Rh2-enriched Korean ginseng (Ginseng Rh2+) inhibits tumor growth and development of metastasis of non-small cell lung cancer.

BACKGROUND AND OBJECTIVE: While there are multiple studies on the anti-tumoral effects of Panax ginseng as active ingredients (one or more ginsenosides derived from the extract) or as a whole plant extract, there is a lack of studies to assess the effects Panax ginseng's of active ingredients combined with the whole plant extract. Our aim was to study the effect of whole ginseng, enriched in the anti-tumoral Rh2 component and other ginsenosides (Ginseng Rh2+), on the metastatic capacity of non-small cell lung cancer (NSCLC). METHODS: We evaluated the effects of Ginseng Rh2+ on survival, migration and motility, induction of apoptosis, and expression of its apoptosis-related proteins in non-small cell lung cancer (NSCLC) cells in vitro and on primary tumor growth and metastatic capacity in a syngeneic mouse lung cancer model in vivo. The effects of Ginseng Rh2+ on NSCLC cells were studied in vitro using: a colorimetric tetrazolium salt (XTT) assay, annexin V-FITC/PI, western blotting, wound healing motility assay, Transwell migration and cell adhesion assays. In vivo, mice were inoculated with Lewis mouse lung carcinoma cells subcutaneously to evaluate local tumor growth, or intravenously to evaluate the effects of Ginseng Rh2+ on development of experimental metastases. Mice were treated by intraperitoneal administration of Ginseng Rh2+ (0.005-0.5 g kg-1) on days 6, 10, and 14 after tumor injection. RESULTS: We found that Ginseng Rh2+ increased the apoptosis of NSCLC cells in vitro, demonstrating dose dependent down-regulation of the Bcl-2 anti-apoptotic gene and concurrent up-regulation of the Bax pro-apoptotic gene. Ginseng Rh2+ inhibited the tumor cells' capacity to attach to the ECM-related matrix and reduced cell migration. In vivo, Ginseng Rh2+ inhibited local tumor growth and reduced the development of experimental lung metastases. CONCLUSION: Our study suggests that Ginseng Rh2+ may potentially be used as a therapeutic agent for treatment of NSCLC.

Combined Effect of Moringa oleifera and Ionizing Radiation on Survival and Metastatic Activity of Pancreatic Cancer Cells.

BACKGROUND: Radiotherapy is one of the main treatments for malignancies. Radioresistance is a major obstacle in this treatment, calling for new treatments to improve radiotherapy outcome. Herbal medicine has low toxicity and could be a source for new radio-enhancing agents. Moringa oleifera (moringa) is a well-known medicinal plant with antiproliferative and antimetastatic properties. Possible mechanisms of moringa anticancer activity may be related to the expression of PARP-1, Bcl-2, COX-2, p65, p-IκB-a, and others. PURPOSE: The aims of the present study were to investigate effect of moringa alone and combined with radiation on survival and metastatic activity of pancreatic cancer cells and on tumor growth. METHODS AND RESULTS: The combination of moringa and radiation significantly inhibited PANC-1 cell survival in a dose-dependent manner, as tested by clonogenic and XTT assays. Moreover, standard transwell cell migration/invasion assays demonstrated reduced metastatic activity of these cells. Pyruvate mitigated the inhibitory effect of combined treatment on cell survival. Flow cytometry of moringa-treated cells revealed induction of apoptosis. Western blot analysis found that the combined treatment decreased expression of the pro-apoptotic protein Bcl-2, and downregulated the key component of DNA repair pathways PARP-1 and the NF-κB-related proteins IκB-α, p65-subunit, and COX-2. Moringa significantly inhibited growth of subcutaneous tumors generated by PANC-1 cells in nude mice. Immunohistochemical analysis demonstrated moringa's antiproliferative and antiangiogenic effects. CONCLUSIONS: Moringa decreased pancreatic cancer cell survival and metastatic activity and significantly inhibited tumor growth. The combination of moringa plus radiation resulted in an additional inhibitory effect that provided the rationale for further investigation of this combination as a novel strategy to overcome pancreatic cancer cell radioresistance.

