Abstract
F10 is a novel anti-tumor agent with minimal systemic toxicity in vivo and which displays strong cytotoxicity towards glioblastoma (GBM) cells in vitro. Here we investigate the cytotoxicity of F10 towards GBM cells and evaluate the anti-tumor activity of locally-administered F10 towards an orthotopic xenograft model of GBM. The effects of F10 on thymidylate synthase (TS) inhibition and Topoisomerase 1 (Top1) cleavage complex formation were evaluated using TS activity assays and in vivo complex of enzyme bioassays. Cytotoxicity of F10 towards normal brain was evaluated using cortices from embryonic (day 18) mice. F10 displays minimal penetrance of the blood–brain barrier and was delivered by intra-cerebral (i.c.) administration and prospective anti-tumor response towards luciferase-expressing G48a human GBM tumors in nude mice was evaluated using IVIS imaging. Histological examination of tumor and normal brain tissue was used to assess the selectivity of anti-tumor activity. F10 is cytotoxic towards G48a, SNB-19, and U-251 MG GBM cells through dual targeting of TS and Top1. F10 is not toxic to murine primary neuronal cultures. F10 is well-tolerated upon i.c. administration and induces significant regression of G48a tumors that is dose-dependent. Histological analysis from F10-treated mice revealed tumors were essentially completely eradicated in F10-treated mice while vehicle-treated mice displayed substantial infiltration into normal tissue. F10 displays strong efficacy for GBM treatment with minimal toxicity upon i.c. administration establishing F10 as a promising drug-candidate for treating GBM in human patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-013-1321-1) contains supplementary material, which is available to authorized users.
Highlights
Glioblastoma (GBM) is the most common malignant brain tumor and one of the deadliest human malignancies [1, 2]
We evaluated thymidylate synthase (TS) activity and the ability of exogenous thymidine (Thy) to rescue the cytotoxic effects of F10 to determine to what extent F10-induced thymineless death towards GBM cells (Fig. 1)
Analysis of data from the NCI 60 cell line screen indicated cells derived from human central nervous system (CNS) malignancies were sensitive to F10 treatment with nanomolar potency towards several cell lines (e.g. SF268) and a remarkably large differential sensitivity for F10 relative to 5-FU (*10,000-fold for several GBM cell lines [8])
Summary
Glioblastoma (GBM) is the most common malignant brain tumor and one of the deadliest human malignancies [1, 2]. Optimal therapy results in survival times of *15 months for newly diagnosed cancer and 5–7 months for recurrent disease [3]. We recently demonstrated that the novel fluoropyrimidine (FP) anti-tumor agent F10 (Fig. 1a) displayed strong anti-leukemic activity towards genetically-engineered syngeneic murine models [4] of acute myeloid [5] and acute lymphoid leukemia [6] that replicate the poor response of human patients to chemotherapy. F10 is a polymer of 5-fluoro-20-deoxyuridine-50-O-monophosphate (FdUMP), the thymidylate synthase (TS) inhibitory metabolite of 5-fluorouracil (5-FU). Anti-leukemic activity with F10 is achieved with markedly reduced systemic
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