Ivan Ding

University Center Rochester, Rochester, Minnesota, United States

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Publications (57)189.9 Total impact

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    ABSTRACT: The lack of effective treatment for pancreatic cancer results in a very low survival rate. This study explores the enhancement of the therapeutic effect on human pancreatic cancer via the combination of triptolide and ionizing radiation (IR). In vitro AsPC-1 human pancreatic cancer cells were treated with triptolide alone, IR alone, or triptolide plus IR. Cell proliferation was analyzed with sulforhodamine B (SRB) method and clonogenic survival; comparison of apoptosis induced by the above treatment was analyzed by annexin V-propidium iodide (PI) staining. Furthermore, the expression of apoptotic pathway intermediates was measured by the assay of caspase activity and Western blot. Mitochondrial transmembrane potential was determined by JC-1 assay. In vivo, AsPC-1 xenografts were treated with 0.25 mg/kg triptolide, 10 Gy IR, or triptolide plus IR. The tumors were measured for volume and weight at the end of the experiment. Tumor tissues were tested for terminal nucleotidyl transferase-mediated nick end labeling (TUNEL) and immunohistochemistry. The combination of triptolide plus IR reduced cell survival to 21% and enhanced apoptosis, compared with single treatment. In vivo, tumor growth of AsPC-1 xenografts was reduced further in the group treated with triptolide plus IR compared with single treatment. TUNEL and immunohistochemistry of caspase-3 cleavage in tumor tissues indicated that the combination of triptolide plus IR resulted in significantly enhanced apoptosis compared with single treatments. Triptolide in combination with ionizing radiation produced synergistic antitumor effects on pancreatic cancer both in vitro and in vivo and seems promising in the combined modality therapy of pancreatic cancer.
    Clinical Cancer Research 09/2007; 13(16):4891-9. · 7.84 Impact Factor
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    ABSTRACT: The biological and physiological effects of exogenous FGF 1 and VEGF were measured using the KHT murine fibrosarcoma tumor model. Tumor-bearing C3H mice were treated intratumorally with either one or six daily doses of 6 microg/mouse FGF1, VEGF, or saline. Tumors were excised 24 hrs after the final injection. Compared to controls, only FGF1 treatment significantly increased tumor weight and size, and only in the 6 dose group. Both FGF1 and VEGF administration (6 dose) decreased tumor cell hypoxia as detected by EF5 uptake: 85% +/- 5% for FGF1 and 82% +/- 6% for VEGF versus 100% +/- 6% for controls. Decreased tumor cell EF5 staining, however, was not associated with changes in numbers of structural or angiogenic vessels. DiOC7 staining showed a slight decrease in perfused vessel numbers in tumors treated with daily VEGF. Intratumoral injections of FGF1 or VEGF also slightly decreased the tumor tissue chemokine MCP-1, interleukins (IL-1beta, IL-6, and IL-18) mRNA expression, and increased NFkappaB binding without altering Ap-1 binding of IkappaB protein expression. In summary, single pulse exposures of tumors to angiogenic factors had little or no effects on tumor growth or perfusion, while daily exposures stimulated tumor growth through improved tumor oxygenation. This improved vascular function occurs without an increase in vascular density.
    Advances in experimental medicine and biology 02/2007; 599:109-16. · 1.83 Impact Factor
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    ABSTRACT: Endostatin, a fragment of the C-terminal domain of mouse collagen XVIII, is a recently demonstrated endogenous inhibitor of tumor angiogenesis. Although endostatin can be detected in blood and urine of tumor-bearing as well as normal mice, the exact localization of the endogenous protein and its related peptides in tumor tissues is unknown. We used immunohistochemistry and immunoblotting to identify endostatin tissue location and staining patterns in tumor, as well as to determine the differences in the levels of endostatin expression between tumor cells (in vitro) and tumor tissues (in vivo). Using a specific polyclonal antibody against murine endostatin, we quantitatively determined the levels of endostatin in five murine mammary tumors and the KHT sarcoma by Western blotting. The staining patterns for this protein in tumor sections were examined histologically by immunohistochemistry. Our results show that: (1) Endogenous endostatin and its related peptides are widely distributed in all in vivo tumor types tested, but not in most of the cultured tumor cell lines. (2) Endogenous endostatin stained most tumor stromal components, including vessel walls, basement membranes, extracellular spaces, and tumor cells. (3) Staining patterns and localization of endostatin and thrombospondin-1 were similar in these tumor sections.