Modified Citrus Pectin as a Potential Sensitizer for Radiotherapy in Prostate Cancer.

BACKGROUND: Radiotherapy is one of the primary therapies for localized prostatic carcinoma. Therefore, there is an emerging need to sensitize prostatic cancer cells to chemotherapy/radiotherapy. Modified citrus pectin (MCP) is an effective inhibitor of galectin-3 (Gal-3), which is correlated with tumor progression, proliferation, angiogenesis, and apoptosis. PURPOSE: This study was directed to evaluate the efficacy of combining ionizing radiation (IR) with MCP on PCa cells. STUDY DESIGN: Effects of treatments on PCa cells survival were evaluated using XTT assay, flow cytometry, and clonogenic survival assay. Expression of selected proteins was estimated using western blotting. Cell motility, migration, and invasion were determined. Contribution of reactive oxygen species production to treatment effects on cell viability was tested. RESULTS: Radiotherapy combined with MCP reduced viability and enhanced radiosensitivity associated with a decrease in Gal-3, cleavage of the precursor of caspase-3, increased expression of the pro-apoptotic protein Bax, and downregulation of DNA repair pathways, poly-ADP-ribose polymerase, and proliferating cell nuclear antigen. MCP significantly reduced the invasive and migratory potential of PCa cells. Combining sodium pyruvate with MCP and IR mitigated the effect on cell viability. CONCLUSION: Our findings demonstrated that MCP sensitized PCa cells to IR by downregulating anti-apoptotic Gal-3, modulating DNA repair pathways, and increasing ROS production. For the first time the correlation between MCP, radiotherapy, and Gal-3 for prostatic cancer treatment was found. In addition, MCP reduced the metastatic properties of PCa cells. These findings provide MCP as a radiosensitizing agent to enhance IR cytotoxicity, overcome radioresistance, and reduce clinical IR dose.

Combined acetyl-11-keto-ß-boswellic acid and radiation treatment inhibited glioblastoma tumor cells.

Glioblastoma multiforme (GBM) is the most common and most aggressive subtype of malignant gliomas. The current standard of care for newly diagnosed GBM patients involves maximal surgical debulking, followed by radiation therapy and temozolomide chemotherapy. Despite the advances in GBM therapy, its outcome remains poor with a median survival of less than two years. This poor outcome is partly due to the ability of GBM tumors to acquire adaptive resistance to therapy and in particular to radiation. One of the mechanisms contributing to GBM tumor progression and resistance is an aberrant activation of NF-ĸB, a family of inducible transcription factors that play a pivotal role in regulation of many immune, inflammatory and carcinogenic responses. Acetyl-11-keto-ß-boswellic acid (AKBA) is a pentacyclic terpenoid extracted from the gum Ayurvedic therapeutic plant Boswellia serrata. AKBA is anti-inflammatory agent that exhibits potent cytotoxic activities against various types of tumors including GBM. One of the mechanisms underlying AKBA anti-tumor activity is its ability to modulate the NF-ĸB signaling pathway. The present study investigated in vitro and in vivo the effect of combining AKBA with ionizing radiation in the treatment of GBM and assessed AKBA anti-tumor activity and radio-enhancing potential. The effect of AKBA and/or radiation on the survival of cultured glioblastoma cancer cells was evaluated by XTT assay. The mode of interaction of treatments tested was calculated using CalcuSyn software. Inducing of apoptosis following AKBA treatment was evaluated using flow cytometry. The effect of combined treatment on the expression of PARP protein was analysed by Western blot assay. Ectopic (subcutaneous) GBM model in nude mice was used for the evaluation of the effect of combined treatment on tumor growth. Immunohistochemical analysis of formalin-fixed paraffin-embedded tumor sections was used to assess treatment-related changes in Ki-67, CD31, p53, Bcl-2 and NF-ĸB-inhibitor IĸB-α. AKBA treatment was found to inhibit the survival of all four tested cell lines in a dose dependent manner. The combined treatment resulted in a more significant inhibitory effect compared to the effect of treatment with radiation alone. A synergistic effect was detected in some of the tested cell lines. Flow cytometric analysis with Annexin V-FITC/PI double staining of AKBA treated cells indicated induction of apoptosis. AKBA apoptotic activity was also confirmed by PARP cleavage detected by Western blot analysis. The combined treatment suppressed tumor growth in vivo compared to no treatment and each treatment alone. Immunohistochemical analysis showed anti-angiogenic and anti-proliferative activity of AKBA in vivo. It also demonstrated a decrease in p53 nuclear staining and in Bcl-2 staining and an increase in IĸB-α staining following AKBA treatment both alone and in combination with radiotherapy. In this study, we demonstrated that AKBA exerts potent anti-proliferative and apoptotic activity, and significantly inhibits both the survival of glioblastoma cells in vitro and the growth of tumors generated by these cells. Combination of AKBA with radiotherapy was found to inhibit factors which involved in cell death regulation, tumor progression and radioresistence, therefore it may serve as a novel approach for GBM patients.

