OBJECTIVETo observe the efficacy and safety of chemotherapy regimens oxaliplatin combined with capecitabine (CAPOX) or oxaliplatin combined with tegafur, gimeracil and oteracil potassium capsules (S-1)(SOX), and to investigate the value of expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) proteins in tumor tissue for predicting the efficacy of CAPOX and SOX regimens in advanced gastric cancer patients.

METHODSA total of 107 newly-diagnosed, stage Ⅲc/Ⅳ gastric cancer patients (no surgical indication, ECOG performance scores 0-2 and expected survival time ≥3 months) were recruited with 101 patients evaluated. The patients were randomly divided into two groups. One was study group in which the patients received CAPOX regimen. The other was control group received SOX regimen. Each patient received four cycles, at least two cycles chemotherapy every three weeks and followed up until death or lost. Tumor biopsies were obtained by gastroscopy for immunohistochemical examination of the expression of TP and DPD proteins before chemotherapy. Response rate (ORR), overall survival (OS) and time to tumor progression (TTP) of the patients were assessed.

RESULTSThe objective response rate (ORR) of the study and control groups was 49.0% (5/51) vs. 46.0% (23/50), respectively (P>0.05). The overall survival (OS) was 357.36±24.69 days in the study group and 349.87±22.63 days in the control group, and the time-to-progression (TTP) was 216.75±19.32 days in the study group and 220.54±18.47 days in the control group (P>0.05 for both). Stratified analysis showed that the ORR of TP-positive patients in the study group was significantly higher than that in the control group (72.0 % vs. 41.7 %, P=0.032). There was no significant difference in ORR between the TP-negative patients in the study and control groups (26.9% vs. 50.0%, P=0.087), while the ORR of DPD-positive patients in the control group was significantly higher than that of the study group (51.9% vs. 34.6%, P=0.046). There was no significant difference in the ORR between DPD-negative patients in the study and control groups (64.0% vs. 39.1%, P=0.084). The follow-up showed that the OS (378.42±22.56 days) and TTP (271.77±24.92 days) in the TP-positive patients of the study group were significantly longer than those of the control group (OS: 326.57±19.84 days, and TTP: 229.13±22.68 days)( P<0.05). The OS was 371.25±23.97 days and TTP was 264.66±21.36 days in the DPD-positive patients of control group, significantly longer than those of the study group (OS: 334.73±21.47days, and TTP: 208.58±20.70 days) (P<0.05). But there was no significant difference in the OS and TTP between the TP- and DPD-negative patients in the two groups (P>0.05). In respect of adverse events, both the rates of hematological and non-hematological toxicities were low and similar between the two groups (P>0.05), and well-tolerated by the patients.

CONCLUSIONSBoth CAPOX and SOX regimens are effective chemotherapeutic protocols in treatment of patients with advanced gastric cancer. The expression levels of TP and DPD in tumor tissue can be used as a predictive factor for the efficacy of capecitabine or tegafur, gimeracil and oteracil potassium capsules combined with oxaliplatin regimens. CAPOX chemotherapy regimen is more suitable for the TP-positive gastric cancer patients, and SOX regimen is more suitable for the DPS-positive gastric cancer patients.

Antineoplastic Agents ; adverse effects ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Capecitabine ; administration & dosage ; adverse effects ; Capsules ; Dihydrouracil Dehydrogenase (NADP) ; metabolism ; Disease Progression ; Humans ; Neoplasm Proteins ; metabolism ; Organoplatinum Compounds ; administration & dosage ; adverse effects ; Oxonic Acid ; administration & dosage ; adverse effects ; Pyridines ; administration & dosage ; adverse effects ; Stomach Neoplasms ; drug therapy ; metabolism ; mortality ; pathology ; Tegafur ; administration & dosage ; adverse effects ; Thymidine Phosphorylase ; metabolism