    Advances in experimental medicine and biology 02/2007; 599:147-53. · 1.83 Impact Factor
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    ABSTRACT: To determine whether curcumin ameliorates acute and chronic radiation skin toxicity and to examine the expression of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-18, IL-1Ra, tumor necrosis factor [TNF]-alpha, and lymphotoxin-beta) or fibrogenic cytokines (transforming growth factor [TGF]-beta) during the same acute and chronic phases. Curcumin was given intragastrically or intraperitoneally to C3H/HeN mice either: 5 days before radiation; 5 days after radiation; or both 5 days before and 5 days after radiation. The cutaneous damage was assessed at 15-21 days (acute) and 90 days (chronic) after a single 50 Gy radiation dose was given to the hind leg. Skin and muscle tissues were collected for measurement of cytokine mRNA. Curcumin, administered before or after radiation, markedly reduced acute and chronic skin toxicity in mice (p < 0.05). Additionally, curcumin significantly decreased mRNA expression of early responding cytokines (IL-1 IL-6, IL-18, TNF-alpha, and lymphotoxin-beta) and the fibrogenic cytokine, TGF-beta, in cutaneous tissues at 21 days postradiation. Curcumin has a protective effect on radiation-induced cutaneous damage in mice, which is characterized by a downregulation of both inflammatory and fibrogenic cytokines in irradiated skin and muscle, particularly in the early phase after radiation. These results may provide the molecular basis for the application of curcumin in clinical radiation therapy.
    International Journal of Radiation OncologyBiologyPhysics 07/2006; 65(3):890-8. · 4.52 Impact Factor
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    ABSTRACT: Interleukin 1 beta (IL1B), a potent pro-inflammatory cytokine, is directly up-regulated by radiation and is known to regulate other inflammation-related molecules, such as the matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs). However, the nature of the interaction of IL1B with MMPs and TIMPs in radiation-induced skin fibrosis is unknown. We examined the response of primary dermal keratinocytes, fibroblasts and endothelial cells to single-fraction radiation (10 Gy) and compared the results to a temporal sequence of histology from irradiated C57BL/6 and IL1R1 knockout mice. These studies showed that keratinocytes are the major IL1-producing cells in vitro and that radiation induces an immediate and chronic elevation in the expression of IL1B mRNA in the skin of C57BL/6 mice. This elevation was principally early and was less pronounced in the IL1R1 knockout strain, which also demonstrated reduced late radiation fibrosis. Radiation also increased expression of MMP mRNA in C57BL/6 mice. Finally, exogenous IL1B protein induced robust endogenous IL1B mRNA expression, along with a brisk increase in MMPs and collagen III, but only in the C57BL/6 mice. In conclusion, these data suggest that IL1B plays a critical role in radiation-induced fibrosis and that the increased MMPs fail to block the IL1-related collagen accumulation.
