PubMed · 10442352
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R Pazdur. 1999. Introduction. Beyond 5-fluorouracil.. https://pubmed.ncbi.nlm.nih.gov/10442352/
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Neurotoxicity of methotrexate is a well-documented issue, but development of an intracerebral hematoma following administration of intrathecal methotrexate is an extremely rare entity. A 6-year-old male with the diagnosis of non-Hodgkin lymphoma was put on a treatment regimen, including intrathecal methotrexate. Six days following the last intrathecal methotrexate administration, the patient developed a deteriorating state of consciousness. There was no history of trauma. Coagulation studies and platelet count were normal. Magnetic resonance imaging of the brain demonstrated a large left frontoparietal hematoma. Intracerebral hematoma may be a very rare, but serious, complication of intrathecal methotrexate administration.
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Gadd45alpha is shown to be induced by a wide spectrum of DNA-damaging agents and implicated in negative regulation of cell growth by causing G2-M arrest or induction of apoptosis. In the present study, we explored the involvement of p53 in the promoter activation of Gadd45alpha as well as the role of Gadd45alpha in carboplatin (Carb) or 5-fluorouracil (5-FU)-induced apoptosis in human papillomavirus virus (HPV)-positive HEp-2 and HeLa cells. We report that Carb or 5-FU upregulate Gadd45alpha and p53 in both these cells. Transient transfection of chloramphenicol acetyl transferase (CAT)-reporter construct driven by Gadd45alpha promoter clearly indicated that Gadd45alpha upregulation was mediated through activation of its promoter. Inhibition of p53 function by dominant-negative-p53 expression partially suppressed the activation of Gadd45alpha promoter. Further, the induction of apoptosis was assessed by detection of poly (ADP-ribose) polymerase (PARP) cleavage by Western blot analysis. Inhibition of upregulated Gadd45alpha expression by antisense expression vector did not modulate the Carb or 5-FU-induced apoptosis. Overall, we conclude that Gadd45alpha promoter activation partially depends on p53 function in HPV-positive cells. Moreover, Gadd45alpha protein does not modulate Carb or 5-FU-induced apoptosis in these cells.