Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synergistic mechanism of cisplatin (CDDP) and 5-fluorouracil (5-FU) in combination remains unclear, despite its substantial antitumor activity, which has been demonstrated clinically. To clarify the mechanism(s), we determined the sensitivity or resistance factors to either drug in seven gastrointestinal cancer cell lines and then analyzed the altered gene expression after different exposures to CDDP and 5-FU. At the basal gene expression level, glutathione S-transferase pi (GSTpi) expression correlated with the observed resistance to CDDP, whereas dihydropyrimidine dehydrogenase (DPD) and multidrug resistance-associated protein (MRP) expression was related to 5-FU resistance. GSTpi, DPD, and MRP expression increased in response to the respective drug, but they also increased in response to the other drug as well. Additionally, 5-FU revealed a drastically increased thymidylate synthase (TS) gene expression in 5-FU-resistant cells. However, the increasing actions of CDDP and 5-FU on GSTpi, DPD, MRP, and TS expression varied according to the exposure time, concentration, and schedule. A low concentration of CDDP (1 microg/ml, 30 min) followed by 5-FU (0.5 microg/ml, 72 h) was found to cause a less increased expression of DPD, MRP, GSTpi, and TS than either drug alone, thus resulting in synergistic cytotoxicity in 5-FU-resistant COLO201 and CDDP-resistant HCC-48 cells. The sequential combination of CDDP and 5-FU inhibited the growth of human normal renal proximal tubule cells by less than 20%. Low concentrations of CDDP followed by continuous exposure to 5-FU can repress increased gene expression related to both drug resistances, thereby being synergistically cytotoxic in human gastrointestinal cancer cells.
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PMID:Low-dose cisplatin and 5-fluorouracil in combination can repress increased gene expression of cellular resistance determinants to themselves. 1049 41

Thymidylate synthase (TYMS) and dihydropyrimidine dehydrogenase (DPYD) are associated with the response of tumors to fluoropyrimidines. The aim of the present study was to investigate the association between the levels of TYMS and DPYD mRNAs and the efficacy of S-1 for treating patients with HCC. A total of 35 patients with HCC who received S-1 upon recurrence (S-1 group) and 20 patients who never received a fluoropyrimidine (control group) were studied. The levels of TYMS and DPYD mRNA in surgically resected specimens were determined using reverse transcription-polymerase chain reaction assays. Overall survival (OS) time of S-1 group patients with high levels of DPYD mRNA was significantly longer compared with that of patients with low levels (median 501 days vs. 225 days; P=0.016). Similarly, the OS time of those patients with high levels of TYMS mRNA was significantly longer compared with those with low levels (median 503 days vs. 239 days; P=0.0076). By contrast, there was no difference in OS time of the control group between patients with high and low levels of DPYD and TYMS mRNAs. The levels of TYMS and DPYD mRNAs may serve as predictive markers for patients with HCC who receive S-1 chemotherapy.
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PMID:Elevated levels of mRNAs encoding dihydropyrimidine dehydrogenase and thymidylate synthase are associated with improved survival of patients with hepatocellular carcinoma treated with S-1. 2869 54

Numerous studies concerning hepatic arterial infusion chemotherapy (HAIC) have been conducted by adopting regimens containing 5-fluorouracil (FU), with a favourable efficacy compared with conventional transcatheter arterial chemoembolisation (TACE) treatment; however, the detailed mechanism of HAIC remains unclear. The present study aimed to evaluate peripheral concentration time curves of 5-FU administered through the hepatic artery, which may additionally explain the mechanism of action of HAIC. A total of 10 eligible patients underwent transcatheter arterial embolization and a 2-day HAIC treatment regimen using a folinic acid, fluorouracil and oxaliplatin regimen. Peripheral venous blood sampling was performed in each patient prior to infusion, and at 0, 0.5, 1, 1.5, 2, 5, 10, 15, 22 and 23 h following the start of infusion. The blood sample at 0 h was analysed for dihydropyrimidine dehydrogenase (DPD) levels by high performance liquid chromatography, and the rest of the samples were analysed for 5-FU by optimised liquid chromatography-mass spectrometry (LC-MS). The lower limit of quantification of optimised LC-MS for 5-FU was 5 ng/ml. The steady-state plasma concentration of 5-FU administered through the hepatic artery was achieved after 15 h. This concentration largely varied, ranging from 8.64-152.00 ng/ml. Optimised LC-MS may detect low concentrations of 5-FU. The steady-state concentration of 5-FU administered through the hepatic artery was achieved after 15 h. DPD levels were analysed through determining the ratio of plasma uracil (U) and dihydrouracil (UH2) by HPLC, and the results indicated a mild DPD deficiency in the patients with HCC. These results may provide a basis for the explanation of the clinical efficacy of HAIC, and to additionally optimise its efficacy.
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PMID:Pharmacokinetics of continuous transarterial infusion of 5-fluorouracil in patients with advanced hepatocellular carcinoma. 2972 40