    Radiation Research 03/2006; 165(2):181-91. · 2.70 Impact Factor
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    ABSTRACT: Overexpression of decoy receptor (DcR) 3 protein, a recently discovered member of the tumor necrosis factor receptor superfamily, was examined in 40 esophagogastrectomy specimens containing areas of Barrett esophagus (n = 27), low-grade dysplasia (n = 27), high-grade dysplasia or carcinoma in situ (n = 22), and esophageal adenocarcinoma (EAC; n = 28) with immunohistochemical analysis. The results revealed significantly more overexpression of DcR3 in high-grade dysplasia or carcinoma in situ and EAC than in benign esophageal mucosa (both P < .0001), Barrett esophagus (both P < .001), and low-grade dysplasia (P < .01 and P = .033, respectively). Low-grade dysplasia also showed significant overexpression of DcR3 compared with benign esophagus (P < .05) but not with Barrett esophagus (P > .05). DcR3 overexpression seems to negatively correlate with the grade of EAC. Our results suggest that overexpression of DcR3 protein might aid in the diagnosis of high-grade dysplasia or carcinoma in situ and EAC and also might serve as a potential therapeutic target.
    American Journal of Clinical Pathology 08/2005; 124(2):282-7. · 2.88 Impact Factor
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    ABSTRACT: The negative effects of radiation on the bowel critically limit the treatment doses possible for tumors in the abdomen. The purpose of the present study was to measure mRNA levels of inflammatory cytokines in abdominally irradiated mouse bowel. Eight- to 12-week-old DBA mice were irradiated to the whole bowel in single fractions of 0 (mock irradiation), 12.5, or 13.5 Gy, and sacrificed 18-25 weeks thereafter. Gross bowel reactions were scored for bowel retraction, bowel wall thickening, mesenteric telangiectasia, and petechia. Tissues were snap frozen and processed for RNase protection assay or reverse transcription polymerase chain reaction assay, or both. Transforming growth factor beta1 (TGFbeta1), TGFbeta2, TGFbeta3, tumor necrosis factor alpha, interleukin-6, and interferon gamma mRNA were measured. Radiation at 12.5 Gy and at 13.5 Gy produced significant bowel damage. Levels of all cytokines in irradiated mice were significantly increased (p < 0.05). Late radiation-related bowel fibrovascular toxicity includes cytokine signal pathways that parallel those of many other normal tissues. These cytokine responses include elevations of tumor necrosis factor alpha, TGFbeta1, and interleukin-6. There exist approaches for lowering these cytokine levels that do not also protect tumor, and thus a therapeutic gain is expected. Opportunities to use these cytokine measurements both to predict clinical toxicity and to develop interventions are discussed.
    International Journal of Radiation OncologyBiologyPhysics 06/2005; 62(1):273-8. · 4.52 Impact Factor
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    ABSTRACT: Hyaluronan (HA), a large negatively-charged polysaccharide, is a major component of vessel basal membrane. HA is expressed by a variety of cells, including tumor and endothelial cells. We hypothesized that HA could be up-regulated by hypoxia to enhance vessel formation. To determine the effect of hypoxia on the production of HA, tumor cells were treated with either media alone (control) or a hypoxia inducer (CoCl or NaN3) for 24 h. The level of HA in the media was then measured by ELISA. The results showed that both CoCl and NaN3 induced the production of HA. Since the low molecular weight form of HA (SMW) possesses pro-angiogenic properties, we investigated whether hypoxia-induced HA can be processed into SMW. Under hypoxic conditions, the activity of hyaluronidase, the enzyme responsible for degrading HA, was measured by an ELISA-like assay. The activity of hyaluronidase was shown to be up-regulated by hypoxia and, further, could carry out the function of processing HA into SMW. In addition, the hypoxic areas of tumor tissues were stained strongly with biotinylated HA-binding proteins, indicating that the level of HA was high compared to the oxic areas. This study demonstrates that hypoxia can stimulate the production of HA and the activity of hyaluronidase, which may promote angiogenesis as a compensation mechanism for hypoxia.
