5-Fluorouracil (5-FU) is a potent
antimetabolite used for
chemotherapy of gastrointestinal (GI), breast, and head and neck
malignancies. Although clinical trials have been conducted, the poor therapeutic index of
5-FU has precluded its clinical use for a number of other
tumor types. It is unclear whether this lack of utility is due to problems with
drug delivery or inherent insensitivity. Adenovirus (Ad) vector-mediated
cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy has the potential to overcome pharmacokinetic issues associated with systemic
5-FU and is particularly well suited to use with
tumors in which local control is paramount, such as recurrent, localized
prostate cancer and
malignant gliomas. In this study, the in vitro response by a panel of human tumor cell lines derived from both GI (colon, pancreas) and non-GI (prostate,
glioma)
tumors to
5-FU and to AdCMVCD (an Ad encoding Escherichia coli CD)/5-FC was examined. Whereas the sensitivity (IC(50)) of individual cell lines to these agents varied, no significant difference in median IC(50) for either
5-FU or AdCMVCD/5-FC was evident for the four
tumor types tested (P > 0.1). The relevant contributions of Ad gene transfer efficiency and inherent
5-FU sensitivity in determining response to AdCMVCD/5-FC were then assessed. Multiple linear regression analysis revealed that whereas both factors significantly contribute to the response, inherent
5-FU sensitivity was substantially more important (beta= 0.78 versus 0.48; P < 0.001). Finally, the therapeutic efficacy of a single intratumoral injection of AdCMVCD followed by systemic 5-FC was assessed in three intracranial C.B17 severe combined immunodeficient mouse models of human
glioma. AdCMVCD/5-FC efficacy was specific, virus dose-dependent, and closely paralleled in vitro
5-FU and CD/5-FC sensitivity in two of three models tested. These results reveal that
glioma cells are as sensitive as GI
tumor cells to the
antineoplastic effects of
5-FU, identify inherent
5-FU sensitivity as an important factor in determining CD/5-FC efficacy, and confirm previous findings in rat models that demonstrate the potential clinical utility of AdCMVCD/5-FC gene therapy for
gliomas.