Adenovirus-mediated expression of HSV1-TK or Fas ligand induces cell deathin primary human glioma-derived cell cultures that are resistant to the chemotherapeutic agent CCNU

Due to minimal treatment success with surgery, radiotherapy, and chemothera py, the aim of this study was to test the therapeutic potential of gene the rapy for the treatment of glioblastoma multiforme (GBM). We have quantitati vely analyzed two gene therapy approaches using short-term human glioma cel l cultures derived from surgical biopsies (designated IN859, IN1612, IN2045 , IN1760, and IN1265) and compared the results of gene therapy with the che mosensitivity of the same cells. All of the glioma cell cultures tested wer e susceptible to recombinant adenovirus (RAd)-mediated infection. Expressio n of herpes simplex virus type 1-thymidine kinase (RAd128), followed by gan ciclovir treatment, induced apoptosis in all of the glioma cell cultures st udied, including three that are resistant to the chemotherapeutic drug 1-(2 -(chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Expression of murine Fas ligand (RAdhCMV-mFasL) also induced cell death in four of the five cell cul tures studied. One cell culture that was resistant to CCNU was also resista nt to apoptosis induced by mFasL expression. These results suggest that sen sitivity to chemotherapeutic agents does not necessarily correlate with the sensitivity to gene therapy treatments. RAds expressing therapeutic gene p roducts in human glioma cell cultures are able to induce, apoptosis even in some cells that are resistant to a commonly used chemotherapeutic agent. T herefore, RAd-mediated gene transfer could be a good candidate to further d evelop gene therapy for the treatment of GBM.