1.Response of lymphocytes to radiation in untreated breast cancer patients as detected with three different genetic assays.
Jian-Lin LOU ; Zhi-Jian CHEN ; Jiang WEI ; Ji-Liang HE ; Li-Fen JIN ; Shi-Jie CHEN ; Wei ZHENG ; Shi-Jie XU
Biomedical and Environmental Sciences 2008;21(6):499-508
OBJECTIVETo detect the response of lymphocytes to radiation in untreated breast cancer patients with three different genetic assays.
METHODSBlood samples were collected from 25 untreated patients and 25 controls. Each blood sample was divided into two parts: one was irradiated by 3-Gy X-ray (irradiated sample), the other was not irradiated (non-irradiated sample). The radiosensitivity of lymphocytes was assessed by comet assay, cytokinesis-block micronucleus (CBMN) assay and 6-TG-resistant cells scored (TG) assay.
RESULTSThe baseline values of micronucleated cell frequency (MCF) and micronucleus frequency (MNF) in the patients were significantly higher than those in the controls (P < 0.01), and 3-Gy X-ray induced genetic damage to lymphocytes in the patients increased significantly as compared with that in the controls as detected with the three genetic assays (P < 0.01). The proportion of radiosensitive cases in the patient group was 48% for the mean tail length (MTL), 40% for the mean tail moment (MTM), 40% for MCF, 44% for MNF, and 48% for mutation frequencies of the hprt gene (Mfs-hprt), respectively, whereas the proportion of radiosensitive cases in the control group was only 8% for all the parameters.
CONCLUSIONThe difference in the lymphocyte radiosensitivity between the breast cancer patients and the controls is significant. Moreover, there are wide individual variations in lymphocyte radiosensitivity of patients with breast cancer. In some cases, the radiosensitivity of the same patient may be different as detected with the different assays. It is suggested that multiple assays should be used to assess the radiosensitivity of patients with breast cancer before therapy.
Breast Neoplasms ; blood ; genetics ; Carcinogenicity Tests ; Case-Control Studies ; Comet Assay ; Cytokinesis ; radiation effects ; Drug Resistance ; Female ; Humans ; Lymphocytes ; metabolism ; pathology ; radiation effects ; Micronucleus Tests ; Middle Aged ; Radiation Tolerance ; radiation effects ; Thioguanine ; X-Rays
2.Phospholipase D inhibitor enhances radiosensitivity of breast cancer cells.
Ju Cheol SON ; Dong Woo KANG ; Kwang Mo YANG ; Kang Yell CHOI ; Tae Gen SON ; Do Sik MIN
Experimental & Molecular Medicine 2013;45(8):e38-
Radiation and drug resistance remain the major challenges and causes of mortality in the treatment of locally advanced, recurrent and metastatic breast cancer. Dysregulation of phospholipase D (PLD) has been found in several human cancers and is associated with resistance to anticancer drugs. In the present study, we evaluated the effects of PLD inhibition on cell survival, cell death and DNA damage after exposure to ionizing radiation (IR). Combined IR treatment and PLD inhibition led to an increase in the radiation-induced apoptosis of MDA-MB-231 metastatic breast cancer cells. The selective inhibition of PLD1 and PLD2 led to a significant decrease in the IR-induced colony formation of breast cancer cells. Moreover, PLD inhibition suppressed the radiation-induced activation of extracellular signal-regulated kinase and enhanced the radiation-stimulated phosphorylation of the mitogen-activated protein kinases p38 and c-Jun N-terminal kinase. Furthermore, PLD inhibition, in combination with radiation, was very effective at inducing DNA damage, when compared with radiation alone. Taken together, these results suggest that PLD may be a useful target molecule for the enhancement of the radiotherapy effect.
Breast Neoplasms/*drug therapy/*enzymology/pathology
;
Cell Death/drug effects/radiation effects
;
Cell Line, Tumor
;
Cell Proliferation/drug effects/radiation effects
;
DNA Damage
;
Enzyme Activation/drug effects/radiation effects
;
Enzyme Inhibitors/*pharmacology/*therapeutic use
;
Extracellular Signal-Regulated MAP Kinases/metabolism
;
Female
;
Humans
;
JNK Mitogen-Activated Protein Kinases/metabolism
;
Phospholipase D/*antagonists & inhibitors/metabolism
;
Radiation Tolerance/*drug effects
;
Radiation, Ionizing
;
p38 Mitogen-Activated Protein Kinases/metabolism
3.Simvastatin Reduces Capsular Fibrosis around Silicone Implants.
Kyu Jin CHUNG ; Ki Rin PARK ; Jun Ho LEE ; Tae Gon KIM ; Yong Ha KIM
Journal of Korean Medical Science 2016;31(8):1273-1278
Capsular fibrosis and contracture occurs in most breast reconstruction patients who undergo radiotherapy, and there is no definitive solution for its prevention. Simvastatin was effective at reducing fibrosis in various models. Peri-implant capsular formation is the result of tissue fibrosis development in irradiated breasts. The purpose of this study was to examine the effect of simvastatin on peri-implant fibrosis in rats. Eighteen male Sprague-Dawley rats were allocated to an experimental group (9 rats, 18 implants) or a control group (9 rats, 18 implants). Two hemispherical silicone implants, 10 mm in diameter, were inserted in subpanniculus pockets in each rat. The next day, 10-Gy of radiation from a clinical accelerator was targeted at the implants. Simvastatin (15 mg/kg/day) was administered by oral gavage in the experimental group, while animals in the control group received water. At 12 weeks post-implantation, peri-implant capsules were harvested and examined histologically and by real-time polymerase chain reaction. The average capsular thickness was 371.2 μm in the simvastatin group and 491.2 μm in the control group. The fibrosis ratio was significantly different, with 32.33% in the simvastatin group and 58.44% in the control group (P < 0.001). Connective tissue growth factor (CTGF) and transforming growth factor (TGF)-β1 gene expression decreased significantly in the simvastatin group compared to the control group (P < 0.001). This study shows that simvastatin reduces radiation-induced capsular fibrosis around silicone implants in rats. This finding offers an alternative therapeutic strategy for reducing capsular fibrosis and contracture after implant-based breast reconstruction.
