Biomedical subjects

Lu-Zhe Sun

Publications and source records attributed to Lu-Zhe Sun.

4 recordsLinked to original sources

PubMed2006

Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-beta type I receptor kinase inhibitor.

Transforming growth factor-beta (TGF-beta) signaling has been shown to promote invasion and metastasis in various models of human cancers. In this study, we investigated the efficacy of a TGF-beta type I receptor kinase inhibitor (TbetaRI-I) to limit early systemic metastases in an orthotopic xenograft model of lung metastasis and in an intracardiac injection model of experimental bone and lung metastasis using human breast carcinoma MDA-MB-435-F-L cells, a highly metastatic variant of human breast cancer MDA-MB-435 cells, expressing the enhanced green fluorescent protein (EGFP). Treatment of the cells with the TbetaRI-I had no effect on their growth but blocked TGF-beta-stimulated expression of integrin alpha(v)beta(3) and cell migration in vitro. Systemic administration of the TbetaRI-I via i.p. injection effectively reduced the number and size of the lung metastasis in both orthotopic xenograft and experimental metastasis models with no effects on primary tumor growth rate compared with controls. TbetaRI-I treatment also reduced the incidence of widespread early skeletal metastases in the femur, tibia, mandible, and spine detected by whole-body EGFP fluorescence imaging. Tumor burden in femora and tibiae was also reduced after TbetaRI-I treatment as detected by histomorphometry analysis compared with the placebo controls. Our results indicate for the first time that abrogation of TGF-beta signaling by systemic administration of the TbetaRI-I can inhibit both early lung and bone metastasis in animal model systems and suggest antimetastatic therapeutic potential of the TbetaRI-I.

Activin Receptors, Type I↗

PubMed2005

Therapeutic Electromagnetic Field (TEMF) and gamma irradiation on human breast cancer xenograft growth, angiogenesis and metastasis.

BACKGROUND: The effects of a rectified semi-sinewave signal (15 mT amplitude, 120 pulses per second, EMF Therapeutics, Inc.) (TEMF) alone and in combination with gamma irradiation (IR) therapy in nude mice bearing a human MDA MB231 breast cancer xenograft were tested. Green fluorescence protein transfected cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into four treatment groups: untreated controls; 10 minute daily TEMF; 200 cGy of IR every other day (total 800 cGy); IR plus daily TEMF. Some mice in each group were euthanized 24 hours after the end of IR. TEMF treatment continued for 3 additional weeks. Tumor sections were stained for: endothelial cells with CD31 and PAS or hypoxia inducible factor 1alpha (HIF). RESULTS: Most tumors <35 mm3 were white but tumors >35 mm3 were pink and had a vascularized capsule. The cortex within 100 microns of the capsule had little vascularization. Blood vessels, capillaries, and endothelial pseudopods were found at >100 microns from the capsule (subcortex). Tumors >35 mm3 treated with IR 24 hours previously or with TEMF had decreased blood vessels in the subcortex and more endothelial pseudopods projecting into hypoxic, HIF positive areas than tumors from the control group. Mice that received either IR or TEMF had significantly fewer lung metastatic sites and slower tumor growth than did untreated mice. No harmful side effects were attributed to TEMF. CONCLUSION: TEMF therapy provided a safe means for retarding tumor vascularization, growth and metastasis.

Journal Article↗

PubMed2005

Development and gene expression profiling of a metastatic variant of the human breast cancer MDA-MB-435 cells.

We have developed a model system of late stage metastatic progression by isolating a highly malignant variant of human breast cancer cells from the parental MDA-MB-435 cell line. These cells, isolated from early lung metastasis, displayed increased anchorage independent growth in vitro and when transplanted ortho-topically into nude mice showed accelerated tumor growth rate and early lung spontaneous metastasis when compared to its parental counterpart. These cells, designated as MDA-MB-435-F-L, also showed intense wide spread early skeletal metastasis in vertebrae, mandible, femur, tibia and skull as detected by fluorescence imaging in an experimental bone metastasis model. Gene expression profiles from cDNA microarray showed up or downregulation of the expression of several significant genes regulating angiogenesis, apoptosis, ECM remodeling and metastasis in the MDA-MB-435-F-L cells in comparison to the parental cells. Among the up or downregulated genes, some have also been implicated in the survival of breast cancer patients. As such, the candidate genes selected in this breast cancer progression model system may serve as biomarkers of metastatic progression and also as potential tumor targets for breast cancer therapy.

Animals↗

PubMed2004

Novel vitamin E analogue and 9-nitro-camptothecin administered as liposome aerosols decrease syngeneic mouse mammary tumor burden and inhibit metastasis.

PURPOSE: To test the anticancer properties of a nonhydrolyzable ether-linked acetic acid analogue of vitamin E, 2,5,7,8-tetramethyl-2R-(4R,8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid (alpha-TEA), and a derivative of camptothecin, 9-nitrocamptothecin (9-NC)singly and in combination against mouse mammary tumor cells (line 66 clone 4 stably transfected with green fluorescent protein; 66cl-4-GFP) cultured in vitro or transplanted subcutaneously into the inguinal region of female BALB/c mice to form established tumors. METHODS: Following in vitro treatment of 66cl-4-GFP cells with alpha-TEA and suboptimal concentrations of 9-NC, singly or in combination, apoptosis was measured by morphological evaluation of nuclei stained with 4',6-diamidino-2-phenylindole (DAPI), and DNA synthesis arrest was measured by tritiated thymidine uptake. For in vivo analyses alpha-TEA and 9-NC, both water-insoluble compounds, were formulated into liposomes using dil-auroylphosphatidylcholine and administered by aerosol to deliver doses calculated to be 36 and 0.4 microg/mouse per day, respectively, (singly or each separately for combined treatments) 7 days per week. RESULTS: Treatment of 66cl-4-GFP cells in culture for 3 days with a combination of alpha-TEA (10 microg/ml; singly produces 38% apoptosis), and suboptimal concentrations of 9-NC(15.6, 31.3, 62.5, or 125 ng/ml; singly produce 2-7% apoptosis), produced 47%, 58%, 64%, and 69% apoptosis. Likewise, combinations of alpha-TEA 9-NC inhibited DNA synthesis more than either agent administered singly. A significant reduction (P< 0.001)in growth of subcutaneous transplanted tumors was observed with liposome-formulated and aerosolized delivery of alpha-TEA + 9-NC to BALB/c mice. The incidence of macroscopic lung metastasis was 83% in control vs 8 % in alpha-TEA-, 9-NC-, or combination-treated mice. Fluorescence microscopic examination of lungs and axillary and brachial lymph nodes showed a statistically significant decrease in metastasis observed in alpha-TEA-,9-NC-, and combination- vs control-treated animals. Analyses of primary tumor tissue for proliferation and apoptosis showed treatment groups to have lower Ki-67 and higher terminal deoxynucleotidyl transferase-mediated nick end labeling, respectively. Treatments showed no measurable effects on two angiogenesis parameters,namely intratumoral blood volume as assessed by hemoglobin content and intratumoral blood vessel density as assessed with CD31 staining. CONCLUSIONS: Combination treatments enhanced antiproliferative and proapoptotic activities in cell culture, and when formulated in liposomes and delivered via aerosolization to treat an aggressive and metastatic syngeneic murine mammary tumor, the combination treatment showed a significant reduction in tumor volume in comparison to either treatment alone. Mechanistically, it appears that neither enhanced apoptosis, reduced cell proliferation,nor reduced blood vessel density can fully account for the enhanced effects of the combination treatment.

Aerosols↗