In vitro study on intrathecal use of 5-fluoro-2'-deoxyuridine (FdUrd) for meningeal dissemination of malignant brain tumors.
We investigated 5-fluoro-2'-deoxyuridine (FdUrd) as a potential agent for intrathecal treatment of malignant brain tumors with meningeal dissemination. We examined the neurotoxicity of FdUrd in vitro using primary cultures of neurons from C57BL/6 mice (ED14). Tumoricidal activity was also studied in four glioma cell lines and one medulloblastoma cell line. In addition, thymidine phosphorylase (TPase) and thymidine kinase (TK), which are key enzymes for FdUrd metabolism, were measured in the cerebrospinal fluid (CSF) of 36 patients with brain tumors. The antitumor activity of FdUrd for murine glioma cells was approximately 20- to 200-fold higher than that of 5-fluorouracil (5-FU). Against human cell lines, it was 3- to 500-fold higher than that of 5-FU. The neurotoxic effect of FdUrd on cultured neurons was far less than that of 5-FU or 5-fluorouridine (FUrd). Cerebrospinal fluid contained no detectable thymidine phosphorylase in most patients with brain tumors. Several studies have indicated that FdUrd is rapidly converted to 5-FU in the presence of thymidine phosphorylase, so that a high dose of FdUrd must be administered to obtain good efficacy. However, a high dose FdUrd frequently cause severe toxicity. In contrast, the data obtained here suggest that no enzymatic conversion of FdUrd to 5-FU should occur in the CSF. In addition, FdUrd has an excellent antitumor activity and minimal neurotoxicity. We therefore conclude that intrathecal FdUrd is a potential therapy for CSF dissemination of malignant brain tumors.
Yamada
M
M
Department of Neurosurgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Center for Adult Diseases, Osaka, Japan.
Nakagawa
H
H
Fukushima
M
M
Shimizu
K
K
Hayakawa
T
T
Ikenaka
K
K
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000473:pathology*; D005467:Floxuridine / Q000008:administration & dosage* / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007278:Injections, Spinal; D008527:Medulloblastoma / Q000188:drug therapy / Q000473:pathology; D008578:Meninges / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013937:Thymidine Kinase / Q000134:cerebrospinal fluid; D013939:Thymidine Phosphorylase / Q000134:cerebrospinal fluid; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D005467:Floxuridine; D013939:Thymidine Phosphorylase; D013937:Thymidine Kinase