Curcumin induces apoptosis and inhibits growth of orthotopic human non-small cell lung cancer xenografts.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality. Curcumin is involved in various biological pathways leading to inhibition of NSCLC growth. The purpose of this study was to evaluate the effect of curcumin on expression of nuclear factor κB-related proteins in vitro and in vivo and on growth and metastasis in an intralung tumor mouse model. H1975 NSCLC cells were treated with curcumin (0-50 µM) alone, or combined with gemcitabine or cisplatin. The effects of curcumin were evaluated in cell cultures and in vivo, using ectopic and orthotopic lung tumor mouse models. Twenty mice were randomly selected into two equal groups, one that received AIN-076 control diet and one that received the same food but with the addition of 0.6% curcumin 14 days prior to cell implantation and until the end of the experiment. To generate orthotopic tumor, lung cancer cells in Matrigel were injected percutaneously into the left lung of CD-1 nude mice. Western blot analysis showed that the expressions of IkB, nuclear p65, cyclooxygenase 2 (COX-2) and p-ERK1/2 were down-regulated by curcumin in vitro. Curcumin potentiated the gemcitabine- or cisplatin-mediated antitumor effects. Curcumin reduced COX-2 expression in subcutaneous tumors in vivo and caused a 36% decrease in weight of intralung tumors (P=.048) accompanied by a significant survival rate increase (hazard ratio=2.728, P=.036). Curcumin inhibition of COX-2, p65 expression and ERK1/2 activity in NSCLC cells was associated with decreased survival and increased induction of apoptosis. Curcumin significantly reduced tumor growth of orthotopic human NSCLC xenografts and increased survival of treated athymic mice. To evaluate the role of curcumin in chemoprevention and treatment of NSCLC, further clinical trials are required.

Moringa Oleifera aqueous leaf extract down-regulates nuclear factor-kappaB and increases cytotoxic effect of chemotherapy in pancreatic cancer cells.

BACKGROUND: Fewer than 6% patients with adenocarcinoma of the pancreas live up to five years after diagnosis. Chemotherapy is currently the standard treatment, however, these tumors often develop drug resistance over time. Agents for increasing the cytotoxic effects of chemotherapy or reducing the cancer cells' chemo-resistance to the drugs are required to improve treatment outcome. Nuclear factor kappa B (NF-kB), a pro-inflammatory transcription factor, reportedly plays a significant role in the resistance of pancreatic cancer cells to apoptosis-based chemotherapy. This study investigated the effect of aqueous Moringa Oleifera leaf extract on cultured human pancreatic cancer cells - Panc-1, p34, and COLO 357, and whether it can potentiates the effect of cisplatin chemotherapy on these cells. METHODS: The effect of Moringa Oleifera leaf extract alone and in combination with cisplatin on the survival of cultured human pancreatic cancer cells was evaluated by XTT-based colorimetric assay. The distribution of Panc-1 cells in the cell cycle following treatment with Moringa leaf extract was evaluated by flow cytometry, and evaluations of protein levels were via immunoblotting. Data of cell survival following combined treatments were analyzed with Calcusyn software. RESULTS: Moringa Oleifera leaf extract inhibited the growth of all pancreatic cell lines tested. This effect was significant in all cells following exposure to ≥0.75 mg/ml of the extract. Exposure of Panc-1 cells to Moringa leaf extract induced an elevation in the sub-G1 cell population of the cell-cycle, and reduced the expression of p65, p-IkBα and IkBα proteins in crude cell extracts. Lastly, Moringa Oleifera leaf extract synergistically enhanced the cytotoxic effect of cisplatin on Panc-1 cells. CONCLUSION: Moringa Oleifera leaf extract inhibits the growth of pancreatic cancer cells, the cells NF-κB signaling pathway, and increases the efficacy of chemotherapy in human pancreatic cancer cells.