    Advances in experimental medicine and biology 02/2005; 566:249-56. · 1.83 Impact Factor
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    ABSTRACT: Since conventional therapies are directly dependent on the supply of either drugs or oxygen, a key question is whether antiangiogenic agents produce detrimental effects on tumor vascular function, thus compromising combination therapies. A second question is whether experimental results based on fast-growing, transplanted tumors mimic those in slowly developing spontaneous tumors, which may be more representative of response in human primary tumors. To investigate changes in tumor pathophysiology, three antiangiogenic agents were compared: a) endostatin, b) anti-VEGFR-2 (DC101), and c) celecoxib. Total blood vessels were identified using anti-CD31, perfused vessels using DiOC7, and hypoxia by EF5 uptake. Although individual tumor growth rates varied substantially, DC101 produced the most striking inhibition. DC101 increased total and perfused vessel spacing as well as overall hypoxia, while endostatin increased total vessel spacing, and hypoxia and celecoxib had no marked effects. These results reinforce the idea that pathophysiological changes in spontaneous tumors are in general reflective of response in transplanted tumors. Furthermore, although DC101 inhibited growth in roughly half of the spontaneous tumors, the remaining tumors were unaffected. A key focus of future studies will be to investigate the underlying rationale for the widely varying antiangiogenic response among tumors that outwardly appear so similar.
    Advances in experimental medicine and biology 02/2005; 566:59-65. · 1.83 Impact Factor
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    ABSTRACT: Although clinical trials of antiangiogenic strategies have been disappointing when administered as single agents, such approaches can play an important role in cancer treatment when combined with conventional therapies. Previous studies have shown that DC101, an antiangiogenic monoclonal antibody against vascular endothelial growth factor receptor-2, can produce significant growth inhibition in spontaneous and transplanted tumors but can also induce substantial hypoxia. Because DC101 appears to potentiate radiotherapy in some tumors, the present studies were undertaken to characterize pathophysiological changes following combined therapy and to determine whether radioresponse is enhanced despite the induction of hypoxia. MCa-4 and MCa-35 mammary carcinomas were treated with: (a) DC101; (b) 5 x 6 Gy radiation fractions; or (c) the combination. Image analysis of frozen tumor sections was used to quantitate: (a) hypoxia; (b) spacing of total and perfused blood vessels; and (c) endothelial and tumor cell apoptosis. For MCa-4, combination treatment schedules produced significant and prolonged delays in tumor growth, whereas single-modality treatments had minor effects. For MCa-35, radiation or the combination led to equivalent growth inhibition. In all tumors, hypoxia increased markedly after either radiation or DC101 alone. Although combination therapy produced no immediate pathophysiological changes, hypoxia ultimately increased after cessation of therapy. Preferential increases in endothelial apoptosis following combination treatment suggest that in addition to blocking tumor angiogenesis, DC101 enhances radiotherapy by specifically sensitizing endothelial cells, leading to degeneration of newly formed blood vessels.
    Cancer Research 09/2004; 64(16):5712-9. · 8.65 Impact Factor
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    ABSTRACT: The primary objectives of this study were to address two major questions. (1) Does VEGF receptor-2 antibody (DC101) produce detrimental effects on tumor vascular function and oxygenation that could compromise adjuvant therapies? (2) Is pathophysiological response to such antiangiogenic strategies different in transplanted versus primary spontaneous tumors? The effects of early and late initiation DC101 treatment were evaluated using spontaneous murine mammary carcinomas and two markedly different transplanted mammary tumors, MCa-35 and MCa-4. Mice were administered DC101 or saline, tumors were frozen, and immunohistochemical staining was quantified using image analysis of multiply-stained frozen sections. Total blood vessels were identified using antibodies to CD31 or panendothelial antigen, perfused vessels via i.v. injection of fluorescent DiOC7, and tumor hypoxia by hypoxia marker (EF5) uptake. Tumor growth was significantly inhibited following DC101 administration in all tumor models. In general, early initiation DC101 treatment reduced perfused vessel counts and increased tumor hypoxia, while late initiation treatment had no significant impact on either. Results indicate that DC101 slows tumor growth through a decrease in vascular function, leading to increased tumor cell apoptosis and necrosis at sites distant from perfused blood vessels, and suggest that DC101 accelerates the rate at which tumor cells outgrow their functional vascular supply. Although highly variable among individual spontaneous tumors, the overall effects of DC101 on tumor hypoxia were quite similar between spontaneous and transplanted tumors. Since reductions in tumor oxygenation due to antiangiogenic treatment were transient, initial pathophysiological deficiencies that could compromise conventional therapies over the short-term may be of less relevance when administered over more extended treatment schedules.
