[Efficacy of Hyper-CVAD/MA and CHALL-01 regimens in the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia patients under 60 years old].

Objective: To compare the difference of efficacy between traditional Hyper-CVAD/MA regimen and the adolescents inspired chemotherapy regimen, CH ALL-01, in treatment of adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) . Methods: In this study we retrospectively analyzed 158 Ph(+) ALL patients receiving Hyper-CVAD/MA regimen (n=63) or CHALL-01 regimen (n=95) in our center and Changzheng hospital from January 2007 to December 2017, excluding patients with chronic myeloid leukemia in blast crisis. Tyrosine kinase inhibitor (TKI) was administered during induction and consolidation chemotherapy. Patients who underwent hematopoietic stem cell transplantation received TKI as maintenance therapy. Results: Of them, 91.1% (144/158) patients achieved complete remission (CR) after 1-2 courses of induction. CR rate was 90.5% (57/63) for patients in Hyper-CVAD/MA group and 91.6% (87/95) for patients in CHALL-01 group. There was no difference in CR rates between the two groups (χ(2)=0.057, P=0.811) . The last follow-up was June 2018. A cohort of 134 CR patients could be used for further analysis, among them, 53 patients received Hyper-CVAD/MA regimen and other 81 patients received CHALL-01 regimen. The molecular remission rates were significantly higher in CHALL-01 group (complete molecular response: 44.4%vs 22.6%; major molecular response: 9.9% vs 18.9%) (χ(2)=7.216, P=0.027) . For the patients in Hyper-CVAD/MA group, the 4-year overall survival (OS) was 44.81% (95%CI: 30.80%-57.86%) and the 4-year disease free survival (DFS) was 37.95% (95%CI: 24.87%-50.93%) . For patients received CHALL-01 regimen, the 4-year OS was 55.63% (95%CI: 39.07%-69.36%) (P=0.037) and 4 year DFS was 49.06% (95%CI: 34.24%-62.29%) (P=0.015) , while there was no significant difference in 4 year cumulative incidence of relapse (CIR) (P=0.328) or cumulative incidence of nonrelapse mortality (CI-NRM) (P=0.138) . The rate of pulmonary infection was lower in patients received CHALL-01 regimen compared with patients received Hyper-CVAD regimen (43.4% vs 67.9%, χ(2)=7.908, P=0.005) . Conclusions: Outcome with CHALL-01 regimen appeared better than that with the Hyper-CVAD/MA regimen in Ph(+) ALL, which has lower incidence of pulmonary infection, higher molecular remission rate and better OS and DFS.

Expression of Smac induced by the Egr1 promoter enhances the radiosensitivity of breast cancer cells.

Breast cancer is one of the most prevalent cancers worldwide. Moreover, despite advances in antineoplastic therapies, induction of tumor cell death without off-target cytotoxicity remains a challenge. However, recent developments in localized radiotherapy and gene therapy have provided an opportunity to explore the potential for these strategies to be additive for the induction of cell death in tumor cells. Here, a novel adenoviral shuttle vector containing the proapoptotic gene Smac under the control of the ionizing radiation (IR)-induced Egr1 promoter was constructed. Following the transient transfection of the construct into MCF-7 and MDA-MB-435 breast cancer cell lines, acute and abundant expression of Smac was observed in response to IR treatment. Further analysis confirmed that the induction of Smac expression resulted in a decrease in cell viability, a slower rate of cell growth, a higher level of apoptosis and altered cell cycle progression. Using a clonogenic assay, IR-induced Smac expression was also found to significantly sensitize Smac-expressing cells to radiation-induced cell death. Taken together, these data suggest that Smac expression driven by the Egr1 promoter has the potential to serve as a radiotherapy-dependent gene therapy agent.

Radiosensitization of breast cancer cells by TRAIL-endostatin-targeting gene therapy.

One of the key issues in cancer radiotherapy research is to sensitize tumor cells to the cell killing effects of ionizing radiation while leaving normal tissues intact. One potential approach to achieve this is gene-radiotherapy, i.e. a combination of radiation therapy and gene therapy. It is to choose certain exogenous radiation-inducible regulatory genes, for example, early growth response-1 (Egr-1), and transcript its downstream tumor-therapeutic genes under ionizing radiation so as to kill the tumor cells synergistically by the expressed gene products together after transfection and irradiation exposure. In this study, we engineered a plasmid encoding both TRAIL and endostatin under the control of the radiation-inducible Egr-1 promoter, and evaluated its anti-tumor efficacy in combination with radiotherapy. Our plasmid showed significant efficacy in up-regulating the levels of TRAIL and endostatin proteins after transfected into breast cancer cells and exposed to X-ray irradiation. The detected cellular effects in vitro manifested that TRAIL-endostatin-based gene therapy could enhance radiosensitizing effects in breast cancer cells in terms of tumor cell growth inhibition, promoting apoptosis and the induction of cell cycle arrest. In summary, our results suggest that TRAIL-endostain-targeting approach might be a promising method to sensitize solid tumors to radiation therapy.

Effects of low dose radiation on signal transduction of neurons in mouse hypothalamus.

OBJECTIVE: Effects of low dose radiation on signal transduction of neurons in mouse hypothalamus were investigated. METHODS: In the present study competitive protein binding assay, radioimmunoassay, in situ hybridization and immunohistochemistry were used to observe the effects of whole-body irradiation with 75 mGy X-rays on the contents of cAMP and cGMP and the expressions of c-fos mRNA, Fos protein and proopiomelanocortin (POMC) mRNA in the neurons of mouse hypothalamus. RESULTS: The results showed that cAMP content in mouse hypothalamus immediately increased significantly and reached the peak value in 15 min after irradiation, and then returned to near sham-irradiation level 1 h after irradiation, followed by a small fluctuation of increase and decrease; the changes of cGMP content were basically opposite to those of cAMP content, while the changes of cAMP/cGMP ratio were basically consistent with those of cAMP content. The expression of c-fos mRNA in the neurons of hypothalamus appeared 15 min after irradiation, reached its peak value within 1 h, began to abate 2 h with its total disappearance 8 h after irradiation; the expression of Fos protein reached its peak value 8 h after irradiation, and then gradually returned to sham-irradiation level 48 h after irradiation; the expression of POMC mRNA decreased significantly 1 h after irradiation and remained at a lower level in the observation period of 12 h. CONCLUSION: These findings implicate that low dose radiation may potentiate the activity of the neurons in mouse hypothalamus, expedite their signal transduction, and down-regulate the functions of hypothalamus-pituitary-adrenocortical axis.

[Protective effect of panaxatriols on function of reproductive endocrine axis in radiation-injured rats].

After whole body irradiation with X-ray 5 Gy (radiation condition: 0.31 Gy.min-1, 200 kV, 10 mA, 0.5 mm Cu and 1.0 mm Al), the male rats were given ip panaxatriols 5 mg.d-1 24 h before and after irradiation for 14 d. The results showed that hypothalamic leu-enkephalin (165 +/- 12 vs 131 +/- 14 pg.mg-1), pituitary beta-endorphin (2.3 +/- 0.5 vs 1.6 +/- 0.3 ng.mg-1) contents, and serum testosterone (1.66 +/- 0.15 vs 0.82 +/- 0.23 ng.ml-1) level were decreased, while serum FSH (1.34 +/- 0.10 vs 1.99 +/- 0.10 ng.ml-1) level increased in irradiation group vs normal control. These indices approached to control levels in irradiation + panaxatriols group. These suggest that panaxatriols have protective effects on reproductive endocrine axis and promote their recovering course from the radiation injuries.