The interaction of thymidylate synthase expression with p53-regulated signaling pathways in tumor cells

Abstract

Thymidylate synthase (TS) is a chemotherapeutic target for the fluoropyrimidine 5-fluorouracil (5-FU) and antifolate tomudex (TDX). Using the MCF-7 breast cancer line, we have developed a cell line with inducible TS expression termed M7TS90. Inducible TS expression in this line resulted in a moderate (approximately 3-fold) increase in 5-FU 50% inhibitory concentration at 72 hours (IC-50(72 h)) dose and a dramatic (approximately 24-fold) increase in the IC-50(72 h) dose of TDX, but did not affect chemosensitivity to cisplatin, oxaliplatin, irinotecan, and paclitaxel. In the absence of drug treatment, inducible TS expression had no effect on expression of the p53 tumor suppressor gene. However, TS induction abrogated p53, p21, Fas, and Bak induction in response to TDX, but not 5-FU. Similarly, downregulation of Bcl-2 was reversed by inducible TS expression in TDX, but not 5-FU-treated cells. Our results indicate that inducible TS expression in M7TS90 cells modulates p53 and p53 target gene expression in response to TDX, but not 5-FU.

Pretreatment with Saccharomyces boulardii does not prevent the experimental mucositis in Swiss mice

“…5-FU also exerts its cytotoxic effects through incorporation into RNA and DNA, triggering apoptosis of cancer cells and cells of healthy tissues with high rates of cell division, including cells in the gut [26,27]. As a consequence, there is increased oxidative stress, activation of transcription factors and increased production of inflammatory cytokines leading to destruction of the intestinal mucosa [28,29]. …”

Oxidative Stress Gene Expression Profile Correlates with Cancer Patient Poor Prognosis: Identification of Crucial Pathways Might Select Novel Therapeutic Approaches

“…Indeed, doxorubicin and arsenic trioxide penetrate in the inner membrane of the mitochondria and induce superoxide radical production by modulating the electron transport chain. Also 5-fluorouracil increases mitochondrial ROS with a different mechanism, mediated by p53 [ 4 , 31 ]. Ionizing radiations represent other important ROS inducers, because they are able to promote by themselves high level of ROS and also because they might increase NADPH oxidase, an important source of ROS [ 32 ].…”

Chemotherapeutic agents for the treatment of hepatocellular carcinoma: efficacy and mode of action

“…Indeed, the efficacy and safety of bevacizumab have not yet been investigated any further in phase III trials either alone or in combination with other agents for the treatment of HCC. Chemotherapeutic agents used for HCC treatment and their chemical structures are summarized in Table 1 15-17 , 20-25 , 27 , 28 , 35 , 36 , 42-46 , 50 , 51 , 57 , 58 , 65-67 , 71 , 81-84 , 86-89 , 92-97 , 107-109 , 113-115 , 117-121 , 128 , 131 , 141-150 and Figure 1 .…”