Administration, Oral
;
Animals
;
Breast/*drug effects/metabolism/pathology/radiation effects
;
*Breast Implants
;
Connective Tissue Growth Factor/genetics/metabolism
;
Fibrosis
;
Gamma Rays
;
Male
;
Rats
;
Rats, Sprague-Dawley
;
Real-Time Polymerase Chain Reaction
;
Silicone Gels/*chemistry
;
Simvastatin/*pharmacology
;
Transforming Growth Factor beta1/metabolism
4.Simvastatin Reduces Capsular Fibrosis around Silicone Implants.
Kyu Jin CHUNG ; Ki Rin PARK ; Jun Ho LEE ; Tae Gon KIM ; Yong Ha KIM
Journal of Korean Medical Science 2016;31(8):1273-1278
Capsular fibrosis and contracture occurs in most breast reconstruction patients who undergo radiotherapy, and there is no definitive solution for its prevention. Simvastatin was effective at reducing fibrosis in various models. Peri-implant capsular formation is the result of tissue fibrosis development in irradiated breasts. The purpose of this study was to examine the effect of simvastatin on peri-implant fibrosis in rats. Eighteen male Sprague-Dawley rats were allocated to an experimental group (9 rats, 18 implants) or a control group (9 rats, 18 implants). Two hemispherical silicone implants, 10 mm in diameter, were inserted in subpanniculus pockets in each rat. The next day, 10-Gy of radiation from a clinical accelerator was targeted at the implants. Simvastatin (15 mg/kg/day) was administered by oral gavage in the experimental group, while animals in the control group received water. At 12 weeks post-implantation, peri-implant capsules were harvested and examined histologically and by real-time polymerase chain reaction. The average capsular thickness was 371.2 μm in the simvastatin group and 491.2 μm in the control group. The fibrosis ratio was significantly different, with 32.33% in the simvastatin group and 58.44% in the control group (P < 0.001). Connective tissue growth factor (CTGF) and transforming growth factor (TGF)-β1 gene expression decreased significantly in the simvastatin group compared to the control group (P < 0.001). This study shows that simvastatin reduces radiation-induced capsular fibrosis around silicone implants in rats. This finding offers an alternative therapeutic strategy for reducing capsular fibrosis and contracture after implant-based breast reconstruction.
Administration, Oral
;
Animals
;
Breast/*drug effects/metabolism/pathology/radiation effects
;
*Breast Implants
;
Connective Tissue Growth Factor/genetics/metabolism
;
Fibrosis
;
Gamma Rays
;
Male
;
Rats
;
Rats, Sprague-Dawley
;
Real-Time Polymerase Chain Reaction
;
Silicone Gels/*chemistry
;
Simvastatin/*pharmacology
;
Transforming Growth Factor beta1/metabolism
5.The effect of HER2/neu overexpression on p53 gene expression, cell proliferation and sensitivity to gamma-irradiation via the PI3K/Akt pathway in breast cancer cell MCF7.
Li ZHENG ; Jia-qiang REN ; Qi CHEN ; Hui-ping ZHANG ; Hong-guang ZHU
Chinese Journal of Oncology 2004;26(10):594-597
OBJECTIVETo investigate the effect of HER2/neu overexpression on the wild p53 gene expression, cell proliferation and sensitivity to gamma-irradiation via phosphatidylinositol 3-kinase (PI3K) pathway in human breast cancer cell MCF7.
METHODSLipofectin-mediated gene transfection method was used to transfer HER2/neu into MCF7 cells. Expression of HER2/neu, p53, Akt and p-Akt protein after PI3K pathway inhibitor LY294002 treatment was determined by Western blot. Cell proliferation and cell surviving fraction after gamma-irradiation treatment were assayed by MTT.
RESULTSEighteen of HER2/neu stably transfected MCF7 cell clones were established, one of them was HER2/neu overexpressing. HER2/neu overexpressing MCF7 cells showed higher p-Akt expression and lower p53 expression than those of parental MCF7 cells, which could be abrogated by LY294002. HER2/neu overexpressing MCF7 cells had higher proliferation rate and lower sensitivity to gamma-irradiation than those of parental MCF7 cells, which could be opposed by LY294002.
CONCLUSIONOverexpression of HER2/neu induces reduced expression of wild-type p53 protein, relatively high cell proliferation and low sensitivity to gamma-irradiation in breast cancer cell MCF7 by activating PI3K/Akt pathway, which may contribute to therapeutic resistance in some breast cancer patients with wild-type p53 gene status.
Breast Neoplasms ; metabolism ; pathology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cesium Radioisotopes ; Chromones ; pharmacology ; Female ; Gene Expression Regulation, Neoplastic ; Genes, erbB-2 ; Humans ; Morpholines ; pharmacology ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Radiation Tolerance ; Receptor, ErbB-2 ; biosynthesis ; genetics ; Signal Transduction ; Transfection ; Tumor Suppressor Protein p53 ; metabolism