    Radiotherapy and Oncology 09/2004; 72(2):221-30. · 4.52 Impact Factor
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    ABSTRACT: Fibrotic sequelae remain the most important dose-limiting toxicity of radiation therapy to soft tissue. Functionally, this is reflected in loss of range of motion and muscle strength and the development of limb edema and pain. Tumor necrosis factor alpha and fibroblast growth factor 2 (FGF2), which are abnormally elevated in irradiated tissues, may mediate radiation fibrovascular injury. In an open label drug trial, we studied the effects of pentoxifylline (400 mg orally tid for 8 weeks) on 30 patients who displayed late, radiation-induced fibrosis at 1 to 29 years posttreatment (40 to 84 Gy). The primary outcome measurement was change in physical impairments thought to be secondary to radiation, including active and passive range of motion (AROM and PROM), muscle strength, limb edema, and pain. Plasma levels of cytokines (tumor necrosis factor alpha and FGF2) also were measured. Twenty-seven patients completed baseline and 8-week assessments, and 24 patients completed baseline, 8-week, and 16-week assessments. After 8 weeks of pentoxifylline intervention, 20 of 23 patients with impaired AROM and 19 of 22 with impaired PROM improved; 11 of 19 patients with muscle weakness showed improved motor strength; five of seven patients with edema had decreased limb girth; and nine of 20 patients had decreased pain. Pretreatment FGF2 levels dropped from an average of 44.9 pg/mL to 24.0 pg/mL after 8 weeks of treatment. Patients receiving pentoxifylline demonstrated improved AROM, PROM, and muscle strength and decreased limb edema and pain. Reversal of these delayed radiation effects was associated with a decrease in circulating FGF2.
    Journal of Clinical Oncology 07/2004; 22(11):2207-13. · 18.04 Impact Factor
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    ABSTRACT: Vascular endothelial growth factor (VEGF) is an intensively studied molecule that has significant potential, both in stimulating angiogenesis and as a target for antiangiogenic approaches. We utilised MCF-7 breast cancer cells transfected with either of two of the major VEGF isoforms, VEGF121 or VEGF165, or fibroblast growth factor-1 (FGF-1) to distinguish the effects of these factors on tumour growth, vascular function, and oxygen delivery. While each transfectant demonstrated substantially increased tumorigenicity and growth rate compared to vector controls, only VEGF121 produced a combination of significantly reduced total and perfused vessel spacing, as well as a corresponding reduction in overall tumour hypoxia. Such pathophysiological effects are of potential importance, since antiangiogenic agents designed to block VEGF isoforms could in turn result in the development of therapeutically unfavourable environments. If antiangiogenic agents are also combined with conventional therapies such as irradiation or chemotherapy, microregional deficiencies in oxygenation could play a key role in ultimate therapeutic success.
    British Journal of Cancer 01/2004; 90(2):430-435. · 5.08 Impact Factor
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    ABSTRACT: Recent results in the literature have demonstrated that the antiangiogenic agent endostatin can enhance antitumor effects when administered before or during radiotherapy. To better understand the underlying pathophysiologic basis for this radiosensitization, the current study investigated whether short-term endostatin administration is linked to alterations in tumor vascular perfusion and oxygen delivery. Three daily doses of recombinant endostatin (20 mg/kg) were administered to two murine mammary carcinomas, the highly vascularized MCa-35 and the less vascularized MCa-4. Image analysis techniques were used to quantify (1) total and perfused vascular spacing, and (2) changes in tumor hypoxia as a function of distance from the nearest blood vessel. In MCa-35 tumors, endostatin had no effect on vessel spacing, tumor hypoxia, or tumor growth. In MCa-4 tumors, total and perfused vessel spacings were also unchanged, but tumor growth was inhibited, and tumor hypoxia significantly decreased. These tumors demonstrated an increased vascular functionality suggestive of an increase in the number of intermittently perfused vessels, without corresponding alterations in tumor oxygen consumption rate. Poorly vascularized, hypoxic mammary carcinomas were much more responsive to short-term endostatin treatment than well-vascularized, more homogeneously oxygenated tumors. Oxygen levels in the responsive tumors were transiently improved after treatment, which could have substantial implications with respect to the therapeutic effectiveness of combining antiangiogenic agents with conventional therapies.