BACKGROUND/AIMS: The aim of this study was to evaluate the estimated glomerular filtration rate (eGFR) during telbivudine (LdT) versus entecavir (ETV) treatment in chronic hepatitis B (CHB) patients with underlying comorbidities such as diabetes mellitus (DM), hypertension, and cirrhosis. METHODS: From 2010 to 2012, 116 CHB patients treated with LdT and 578 treated with ETV were compared in this real-practice cohort. The mean changes in eGFR (Modification of Diet in Renal Disease [MDRD] formula) from baseline to months 6, 12, and 18 were analyzed using a linear mixed model. RESULTS: In LdT-treated patients, the mean eGFR increased by 7.6% at month 18 compared with the eGFR at baseline (MDRD formula in mL/min/1.73 m2). However, in ETV-treated patients, the mean eGFR decreased by 4.1% at month 18 compared with the eGFR at baseline. In the LdT-treated patients with DM, hypertension, cirrhosis or low eGFR <90 mL/min/1.73 m2, the mean eGFR showed a steady improvement, whereas the mean eGFR was reduced in the same subgroups of ETV-treated patients. CONCLUSIONS: The eGFR gradually increased over time during LdT treatment, especially in patients with mild abnormal eGFR at baseline, and in those with DM, hypertension, and cirrhosis, whereas a reduction in eGFR was seen with ETV treatment.
Adult ; Antiviral Agents/*administration & dosage ; Diabetes Complications ; Diabetes Mellitus ; Drug Administration Schedule ; Female ; Fibrosis/complications ; Glomerular Filtration Rate/*drug effects ; Guanine/administration & dosage/*analogs & derivatives ; Hepatitis B, Chronic/complications/*drug therapy/physiopathology ; Humans ; Hypertension/complications ; Linear Models ; Male ; Middle Aged ; Thymidine/administration & dosage/*analogs & derivatives ; Time Factors ; Treatment Outcome

OBJECTIVETo prospectively observe the long-term antiviral efficacy and safety of telbivudine (LDT) administered as a monotherapy and as a combination therapy with adefovir dipivoxil (ADV) in patients diagnosed with chronic hepatitis B (CHB) and positivity for hepatitis B e antigen (HBeAg).

METHODSA total of 140 patients with HBeAg-positive CHB were randomly divided into treatment groups for LDT monotherapy (n = 75; 600 mg orally, once daily) and LDT+ADV combination therapy (n = 65; LDT 600 mg plus ADV 10 mg orally, once daily). The shortest treatment course was 96 weeks and the longest was 240 weeks. At treatment weeks 12, 24, 48?, 96, 144, 192, and 240 patients were tested for hepatitis B virus (HBV) DNA, HBeAg seroconversion and ALT normalization time; in addition, the incidence and type of adverse drug reactions were recorded. Data were statistically analyzed to determine the significance of differences observed between groups.

RESULTSThe rate of patients experiencing more than or equal to 2 log HBV DNA reduction was higher in the LDT + ADV group (92.3%(60/65) vs. LDT: 86.7%(65/75), X2 = 1.58). The HBV DNA negative rates of the LDT and LDT + ADV groups were 62.7% and 61.5% (X2 = 0.01) at week 24, 76.0% and 81.5% (X2 = 0.63) at week 48, 80.0% and 89.2% (X2 = 2.2) at week 96, 78.3% and 93.3% (X2 = 3.24) at week 144, 83.7% and 91.7% (X2 = 0.47) at week 192, and 93.3% and 88.9% at week 240 (comparison between two groups for each point P more than 0.05); both groups showed higher early and rapid sustained HBV DNA negative rates. For the HBeAg seroconversion, the rates of the LDT and LDT + ADV groups were 17.3% and 23.1% (X2 = 0.71) at week 24, 29.3% and 30.8% (X2 = 0.03) at week 48, 42.7% and 40.0% (X2 = 0.10) at week 96, 55.0% and 43.3% (X2 = 1.08) at week 144, 55.8% and 66.7% (X2 = 0.45) at week 192, and 63.3% and 66.7% at week 240; however, pairwise comparison showed no statistically significant differences between the groups (P more than 0.05). Similarly, there was no significant difference between the two groups in incidence of resistance at week 48 (4.0% and 1.5%), week 96 (5.3% and 3.1%), week 144 (10.0% and 3.3%, X2 = 1.23), week 192 (11.6% and 8.3%), and week 240 (13.3% and 11.1%) (all P more than 0.05). Three patients experienced muscle soreness (LDT, n = 2; LDT + ADV, n = 1) and two patients experienced increased creatine phosphokinase (LDT, n = 1; LDT + ADV, n = 1); all side effects resolved spontaneously or with symptom-appropriate treatment.

