.

Acute effects of whole-body proton irradiation on the immune system of the mouse.

The acute effects of proton whole-body irradiation on the distribution and function of leukocyte populations in the spleen and blood were examined and compared to the effects of photons derived from a (60)Co gamma-ray source. Adult female C57BL/6 mice were exposed to a single dose (3 Gy at 0.4 Gy/min) of protons at spread-out Bragg peak (SOBP), protons at the distal entry (E) region, or gamma rays and killed humanely at six different times thereafter. Specific differences were noted in the results, thereby suggesting that the kinetics of the response may be variable. However, the lack of significant differences in most assays at most times suggests that the RBE for both entry and peak regions of the Bragg curve was essentially 1.0 under the conditions of this study. The greatest immunodepression was observed at 4 days postexposure. Flow cytometry and mitogenic stimulation analyses of the spleen and peripheral blood demonstrated that lymphocyte populations differ in radiosensitivity, with B (CD19(+)) cells being most sensitive, T (CD3(+)) cells being moderately sensitive, and natural killer (NK1.1(+)) cells being most resistant. B lymphocytes showed the most rapid recovery. Comparison of the T-lymphocyte subsets showed that CD4(+) T helper/inducer cells were more radiosensitive than the CD8(+) T cytotoxic/suppressor cells. These findings should have an impact on future studies designed to maximize protection of normal tissue during and after proton-radiation exposure.

Hematological and TGF-beta variations after whole-body proton irradiation.

The acute effects of proton whole-body irradiation on five bone-marrow-derived cell types and transforming growth factor-beta 1 (TGF-beta 1) were examined and compared to the effects of photons (60Co). C57BL/6 mice were exposed to 3 Gy (0.4 Gy/min) protons at spread-out Bragg peak (SOBP), protons at entry (E), or 60Co and euthanized on days 0.5-17 thereafter. 60Co-irradiated animals had decreased erythrocytes, hemoglobin and hematocrit at 12 hours post-exposure; depression was not noted in proton (SOBP or E)-irradiated groups until day 4. Significantly decreased leukocyte counts were observed at this same time in all irradiated groups, with lymphocyte loss being greater than that of monocytes, and the depression was generally maintained. In contrast, the levels of neutrophils and thrombocytes fluctuated, especially during the first week; significant differences were noted among irradiated groups in neutrophil levels. Plasma TGF-beta 1 was elevated on day 7 in the 60Co, but not proton, irradiated mice. Collectively, the data show that dramatic and persistent changes occurred in all irradiated groups. However, few differences in assay results were seen between animals exposed to protons (SOBP or E) or photons, as well as between the groups irradiated with either of the two regions of the proton Bragg curve.

What is the role of radiation in the treatment of subfoveal membranes: review of radiobiologic, pathologic, and other considerations to initiate a multimodality discussion.

BACKGROUND: Single-dose-fraction conformal proton beam and multiple-fraction X ray dose schedules have been used to treat subfoveal neovascular membranes. All schedules successfully controlled membrane progression, stabilized vision in most patients, and increased visual acuity in some. Conformal protons also decreased the radiation dose to healthy tissues outside the designated volume (16 mm in diameter). It appears that radiation therapy could be useful and cost-effective, but neither the optimal time-dose schedule single or multiple dose fractions nor the type of radiation proton conformal beam or x-ray therapy are defined. METHODS: By means of an extensive literature survey, we reviewed the rationale for using radiation to treat subfoveal neovascularization, examined a paradigm of radiation interaction with tissue, reviewed the histopathology of neovascular membranes, and documented the role of growth factors in the pathophysiology of the disease. Accepting that the eye is an extracranial brain extension, and that its microvasculature has properties similar to brain microvessels, we reviewed the radiobiologic response of brain microvessels. We also revisited the controversy concerning the efficacy of single-dose-fraction vs. multifraction schedules. RESULTS: This paper outlines parameters within which radiation therapy's role might be defined, and proposes a clinical radiation-biology scoring program to evaluate radiation effects, based on the SOMA concept. CONCLUSION: A prospective, controlled clinical trial is feasible and is indicated to determine radiation therapy's role in managing the proliferative component of age-related macular degeneration.