Targeting EGFR-positive cancer cells with cetuximab-ZZ-PE38: Results of in vitro and in vivo studies.

BACKGROUND: Arming antibody with toxins is a new approach in cancer therapy. We evaluated the efficacy of cetuximab-ZZ-PE38 immunocomplex in killing cancer cells in vitro and inhibiting tumor growth in nude mice. METHODS: Several cancer cell lines and human foreskin fibroblasts were tested for epidermal growth factor receptor (EGFR) expression and cetuximab binding using Western blot assay, enzyme-linked immunosorbent assay (ELISA), and flow cytometry. Cell survival in vitro was estimated by XTT assay. Tumor size was measured twice a week. RESULTS: Cetuximab-ZZ-PE38 immunocomplex was significantly more effective in killing head and neck cancer cells than nonspecific IgG-ZZ-PE38 complex or free ZZ-PE38, whereas normal cells were not affected. Tumor treatment with immunocomplex resulted in tumor shrinkage. The immunocomplex was safe to mice at a therapeutic dosage of 0.25 mg/mL, whereas the dosage of 0.50 mg/mL induced liver toxicity. CONCLUSIONS: Cetuximab-ZZ-PE38 immunocomplex is a highly effective agent in killing EGFR-positive cancer cells and in tumor shrinkage.

Targeting ErbB-1 and ErbB-4 in irradiated head and neck cancer: results of in vitro and in vivo studies.

BACKGROUND: ErbB oncogenes have a major role in cancer. The role of ErbB-4 in cancer cell biology and the effect of anti-ErbB-1 and anti-ErbB-4 monoclonal antibodies were evaluated in this study. METHODS: ErbB-4 expression and binding was evaluated by Western blot, enzyme-linked immunosorbent assay (ELISA), fluorescent microscopy, and flow cytometry. Cell survival was measured by XTT assay. Tumor progression was followed up in nude mice model. RESULTS: High ErbB-1 levels in head and neck cancer cell lines were determined, whereas ErbB-4 expression varied. Specific antibody binding to the cells was demonstrated. High ErbB-4 expressing squamous cell carcinoma 1 (SCC-1) cells proliferated faster and generated faster growing tumors in mice. Cetuximab and mAb-3 reduced cell survival proportional to ErbB-1 and ErbB-4 expression. Combination of antibodies with irradiation was most effective in reducing cell survival and tumor growth. CONCLUSION: ErbB-4 plays a role in head and neck cancer cell biology. Anti-ErbB-4 targeted therapy can serve as a new strategy against head and neck cancer when combined with established treatments.

Curcumin: a potential radio-enhancer in head and neck cancer.

OBJECTIVES/HYPOTHESIS: To investigate whether curcumin enhances the cytotoxic effect of radiotherapy in head and neck squamous cell carcinoma (HNSCC). METHODS: HNSCC cell lines SCC-1, SCC-9, KB, as well as A431 cell line were treated with curcumin, irradiation, or their combination. Cell viability was evaluated by XTT assay. Cyclooxygenase-2 (COX-2), epithelial growth factor receptor (EGFR), and p-Erk1/2 were measured by Western blot analysis. CD-1 athymic nude mice with orthotopic implanted SCC-1 cells, were treated with control diet, curcumin containing diet, local single-dose radiation, or combination. RESULTS: Curcumin (IC50 range, 15-22 microM) and radiation inhibited cell viability in all cell lines were tested. The combination of curcumin and radiation resulted in additive effect. Curcumin decreased COX-2 expression and inhibited phosphorylation of EGFR in SCC-1 cells. In tumor-bearing mice the combination regimen showed a decrease in both tumor weight (25%, P = .09) and tumor size (15%, P = .23) compared to the nontreated mice. CONCLUSIONS: : Curcumin inhibited HNSCC cell growth and augmented the effect of radiation in vitro and in vivo. A possible mechanism is inhibition of COX-2 expression and EGFR phosphorylation.