CONCLUSIONThe long-term efficacy of LDT as a monotherapy or as a combination therapy with ADV was similar and the two different treatment approaches were associated with similar rates of resistance. The long-term safety was good for both treatment approaches.

Adenine ; administration & dosage ; analogs & derivatives ; therapeutic use ; Adolescent ; Adult ; Antiviral Agents ; administration & dosage ; therapeutic use ; Drug Therapy, Combination ; Female ; Hepatitis B e Antigens ; blood ; Hepatitis B, Chronic ; blood ; drug therapy ; Humans ; Male ; Middle Aged ; Organophosphonates ; administration & dosage ; therapeutic use ; Retrospective Studies ; Thymidine ; administration & dosage ; adverse effects ; analogs & derivatives ; therapeutic use ; Young Adult

OBJECTIVETo investigate the therapeutic benefit of sequential interferon alpha-1b (IFNa-1b) in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) who showed early complete response to telbivudine (LdT) treatment, and to explore the clinical value of serum hepatitis B surface antigen (HBsAg) for predicting sustained virological response (SVR).

METHODSTwenty HBeAg+ CHB patients who had shown a complete response to LdT therapy before treatment week 52 were divided into two treatment groups: one continued on the LdT treatment for an additional 6 months, and the other switched to IFNa-1b for 6 months. Each patient presented for follow-up examinations at 1, 2, 3, 6, 9, 12, 18, 24, 30 and 36 months after treatment cessation. Serum levels of alanine aminotransferase (ALT) and creatinine were detected by an automated biochemical analyzer. HBV DNA load was determined by real-time PCR. HBsAg and HBeAg levels were assessed by chemiluminescence.

RESULTSThe relapse rate was lower in the group treated with sequential IFN than in the group who continued LdT treatment (30% vs. 40%, P more than 0.05). The area under the receiver operating characteristic curve at week 24 (0.689) was significantly higher than at week 12 and week 48 (0.652 vs. 0.545, P less than 0.05). Decline in serum HBsAg levels at week 24 were predictive of SVR after treatment cessation. Patients showing a decrease more than 1000 IU/ml in serum HBsAg levels at week 24 had a significantly higher SVR rate than the patients who showed a decrease less than 1000 IU/ ml (90.9%(10/11) vs. 33.3%(3/9), P less than 0.05). At the end of treatment, patients showing a decrease less than 200 IU/ml of serum HBsAg levels had a significantly higher SVR rate than those showing more than 200 IU/ml (100% vs. 53.3%, P less than 0.05).

CONCLUSIONSequential IFNa-1b consolidation therapy does not reduce the rate of relapse after treatment cessation. However, patients with a decrease in serum HBsAg levels of more than 1000 IU/ml at treatment week 24 are more likely to achieve SVR.

Adult ; Female ; Hepatitis B Surface Antigens ; blood ; Hepatitis B e Antigens ; blood ; Hepatitis B, Chronic ; blood ; drug therapy ; Humans ; Interferon-alpha ; administration & dosage ; therapeutic use ; Male ; Middle Aged ; Recurrence ; Thymidine ; administration & dosage ; analogs & derivatives ; therapeutic use ; Treatment Outcome ; Viral Load ; Young Adult

Adult ; Antiviral Agents ; administration & dosage ; adverse effects ; therapeutic use ; Female ; Hepatitis B ; prevention & control ; transmission ; Humans ; Infectious Disease Transmission, Vertical ; prevention & control ; Mothers ; Pregnancy ; Pregnancy Complications, Infectious ; drug therapy ; virology ; Thymidine ; administration & dosage ; adverse effects ; analogs & derivatives ; therapeutic use ; Young Adult

OBJECTIVETo investigate the efficacy of telbivudine on intrauterine hepatitis B virus (HBV) infection during the last stage of pregnancy.