Tumor necrosis factor-alpha enhances antitumor effects of radiation against glioma xenografts.

Long-term control of high-grade brain tumors is rarely achieved with current therapeutic regimens. The aim of this study was to determine if low doses of tumor necrosis factor-alpha (TNF-alpha) could augment the effects of radiation in a glioma xenograft model and to evaluate hematological and other parameters that might indicate treatment-related toxicity. Nude mice were injected subcutaneously with C6 rat glioma cells and randomized into groups. Two different time-dose protocols were employed using intravenous human recombinant TNF-alpha and radiation beginning within 24 h after tumor cell implantation. The administration of radiation as a single agent slowed tumor progression, whereas TNF-alpha alone had no effect. However, TNF-alpha, especially when given twice per week before radiation for a total of four doses each, significantly increased the efficacy of the radiation. Low leukocyte counts were associated with combination treatment, whereas transforming growth factor-beta 1 levels were depressed in all treated groups. TNF-alpha did not modulate radiation-induced inhibition of C6 cell proliferation in vitro. The data show that TNF-alpha at relatively nontoxic doses can significantly enhance the antitumor effects of radiation against a rapidly growing glioma. This effect was more than additive, because TNF-alpha alone did not slow tumor progression.

Immunotherapy with low-dose interleukin-2 and a polysaccharopeptide derived from Coriolus versicolor.

The purpose of the present study was to evaluate the therapeutic efficacy of locally administered low-dose interleukin-2 (IL-2) and a polysaccharopeptide (PSP) derived from Cariolous versicolor in a herpes virus Type 2-transformed murine tumor (H238) model and to determine possible mechanisms of action. BALB/c mice were inoculated subcutaneously (s.c.) with H238 tumor cells and randomized into groups: a) no tumor and no treatment control, b) tumor and no treatment control, c) tumor + IL-2 at 0 to 4 days, d) tumor + PSP at 0 to 10 days, e) tumor + IL-2 at 0 to 4 days + PSP at 0 to 10 days, and f) tumor + IL-2 at 15 to 19 days + PSP at 15 to 25 days. The IL-2 was administered s.c. at 2 x 10(4) i.u./mouse/injection; PSP was given s.c. at 2 mg/mouse/injection. No obvious toxicity was noted during the treatments. IL-2 and, to a lesser extent, PSP significantly slowed (p < 0.05) tumor progression when given alone immediately after tumor cell injection. The combination of the two modalities did not significantly enhance the antitumor effect of IL-2 alone. However, mice receiving both agents had IL-2 in the plasma, their tumors expressed low levels of transforming growth factor-beta, and their splenocyte response to mitogenic stimulation was significantly higher than in untreated controls. Changes in blood leukocyte populations and splenic oxidative burst capacity were associated with tumor presence, but not with the type of treatment. In vitro assays showed that both IL-2 and PSP can suppress the uptake of 3H-thymidine by tumor cells and that the effect is more pronounced whent the agents are used in combination. These results indicate that IL-2 and PSP can slow progression of H238 tumors and that the mechanisms of action may be related to their direct cytotoxic effects, as well to their immunomodulatory properties.

Evaluation of TNF-alpha effects on radiation efficacy in a human lung adenocarcinoma model.

