Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FdUrd was evaluated in vivo as a potential agent for intrathecal chemotherapy of meningeal carcinomatosis. Neurotoxicity was examined pathologically in normal mice after 4 consecutive intrathecal injections of FdUrd. Using mice models of meningeal carcinomatosis, antitumor activities were studied by evaluating survival time. Pathological examination showed none of the following abnormal findings: demyelination, degeneration and destruction of ependymal linings. FdUrd also had an effect on meningeal carcinomatosis of mice (203 glioma and MM46 transplantable ascitic mammary cancer). In causing FdUrd to exhibit its efficacy, it is necessary to take into consideration the balance between the activity of two key enzymes, thymidine phosphorylase (TPase) (anabolic enzyme) and thymidine kinase (TK) (metabolic enzyme), in tumor tissues as compared with their activity in normal tissues. TPase activity which results in conversion to 5-FU was much lower in malignant glioma and metastatic brain tumors compared with tumors in other extracranial organs. TPase activity in normal brain was much less than in normal tissues in extracranial organs and its activity in gray matter (cortex) was significantly lower than that in white matter. On the other hand, TK activity in malignant brain tumors was much less than that in extracranial organs, however, its activity in normal brain was almost equal to that in normal tissues in extracranial organs. These data obtained in vivo study showed FdUrd to be a possible agent for intrathecal chemotherapy.
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PMID:[In vivo study on intrathecal use of 5-fluoro-2'-deoxyuridine (FdUrd) in meningeal dissemination of malignant tumor]. 978 91

To evaluate the possible intrathecal use of 5-fluoro-2'-deoxyuridine (FdUrd) for neoplastic meningitis, its antitumor activity and neurotoxicity in vivo were assessed. FdUrd at doses in the range 5-100 microg/animal was effective against meningeal carcinomatosis using Walker 256 carcinoma cells in rats and MM46 mammary cancer cells in mice and against meningeal gliomatosis using 203 glioma cells in mice. After four intrathecal injections, FdUrd at these doses also showed minimal neurotoxicity in the C57BL/6 mouse brain. To estimate the mechanism of FdUrd efficacy, thymidine phosphorylase (TPase) and thymidine kinase (TK), key enzymes in the metabolism of FdUrd, were measured in rat, mouse and normal human brain tissue, and in human brain tumor tissues and cerebrospinal fluid (CSF) from patients with malignant brain tumors including meningeal carcinomatosis. TPase levels were lower in brain and malignant brain tumors than in other organs and their tumors. Moreover, the activity of TPase in the gray matter of human brain, which faces the cerebrospinal fluid across the cortical surface and into which malignant cells invade in meningeal carcinomatosis, was lower than that in the white matter. TK was undetectable, and TPase was detected (at very low concentrations) in only 4 of 56 patients with brain tumors or meningeal carcinomatosis. These findings indicate that brain tissue and CSF are favorable sites for FdUrd chemotherapy because the rate of conversion of FdUrd to 5-FU would be minimal. In conclusion, FdUrd is potentially useful for intrathecal treatment of neoplastic meningitis from primary brain tumors and systemic cancer.
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PMID:Intrathecal 5-fluoro-2'-deoxyuridine (FdUrd) for the treatment of solid tumor neoplastic meningitis: an in vivo study. 992 56