title: Combination of gamma-radiation antagonizes the cytotoxic effects of vincristine and vinblastine on both mitotic arrest and apoptosis.
abstract: OBJECTIVE
  Combination therapy with different modalities is a common practice in the treatment of cancer. The promising clinical profile of vincristine and vinblastine has promoted considerable interest in combining these vinca alkaloids with radiation therapy to treat a variety of solid tumors. However, the therapeutic efficacy and the interaction between the vinca alkaloids with radiation is not entirely clear. In this study, we assessed the potential interactions in the combination of vincristine or vinblastine with gamma-radiation against human tumor cells in vitro.
  
  
  METHODS
  Vincristine or vinblastine and gamma-radiation were administrated at three different sequences designed as preradiated, coradiated, and postradiated combinations in human breast cancer cells and human epidermoid carcinoma cells. The cytotoxic interactions and mutual influences between these two modalities were analyzed by a series of assays including cytotoxic, morphologic, and biochemical examinations.
  
  
  RESULTS
  Our results showed that the combination of these two modalities did not produce any synergistic or additive effects. Instead, the clonogenic assays showed the survival rates of these combinations were increased up to 2.17-fold and 2.7-fold, respectively, of those treated with vincristine or vinblastine alone (p < 0.01). DNA fragmentation, TalphaT-mediated dUTP nick end labeling (TUNEL) assay, and flow cytometric assays also showed that the combination of gamma-radiation significantly interfered with the ability of these vinca alkaloids to induce apoptosis. Further analyses indicated that addition of gamma-radiation resulted in cell cycle arrest at the G(2) phase, which subsequently prevented the mitotic arrest induced by vincristine or vinblastine. In addition, biochemical examinations revealed that gamma-radiation regulated p34(cdc2)/cyclin B1 and survivin, and inhibited IkappaBalpha degradation and bcl-2 phosphorylation.
  
  
  CONCLUSIONS
  These results suggest that gamma-radiation might specifically block the cell cycle at the G(2) phase, which in turn interferes with the cytotoxic effects of vincristine or vinblastine on mitotic arrest and apoptosis. Thereby, it eventually results in an antagonistic interaction between these two modalities. This finding may be implicated in the clinical application of combination therapy of vinca alkaloids and radiation.
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 165 Ashley Avenue, Charleston, SC 29425, USA.
authors.forename: Meihua
authors.initials: M
authors.lastname: Sui
authors.forename: Weimin
authors.initials: W
authors.lastname: Fan
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D005720:Gamma Rays / Q000627:therapeutic use*; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D014747:Vinblastine / Q000627:therapeutic use*; D014750:Vincristine / Q000627:therapeutic use*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine; D014747:Vinblastine