METHODS61 pregnant chronic hepatitis B (CHB) patients were enrolled and 31 patients were treated by telbivudine 600 mg once daily, 30 patients in the control group were not received antiviral treatment. Maternal HBV DNA level and the HBsAg positive rate in newborns were investigated.

RESULTSThe levels of serum HBV DNA in patients treated with Telbivudine were significantly reduced (t = 19.09, P less than 0.01). Compared with the control group, serum HBV DNA levels were significantly lower in telbivudine treated patients than those in the control group before parturition (t = 23.64, P less than 0.01). The infection rate of 7-month newborns were 0 and 13.33% (4/30), in telbivudine group and control group, respectively (x2 = 4.29, probability value less than 0.05).

CONCLUSIONSTelbivudine treatment can block intrauterine infection in pregnant chronic hepatitis B patients.

Administration, Oral ; Antiviral Agents ; pharmacology ; therapeutic use ; DNA, Viral ; blood ; Female ; Hepatitis B Surface Antigens ; blood ; Hepatitis B virus ; drug effects ; Hepatitis B, Chronic ; drug therapy ; transmission ; virology ; Humans ; Infant ; Infant, Newborn ; Infectious Disease Transmission, Vertical ; prevention & control ; Nucleosides ; pharmacology ; therapeutic use ; Pregnancy ; Pregnancy Complications, Infectious ; drug therapy ; virology ; Pyrimidinones ; pharmacology ; therapeutic use ; Thymidine ; analogs & derivatives ; Treatment Outcome

Administration, Oral ; Adult ; Alanine Transaminase ; blood ; DNA, Viral ; blood ; Female ; Hepatitis B e Antigens ; blood ; Hepatitis B, Chronic ; blood ; drug therapy ; Humans ; Interferons ; administration & dosage ; therapeutic use ; Male ; Nucleosides ; administration & dosage ; therapeutic use ; Pyrimidinones ; administration & dosage ; therapeutic use ; Retreatment ; Thymidine ; analogs & derivatives ; Treatment Outcome ; Virus Replication ; drug effects

OBJECTIVETo examine how the thymidine phosphorylase (TP) gene expression is upregulated by interferon-alpha (IFN-alpha) in human hepatocellular carcinoma SMMC-7721 cells.

METHODSTP mRNA levels were determined by RT-PCR. Whether the JAK-STAT cascade mediates IFN-alpha-induced TP mRNA expression was studied by pretreatment with Janus Kinase (JAK) inhibitor, AG-490. Effects of IFN-alpha on TP mRNA stability were detected with additional actinomycin D.

RESULTSThe expression of TP mRNA was induced by IFN-alpha in a dose- and time-dependent manner in SMMC-7721 (human hepatocellular carcinoma) cells. TP mRNA levels rose at 8 h, reached the peak value at 12 h, and remained at a high level up to 72 h in SMMC-7721 cells treated with IFN-alpha 10000 U/ml. IFN-alpha at a dose of 5000 or 10000 U/ml up-regulated TP expression about 3 fold compared with that of non-treated cells (P < 0.05). Induction of TP mRNA expression by IFN-alpha was significantly inhibited in SMMC-7721 cells by pretreatment with AG-490, in comparison with that treated with IFN-alpha alone. Pretreatment of SMMC-7721 cells with IFN-alpha 10000 U/ml for 24 h caused a substantial stabilization of TP mRNA, with a half-live of 35.8 h, compared with 8.5 hr in the control SMMC-7721 cells.

CONCLUSIONIFN-alpha at certain doses upregulates TP mRNA expression via both JAK-STAT transcriptional activation and post-transcriptional mRNA stabilization in human hepatocellular carcinoma SMMC-7721 cells.