This study sought to determine if pretreatment with low-dose tumor necrosis factor-alpha (TNF-alpha) can enhance the effects of radiation in an NCI-H441 human lung tumor xenograft model. In vitro assays were performed on spleen cells, blood leukocytes, and plasma from the animals, as well as on cultured tumor cells. Tumors in animals given only TNF-alpha grew as well as, or better than, tumors in their untreated counterparts at all time-dose regimens employed. In contrast, early treatment with a total radiation dose of 16 Gy resulted in complete tumor inhibition, whereas 8 Gy modestly (but significantly, P < 0.05) slowed tumor progression. However, the administration of TNF-alpha (4 x 10(4) total units/mouse) 16-18 h prior to irradiation (8 Gy total dose) enhanced the antitumor effects of radiation when treatment was initiated early (P < 0.05). Oxygen radical production and response to mitogenic stimulation by splenocytes were greatest in untreated tumor-bearing animals. Total leukocyte counts in mice given radiation or TNF-alpha + radiation were low, and treatment-related changes were found in percentages of neutrophils and lymphocytes. In vitro assays of tumor cells showed that TNF-alpha + radiation resulted in greater suppression of clonogenic survival and incorporation of [3H]TdR and [3H]UdR incorporation than either agent alone. These results suggest that the use of low-dose TNF-alpha together with radiation may be beneficial in the clinical setting and so warrant further investigation.

Immunotherapy with low-dose interleukin-2 and interferon-gamma in a murine tumor model.

The aim of this study was to evaluate the therapeutic efficacy of locally administered low-dose interleukin-2 (IL-2) alone or together with interferon-gamma (IFN-gamma) in a herpes simplex virus type 2-transformed murine (H238) fibrosarcoma model. In vitro incubation showed that IL-2, but not IFN-gamma, had a significant inhibitory effect on DNA synthesis in H238 cells. In vivo experiments were performed with BALB/c mice to determine the optimal time of treatment with each cytokine after subcutaneous (sc) tumor implantation. The greatest antitumor effect with IL-2 (1 x 10(5) total international units, sc) was noted when treatment was administered during the first week after tumor injection, whereas with IFN-gamma (500 total units, intraperitoneally) treatment during the second week proved best. Combination of the two agents produced complete tumor regression in 44.4% of mice; regression with single-modality treatment was 0-11%. The presence of H238 tumor induced splenomegaly and enhanced the oxidative burst capacity of phagocytes. Peripheral blood leukocyte counts were low in tumor-bearing groups, regardless of treatment. IL-2 and IFN-gamma were nondetectable in the plasma of tumor-bearing or control mice; however, total TGF-beta 1 was 248% higher with IL-2 treatment compared with tumor-bearing nontreated controls. These results show that IL-2 and IFN-gamma can significantly inhibit the growth of highly aggressive H238 tumors and support further investigations with these agents.

Immunotherapy with low-dose interleukin-2 and anti-transforming growth factor-beta antibody in a murine tumor model.

The purpose of the present study was to evaluate the therapeutic efficacy of low-dose interleukin-2 (IL-2) alone or together with antibody against transforming growth factor-beta (TGF-beta) in a Herpes simplex virus Type 2-transformed (H238) fibrosarcoma model. BALB/c mice were inoculated subcutaneously (s.c.) with 5 x 10(5) H238 tumor cells in one or both hind thighs and treated with IL-2, anti-TGF-beta, or a combination of both agents. Nontreated tumor-bearing and normal animals served as controls. In the appropriate treatment groups, each mouse was given a total of 10(5) international units (i.u.) of IL-2 s.c. at one tumor implantation site and/or 1 microgram of anti-TGF-beta intraperitoneally (i.p.) over a period of 5 days beginning on the day of tumor cell implantation. No toxicity was noted during treatment. The slowest tumor growth was observed in mice with single tumors when treated with IL-2 or anti-TGF-beta alone, whereas combination treatment resulted in growth similar to that of untreated controls. However, in animals with two tumors, the tumor injected with IL-2 grew more rapidly than the untreated one. Spleen cell responsiveness to mitogenic stimulation was generally depressed in tumor-bearing mice compared to normal controls, but some differences were noted with treatment. In contrast, tumor presence induced striking splenomegaly and enhanced the chemiluminescent oxidative burst of phagocytic cells in the spleen. In the groups with a single tumor, plasma TGF-beta levels were similar to those of nontumor-bearing controls, however the concentrations were decreased in the animals with two tumors. These results show that IL-2 or anti-TGF-beta can slow progression of H238 tumors under certain conditions. However, combination of the two modalities proved to be of no benefit.