ET-02 EFFICACY OF THE SALVAGE THERAPY VIA LOMUSTINE AND NIMUSTINE FOR RECURRENT GLIOBLASTOMA WITH TEMOZOLOMIDE RESISTANCE

Abstract

Temozolomide (TMZ) is widely used as a part of the standard treatment of glioblastomas (GBMs). However, GBM often acquires resistance for TMZ after continuous treatment with TMZ and recurs as TMZ resistance GBM (TMZ-R GBM). Other alkylating agents such as lomustine (CCNU) or nimustine (ACNU) have been sometimes used as a salvage therapy for those TMZ-R GBMs, however, their efficacy against TMZ-R GBMs has not been thoroughly investigated yet. In this study, we investigated anti-tumor effects of CCNU and ACNU for TMZ-R GBM cell lines in vitro to examine whether these agents could become alternative to TMZ in the therapy of TMZ-R GBMs. TMZ resistant clones of human GBM cell lines U87 MG (U87-R cells) and U251 MG (U251-R cells) were established as the TMZ-R GBM cell lines by cultivating U87 MG cells and U251 MG cells under continuous TMZ treatment for at least 1 year. Induction of growth arrest and apoptosis by TMZ, CCNU or ACNU against these cells were analyzed by dye exclusion assay, vital dye staining assay, and immunoblotting. The results showed that growth arrest and apoptosis were triggered upon these cells after administration of each drugs. As expected, the anti-tumor effects of TMZ for U87-R cells or U251-R cells were significantly reduced compared with those for parental U87 MG cells or U251 MG cells, respectively. On the other hand, CCNU and ACNU showed similar growth suppressive effect upon U87-R cells or U251-R cells as compared with U87 MG cells or U251 MG cells. Throughout these experiments, CCNU demonstrated strongest anti-tumor effects for all cell lines, both parental and TMZ-R GBM cell lines, and ACNU also demonstrated stronger effects than TMZ. These results suggest that CCNU or ACNU may serve as a drug of choice for salvage treatment of TMZ-R GBM.