    International Journal of Radiation OncologyBiologyPhysics 11/2003; 57(4):1038-46. · 4.52 Impact Factor
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    ABSTRACT: Alteration of the phenotype of breast cancers from estrogen-dependent to estrogen-independent growth often leads to the failure of antiestrogenic tumor therapies. We report that overexpression of vascular endothelial growth factor (VEGF) by estrogen-dependent MCF-7 breast cancer cells could abolish estrogen-dependent tumor growth in ovariectomized mice. In the absence of estrogen, MCF-7 VEGF-expressing tumors with increased vessel density showed growth kinetics similar to, or even greater than, that of parental MCF-7 tumors with estrogen supplementation. Overexpression of VEGF by MCF-7 cells or treatment on parental MCF-7 cells with recombinant VEGF also stimulated cell proliferation in culture. Our data suggest that VEGF stimulation of MCF-7 tumor angiogenesis and growth is mediated by both autocrine and paracrine mechanisms.
    Cancer Research 09/2003; 63(15):4684-91. · 8.65 Impact Factor
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    ABSTRACT: The selective cyclooxygenase (COX)-2 inhibitor, celecoxib, alone and in combination with radiation was investigated in vitro and in vivo. Murine mammary tumor line (MCa-35) and human lung carcinoma line (A549) have high and low basal levels of COX-2 protein, respectively. Treatment of both tumor cells with celecoxib alone resulted in a dose- and time-dependent reduction of cell number (clonogenic cell death) and tumor cell growth rate in vitro; however, inhibition of tumor cell growth by celecoxib was not correlated with the reduction of COX-2 protein in tumor cells. Although both tumor cell types had similar DNA damage after celecoxib treatment, significant induction of tumor cell apoptosis was only observed in MCa-35. Celecoxib-mediated radiation sensitization also occurred in MCa-35 cells determined by clonogenic assay, in part due to a G2/M arrest at 8 to 24 hours after treatment. The tumor growth inhibitory effects of celecoxib were also studied in vivo. It was found that celecoxib inhibited both tumor growth after intragastric administration of celecoxib (5 daily doses of 50 mg/kg). Combined with a single 30-Gy dose of radiation, celecoxib resulted in additive effects on A549 tumors. Celecoxib-treated A549 tumors had marginal reduction of total and perfused blood vessels compared with untreated controls. Reduction of tumor angiogenic cytokine and growth factor mRNA was associated with decreased perfused vessels. Finally, reduction of vascular endothelial growth factor protein after celecoxib was also observed in both tumor lines by Western blot. Our results indicate that the selective inhibition of COX-2 combined with radiation has potential application in radiotherapy, and celecoxib-mediated antitumor effects may act through different mechanisms including direct inhibition of tumor cell proliferation, alteration of tumor cell cycle, and antiangiogenesis.