Anti-ERBb4 targeted therapy combined with radiation therapy in prostate cancer. Results of in vitro and in vivo studies.

PURPOSE: To evaluate the efficiency of anti ErbB4 targeted therapy combined with irradiation (XRT) over each modality alone in prostate cancer. RESULTS: Clones with high ErbB4 expression grew faster than those with low ErbB4 expression. XRT inhibited the growth of both expressive and non-expressive ErbB4 cells, while mAb inhibited only high ErbB4-expressing cells. The combination of XRT and mAb resulted in a 30% reduction of the survival of high ErbB4 expressing cells over XRT alone (p = 0.013). In tumor bearing mice the tumor size in the combined arm was 1 mm at 4 weeks compared to 2-3 mm and 4-5 mm in the radiation and mAb arms (p' value of 0.02 and 0.087 respectively). METHODS: Clones with low and high expression of ErbB4 isolated by a limited dilution technique from an androgen-independent Cl-1 cell line were used. The cells from these clones were exposed to XRT (single dose of 2-6 Gy) and to anti-ErbB4 monoclonal antibody (mAb). The XTT test was used to measure cell survival. In addition, tumor-bearing nude mice were treated either by XRT, mAb or by a combined treatment. Tumor sizes were recorded at given time points. CONCLUSION: Anti ErbB4 combined with XRT is possibly more effective than each modality alone in prostate cancer.

Curcumin augments gemcitabine cytotoxic effect on pancreatic adenocarcinoma cell lines.

BACKGROUND AND AIM: Gemcitabine, the first-line agent in pancreatic adenocarcinoma, has shown limited clinical benefit. Cyclooxygenase-2 (COX-2) represent one of the most promising targets for cancer prevention and treatment. In this study, we investigated whether the phytochemical curcumin, a natural COX-2 inhibitor, can potentiate gemcitabine effect on survival of human pancreatic cancer cells. METHODS: P34 (high COX-2 expression) and Panc-1 (low COX-2 expression) pancreatic cancer cell lines were exposed to different concentrations of gemcitabine (0.1-10 microM), curcumin (0-50 microM), and their combination. Cell viability was evaluated by XTT assay. Cell cycle and apoptosis were assessed by flow cytometry. COX-2, EGFR, and p-ERK1/2 expression was measured by Western blot analysis. RESULTS: Curcumin increased the inhibitory effect of gemcitabine on cell viability as well as its pro-apoptotic effect in COX-2 positive, p34 cells, but not in COX-2 negative, Panc-1 cells. In p34 cells, combination of curcumin and gemcitabine downregulated both COX-2 and p-ERK1/2 in a dose-dependent manner. CONCLUSION: The increased cytotoxic effect of the combination on cell survival and on the induction of apoptosis in COX-2 expressing pancreatic cancer cells is probably associated with downregulation of COX-2 and p-ERK1/2 levels. This finding may contribute to the development of an effective treatment of pancreatic adenocarcinoma.

Assessing the effectiveness of Dead Sea products as prophylactic agents for acute radiochemotherapy-induced skin and mucosal toxicity in patients with head and neck cancers: a phase 2 study.