Carcinoma, Hepatocellular ; enzymology ; pathology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Enzyme Inhibitors ; pharmacology ; Gene Expression Regulation, Neoplastic ; Humans ; Interferon-alpha ; administration & dosage ; pharmacology ; Janus Kinases ; metabolism ; Liver Neoplasms ; enzymology ; pathology ; RNA, Messenger ; metabolism ; STAT1 Transcription Factor ; metabolism ; Thymidine Phosphorylase ; biosynthesis ; genetics ; Transcriptional Activation ; drug effects ; Tyrphostins ; pharmacology

OBJECTIVETo approach the treatment efficiency of replication defective adenovirus carrying HSV-tk gene under control of the human telomerase reverse transcriptase (hTERT) promoter in a mouse xenografts model of prostate cancer.

METHODSIt was erected that the model of human prostate cancer in BALB/C nude mouse followed by locally injecting Ad-hTERT-HSV-tk and peritoneal injection of GCV. The anti-tumor efficacy was evaluated by index of tumor volume, tumor weight, relative tumor curative, and tumor growth curve. Afterwards, the TUNEL and transmission electron microscope to overview apoptosis of tumor cells were used. Finally, immunohistochemistry for detecting PCNA of tumor cells were applied.

RESULTSCompared with the control group, all viruses treatment groups demonstrated tumor growth inhibition. Among 3 treatment groups, antitumoral effect of Ad-hTERT-HSV-tk/GCV was much stronger than other two groups (P < 0.05). Obvious necrosis and apoptosis was observed by TUNEL, and PCNA was detected by immunohistochemistry in tumor tissues in all viruses treatment group.

CONCLUSIONSAd-hTERT-HSV-tk/GCV system is highly efficacious to inhabit the growth of human prostate cancer.

Adenoviridae ; enzymology ; genetics ; Animals ; Female ; Genetic Therapy ; methods ; Genetic Vectors ; administration & dosage ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Promoter Regions, Genetic ; genetics ; Prostatic Neoplasms ; pathology ; therapy ; Recombination, Genetic ; Telomerase ; genetics ; Thymidine Kinase ; genetics

PURPOSE: A sufficient response rate and good compliance are both important for instituting chemotherapy to treat metastatic breast cancer. Effective oral chemotherapy regimens have long been studied to improve patients' compliance. 5'-Deoxy-5-fluorouridine (5'-DFUR) is a prodrug of 5-fluorouracil (5-FU), which is known to be converted by thymidine phosphorylase (dThdPase). A recent preclinical study revealed that cyclophosphamide (CPA) upregulated dThdPase activity and especially in tumor cells. The purpose of this study was to examine the efficacy of long-term administration of 5'-DFUR/CPA for the patients suffering with metastatic breast cancer. METHODS: Thirty four cases with metastatic breast cancer after curative surgery were enrolled in this study. All the patients had been previously exposed to standard chemotherapy such as CMF (CPA, methotrexate, and 5-FU) and CAF (CPA, doxorubicin, and 5-FU). All patients had distant metastasis such as in the bone, lung and liver. Daily treatment consisted of 5'-DFUR 800 mg and CPA 100 mg both were given orally. The treatment was continued for at least 24 weeks. RESULTS: The mean age was 49 years and the treatment period ranged from 24 to 60 weeks. The response rate was 35.3%, while it was 26.5% for the patients with stable disease. The mean time to tumor progression was 36 weeks. A significant decrease in pain occurred in twenty patients (69%) with bone metastasis. The frequent adverse effects were leukopenia (32.4%) and gastrointestinal symptoms (20.4%). There was significant correlation between the rate of side effects and the duration of medication (p=0.010). CONCLUSION: These findings show that oral administration of 5'-DFUR and CPA is well tolerated on an outpatient basis and it was proven to suppress tumor progression. So, an oral combination therapy with 5'-DFUR and CPA may be suitable for metastatic breast cancer.
Administration, Oral ; Breast Neoplasms* ; Breast* ; Compliance ; Cyclophosphamide* ; Doxorubicin ; Drug Therapy ; Drug Therapy, Combination* ; Fluorouracil ; Humans ; Leukopenia ; Liver ; Lung ; Methotrexate ; Neoplasm Metastasis ; Outpatients ; Thymidine Phosphorylase