    American journal of clinical oncology 09/2003; 26(4):S103-9. · 2.21 Impact Factor
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    ABSTRACT: Inflammatory cytokine and chemokine production is mediated, at least in part, by prostaglandin E (PGE2). Cyclooxygenases, COX-1 and COX-2, are two key enzymes in the conversion of arachidonic acid to PGE2. Radiation induces the overproduction of cytokines and chemokines, and it also increases PGE2 production, both locally and systemically. In this study, we tested the effects of a COX-2 inhibitor (celecoxib) after 50 Gy radiation of MCa-35 tumor and cutaneous tissues of C3H/He mice. Preclinical toxicity endpoints and associated alterations in chemokine production and cellular infiltrates were measured. Celecoxib was given by daily gavage (50 mg/kg for 15 days), with the first dose delivered either 2 hours before, 2 days after, or 7 days after a single dose of radiation. Celecoxib-treated animals had less inflammation of the dermis compared with saline-treated controls. Severe skin dermatitis occurred in 23.8% (5/21) of mice treated with 50 Gy, whereas only 17.6%, 5.3%, and 11.1% of mice in the 2-hour pre-, or the 2-day post-, and 7-day postirradiation groups, respectively, had severe dermatitis on day 20. The decreased skin toxicity scores were associated with a reduction of both blood vessels and focal necrosis in MCa-35 tumors. Celecoxib also significantly decreased C-C family chemokine (Rantes and MCP-1) mRNA expression in irradiated skin tissues, but not in tumor tissues, which was accompanied by a decrease in skin mRNA expression of both C-C (CCR2 and CCR5) and C-X-C (CXCR2 and CXCR4) chemokine receptors. A significant positive correlation was also found between skin damage (skin scores) and chemokine and its receptor mRNA expression in radiation-treated mice. Finally, celecoxib also decreased the infiltration of monocytes and neutrophils in locally irradiated tumor and surrounding normal tissue. The differential effects of celecoxib on inflammation help to explain the selective protection by celecoxib of irradiated cutaneous tissues without a concurrent protection of MCa-35 tumors.
    American journal of clinical oncology 09/2003; 26(4):S114-21. · 2.21 Impact Factor
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    ABSTRACT: The selective cyclooxygenase (COX)-2 inhibitor, celecoxib, alone and in combination with radiation was investigated in vitro and in vivo. Murine mammary tumor line (MCa-35) and human lung carcinoma line (A549) have high and low basal levels of COX-2 protein, respectively. Treatment of both tumor cells with celecoxib alone resulted in a dose- and time-dependent reduction of cell number (clonogenic cell death) and tumor cell growth rate in vitro; however, inhibition of tumor cell growth by celecoxib was not correlated with the reduction of COX-2 protein in tumor cells. Although both tumor cell types had similar DNA damage after celecoxib treatment, significant induction of tumor cell apoptosis was only observed in MCa-35. Celecoxib-mediated radiation sensitization also occurred in MCa-35 cells determined by clonogenic assay, in part due to a G2/M arrest at 8 to 24 hours after treatment. The tumor growth inhibitory effects of celecoxib were also studied in vivo. It was found that celecoxib inhibited both tumor growth after intragastric administration of celecoxib (5 daily doses of 50 mg/kg). Combined with a single 30-Gy dose of radiation, celecoxib resulted in additive effects on A549 tumors. Celecoxib-treated A549 tumors had marginal reduction of total and perfused blood vessels compared with untreated controls. Reduction of tumor angiogenic cytokine and growth factor mRNA was associated with decreased perfused vessels. Finally, reduction of vascular endothelial growth factor protein after celecoxib was also observed in both tumor lines by Western blot. Our results indicate that the selective inhibition of COX-2 combined with radiation has potential application in radiotherapy, and celecoxib-mediated antitumor effects may act through different mechanisms including direct inhibition of tumor cell proliferation, alteration of tumor cell cycle, and antiangiogenesis. Cyclooxygenase (COX) is a critical enzyme involved in mammalian physiology and several disease conditions. 1-3 COX-mediated prostaglandin production has recently been implicated in cancer development and tumor angiogenesis. 