BACKGROUND: Mucositis and dermatitis are frequently encountered in patients treated with radiochemotherapy. Dead Sea products that contain minerals and other properties have proven effective in treating various skin diseases. OBJECTIVES: To evaluate the effectiveness of Dead Sea products in reducing acute radiochemotherapy-induced side effects in patients with head and neck cancer. METHODS: In this phase 2 study we compared the outcomes in 24 treated patients and 30 conventionally treated patients matched for age, tumor site, and type of treatment. The Dead Sea products comprised a mouthwash solution (Lenom) and a skin cream (Solaris) used three times daily for 1 week before, during, and up to 2 weeks after completion of radiotherapy. Mucositis and dermatitis were evaluated using common toxicity criteria. RESULTS: Thirteen treated patients (54%) had grade 1-2 and none had 3-4 mucositis, while 17 controls (57%) had grade 1-2 and 4 (13%) had grade 3-4 mucositis. Thirteen treated patients (54%) had grade 1-2 dermatitis; there was no instance of grade 3-4 dermatitis, while 11 patients in the control group (37%) had grade 1-2 and 5 (17%) had grade 3-4 dermatitis. More patients in the control arm needed a break than did patients in the treatment the control arm needed a break than did patients in the treatment arm (P = 0.034). CONCLUSIONS: The two Dead Sea products tested decreased skin and mucosal toxicity in head and neck cancer patients receiving radiochemotherapy.

ErbB-4 may control behavior of prostate cancer cells and serve as a target for molecular therapy.

PURPOSE: To assess ErbB-4 expression in advanced human prostate cancer (PC) cell lines, the role of ErbB-4 in motility, migration, and proliferative/tumorigenic potential of PC cells, and efficacy of anti-ErbB-4 monoclonal antibody (Mab) treatment on PC cells in vitro and tumor growth in vivo. MATERIALS AND METHODS: Established advanced human PC cell lines (PC-3, Cl-1, and Du-145) were evaluated for ErbB-4 expression. Several Cl-1 cell line clones expressing various levels of ErbB-4 were isolated, their motility, migration capacity, and in vitro proliferation as well as survival following Mab treatment were evaluated. Tumorigenicity and proliferation capacity of these clones in vivo and efficacy of Mab treatment on tumor growth were estimated by measurements of subcutaneous tumors developed in nude mice. RESULTS: PC cell lines studied express ErbB-4. Both PC-3 and Du-145 cell lines express high ErbB-4 levels; only 50% of Cl-1 cells express ErbB-4 with large heterogeneity. Cl-1 sub-clones highly expressing ErbB-4 showed increased cell motility, migration, and proliferation rate in vitro and enhanced growth in vivo, compared to clones with low ErbB-4 expression. Mab treatment inhibited the growth of cells expressing high but not low ErbB-4 levels in vitro and decreased the growth of subcutaneous tumors in nude mice generated by ErbB-4 highly expressing cells. CONCLUSIONS: High expression of ErbB-4 in prostate cancer Cl-1 cell clones correlated with high proliferative and migration capacity and high tumorigenic potential. The inhibitory effect of Mab on cell proliferation and on subcutaneous tumor growth suggests ErbB-4's potential as a target for molecular anticancer therapy.

Reduced repair of the oxidative 8-oxoguanine DNA damage and risk of head and neck cancer.

An increasing number of studies indicate that reduced DNA-repair capacity is associated with increased cancer risk. Using a functional assay for the removal of the oxidative DNA lesion 8-oxoguanine by the DNA-repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1), we have previously shown that reduced OGG activity is a risk factor in lung cancer. Here, we report that OGG activity in peripheral blood mononuclear cells from 37 cases with squamous cell carcinoma of the head and neck (SCCHN) was significantly lower than in 93 control subjects, frequency matched for age and gender. Retesting of OGG activity 3 to 4 years after diagnosis and successful treatment of 18 individuals who recovered from the disease showed that OGG activity values were similar to those determined at diagnosis, suggesting that reduced OGG activity in case patients was not caused by the disease. Logistic regression analysis indicated that the adjusted odds ratio (OR) associated with a unit decrease in OGG activity was statistically significantly increased [OR, 2.3; 95% confidence interval (95% CI), 1.5-3.4]. Individuals in the lowest tertile of OGG activity exhibited an increased risk of SCCHN with an OR of 7.0 (95% CI, 2.0-24.5). The combination of smoking and low OGG was associated with a highly increased estimated relative risk for SCCHN. These results suggest that low OGG is associated with the risk of SCCHN, and if confirmed by additional epidemiologic studies, screening of smokers for low OGG activity might be used as a strategy for the prevention of lung cancer and SCCHN.

ErbB4 increases the proliferation potential of human lung cancer cells and its blockage can be used as a target for anti-cancer therapy.

Clinical and experimental data suggest that ErbB-4, a member of the epidermal growth factor receptor family, may have a role in cancer progression and response to treatment. We found recently, using a retrospective clinical analysis, that expression of ErbB-4 receptor is correlated with metastatic potential and patient survival in non-small-cell lung cancer (NSCLC). The purpose of this work was to correlate the expression of the ErbB-4 and lung cancer cells growth in vitro and in vivo and to determine the therapeutic potential of a monoclonal antibody to ErbB-4 against lung cancer. For this aim, we ectopically expressed ErbB-4 in a human NSCLC cell line that did not express the ErbB-4 protein. Overexpression of ErbB-4 produced a constitutively activated ErbB-4 receptor. The transfected ErbB-4 positive clones showed an increased cell proliferation in vitro and in vivo in comparison with parental ErbB-4 negative cells and with the cells transfected by neomycin-resistant gene. A monoclonal antibody to ErbB-4 showed both an inhibitory effect on growth rate and an increasing apoptotic rate in the cells expressing ErbB-4. The results of the current study provide evidence that ErbB-4 plays a significant role in human lung cancer and may serve as a molecular target for anticancer therapy.

Inhibition of pancreatic and lung adenocarcinoma cell survival by curcumin is associated with increased apoptosis, down-regulation of COX-2 and EGFR and inhibition of Erk1/2 activity.

BACKGROUND: Several studies suggested that curcumin inhibits growth of malignant cells via inhibition of cyclooxygenase-2 (COX-2) activity. Other studies indicated that epidermal growth factor receptor (EGFR) is also inhibited by curcumin in vitro and in vivo. Moreover, recent investigations revealed an intracellular cross-talk between EGFR signaling and the COX-2 pathway. Our aim was to evaluate whether the curcumin inhibitory effect on the survival of cancer cells is associated with simultaneous down-regulation of COX-2 and EGFR and inhibition of Erk1/2 (extra-cellular signal regulated kinase) signaling pathway. MATERIALS AND METHODS: Lung and pancreas adenocarcinoma cell lines co-expressing COX-2 and EGFR (PC-14 and p34, respectively) and those expressing EGFR but deficient in COX-2 (H1299 and Panc-1, respectively) were exposed for 72 h to curcumin (0-50 microM). Cell viability was assessed by the XTT assay. Apoptosis was determined by FACS analysis. COX-2, EGFR, ErbB-2 and p-Erk1/2 expressions were measured by Western blot analysis. RESULTS: Curcumin's inhibitory effect on survival and apoptosis of lung and pancreatic adenocarcinoma cell lines was significantly higher in the COX-2-expressing cells than in the COX-2-deficient cells. In the p34 and PC-14 cells, curcumin decreased COX-2, EGFR and p-Erk1/2 expressions in a dose-dependent manner. However, in the Panc-1 and H1299 cell lines, which did not express COX-2, curcumin did not affect EGFR levels. CONCLUSION: Curcumin co-inhibited COX-2 and EGFR expression and decreased Erk1/2 activity. This inhibition was associated with decreased survival and enhanced induction of apoptosis in lung and pancreatic adenocarcinoma cells.

Establishing schedules for repeated doses of strontium and for concurrent chemotherapy in hormone-resistant patients with prostate cancer: measurement of blood and urine strontium levels.

Strontium-89 (Sr-89) alone or with concurrent chemotherapy has a role in the treatment of patients with prostate cancer (PCP). The schedules for repeated doses of Sr-89 or for concurrent chemotherapy is undetermined. The objective of this study was to measure the effective half-life (Te) of Sr-89 using a detector available in a nuclear research facility. Blood and urine samples obtained from PCP treated with Sr-89 (Metastron, Amersham, U.K.) were measured for radioactivity with a High Pure Germanium (HPGe) detector in a gamma spectrometry system (Eurisys, France). Twenty-five urine and 22 blood samples were obtained from 8 patients during a period of 160 days after Metastron injection. Sr-89 radioactivity levels in blood and urine were quite low (<8.2 x 10(-3) microCi/mL) in all patients after 21 days, whereas Sr-85 (available in 0.5% of Metastron) urine and, to a lesser extent, blood radioactivity levels were moderately high and could be detected up to 160 days. Based on Sr-85 urine levels, the calculated Sr-89 Te ranged from 9.6 to 20.7 days. Sr-89 Te can be routinely calculated in PCP based on HPGe detection of Sr-85 radioactivity levels in urine. This measurement can establish schedules for either repeated doses of Sr-89 or concurrent chemotherapy.