2,4-6 Two isoforms, cyclooxygenase (COX-1 and COX-2), are coexpressed in both normal and tumor tissues. COX-1 is constitutively expressed in most tissues producing prostaglandins required for normal physiologic function, whereas COX-2 is expressed at relatively low levels but is induced by a variety of agents, including cytokines, growth factors, radiation, and stress-related stimuli. 7,8 There is also considerable evidence that suggests a causal relationship between COX-2 overexpression and tumor formation in human and animal tumor models. Therefore, selective overexpression of COX-2 in tumors versus normal tissues makes this enzyme a potential target for cancer therapy. COX inhibitors also participate in radiation-mediated antitumor effects. 9 Milas et al. 10 and Furuta et al. 11 have shown that indomethacin enhances the antitumor efficacy of ionizing radiation against prostaglandin-producing, transplanted murine sarcomas. Others recently also reported that other COX inhibitors enhanced the radiosensitivity of human prostate carcinoma cells. 12,13 Because of the overexpression of COX-2 in many human malignancies, the recently developed selective COX-2 inhibitors have been extensively investigated in antineoplastic therapy both alone and in combination with radiation. 2,14 In support of this concept, we recently also reported that celecoxib caused a dramatic enhancement of the in vivo radiation response of esophageal carcinoma cells, and found that celecoxib protected normal soft tissue against damage by radiation. 15 The molecular basis of antitumor effects mediated by COX-2 inhibitors has not been well defined. Antitumor effects of COX-2 inhibitors have been documented, which includes 1) direct reduction of tumor cell proliferation, 2) the inhibition of angiogenesis and reduction of angiogenic growth factor and cytokine production, 3) the regulation of cytokine and growth factor production by reducing prostaglandin production and indirectly affecting tumor cell growth, and 4) increased intrinsic radiosensitivity of tumor cells by alteration of the cell cycle. Celecoxib-mediated antitumor effects could be COX-2 dependent or COX-2 independent. 16,17 To investigate the effects of celecoxib on the radiosensitivity of other types of human tumors, we used two carcinoma cell lines with different endogenous COX-2 expression levels in this study. We now report on the in vitro and in vivo effects of celecoxib alone and in combination with radiation on breast MCa-35 and lung A549 tumor cells.
    American Journal of Clinical Oncology 07/2003; 26(4):S103-S109. · 2.55 Impact Factor
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    ABSTRACT: Breast tumors expressing no detectable FGFs (MCF-7) were compared with tumors transfected with FGF4 or FGF1 (FGF4/MCF-7 or FGF1/MCF-7), and with MDA-MB-435, which produce endogenous FGF2. Tumor blood flow was measured by 133Xe diffusion, oxygen distribution was measured by Eppendorf pO2 histography, and vascular density was measured by CD31 staining. Tumors that overexpress angiogenic factors grew at a rate far exceeding that of MCF-7. The FGF producing tumors also had much higher metastatic rates to lung. Tumor blood flow was significantly higher in the two FGF-transfected xenografts compared with the parent MCF7. Median tumor pO2 was also higher, and tumor oxygenation was preserved even for large tumors. The vascular density as determined by CD31 staining, however, was not markedly increased in tumors overexpressing angiogenic factors. We found that angiogenic factors preserve and augment neovascular function, thus facilitating tumor growth and progression.
    Advances in experimental medicine and biology 02/2003; 530:593-601. · 1.83 Impact Factor
  • Advances in experimental medicine and biology 02/2003; 510:69-75. · 1.83 Impact Factor

Publication Stats

801 Citations
189.90 Total Impact Points

Institutions

  • 2001–2007
    • University Center Rochester
      • Department of Radiation Oncology
      Rochester, Minnesota, United States
  • 1998–2007
    • University of Rochester
      • Department of Radiation Oncology
      Rochester, NY, United States
  • 1995–2005
    • National Institutes of Health
      • Branch of Radiation Oncology
      Maryland, United States
  • 1995–1998
    • National Cancer Institute (USA)
      • Radiation Oncology Branch
      Maryland, United States