Radiation therapy in cancer patients with psoriasis. The fractionated daily dose and the Koebner phenomenon.

Skin side effects following XRT take place more often in patients with skin disorders. In this study six patients with psoriatic lesions were evaluated. The total/daily XRT dose to the tumor site was 50-70/1.8-2.0 Gy. No debilitating effect of XRT was observed in both the psoriatic lesions and in the surrounding normal skin.

Hyperthermia combined with radiation therapy in the treatment of local recurrent breast cancer.

BACKGROUND: Hyperthermia combined with radiation therapy was shown to be more effective in local recurrent breast cancer than radiotherapy alone, but its use is limited due to technical difficulties, stringent reimbursement policies and because it is time consuming. OBJECTIVES: To report our experience with a simple and convenient XRT + HT delivery system. METHODS: XRT was delivered through either electron or photon beams (total dose 30-40 Gy in previously irradiated fields or 50-70 Gy in non-irradiated fields). Hyperthermia was delivered by a dedicated HT device operating at 915 MHz. The heating session lasted 45 minutes. The maximal tumor surface temperature was set at 45 degrees C and modified according to patient comfort. No intratumoral (invasive) thermometry was used. At least two HT sessions were scheduled to each HT field during the entire XRT treatment period. Tumor response was evaluated every 3 months after completion of treatment. The overall survival was measured from XRT + HT initiation until the last follow-up. RESULTS: Fifteen women underwent 114 HT treatments delivered through 28 HT fields. Twenty-four HT fields (15 patients) were previously irradiated. There was complete infield response in 10 fields (6 patients), partial response in 8 fields (4 patients), no response or progressive disease in 4 fields (3 patients), and no parameters in 6 fields (5 patients). Eighteen fields (64%) had complete or partial response. Seven patients had outfield recurrence despite wide XRT + HT fields. Ulceration was the only major side effect (three patients, three fields). CONCLUSIONS: The combined HT+XRT delivery system, with no invasive thermometry, is a simple and effective method for treating local recurrent breast cancer.

Liposome transduction into cells enhanced by haptotactic peptides (Haptides) homologous to fibrinogen C-termini.

Haptides are 19-21mer cell-binding peptides equivalent to sequences on the C-termini of fibrinogen beta chain (Cbeta), gamma chain (preCgamma) and the extended alphaE chain of fibrinogen (CalphaE). In solution, Haptides accumulated in cells by non-saturable kinetics [Exp. Cell Res. 287 (2003) 116]. This study describes Haptide interactions with liposomes and Haptide-mediated liposome uptake by cells. Haptides became incorporated into negatively charged liposomes, changing their zeta potential. Atomic force microscopy and particle sizing by light scattering showed that the liposomes dissolved Haptide nanoparticles and absorbed them from solution. Pre-mixing fluorescent rhodamine-containing liposomes or "stealth" doxorubicin (DOX)-containing liposomes (Doxil) with Cbeta, preCgamma or to a lesser degree CalphaE, significantly enhanced their uptake by fibroblasts and endothelial cells. Confocal microscopy showed Haptide-induced liposome uptake saturated above approximately 40 microM Haptide. Cytotoxicity tests with lower concentrations of Doxil liposomes indicated that premixing with approximately 40 microM Cbeta or preCgamma increased their toxicity by one order of magnitude. It was evident that the liposomes complexed with an amphiphilic Haptide are transduced through cell membranes, probably by a non-receptor-mediated process. These results suggest that Cbeta or pre-Cgamma could be employed to augment the cellular uptake of drugs in liposomal formulations.