BACKGROUND: Recent data showed prolonged administration of direct thrombin inhibitor might be needed to counteract the persistent thrombin activity and reduce the neointimal hyperplasia after arterial injury. We hypothesized that prolonged administration of LB30057, orally active direct thrombin inhibitor, might inhibit the vascular smooth muscle cell (SMC) proliferation in vitro and neointimal hyperplasia in rat carotid injury model. METHODS: In phase I, thrombin stimulated [methyl-3H] thymidine uptake was measured after LB30057 administration in cell culture study using rat aortic SMC. In phase II, LB30057 (low-dose: 5mg/kg, bid: mid-dose: 25mg/kg, bid: high-dose: 50mg/kg, bid) or placebo was administrated orally twice a day starting from 30minutes before injury until sacrifice for 14days in separated 2 sets of experiment. The histo-morphometric analysis for lumen area, intimal area, medial area, intima-to-medial ratio was performed. RESULTS: In vitro rat aortic SMC culture study, LB30057 inhibited thrombin-induced thymidine uptake. The mean neointimal area was significantly less in high-dose and mid-dose group than placebo group (high-dose vs. placebo: 0.14+/-0.02mm2 vs. 0.25+/-0.02mm2: mid-dose vs. placebo: 0.16+/-0.02mm2 vs. 0.29+/-0.03mm2, p<0.005) respectively and the mean ratio of neointima to medial area were significantly less in high-dose and mid-dose group than in placebo group (high-dose vs. placebo: 1.20+/-0.57 vs. 1.94+/-0.67, mid-dose vs. placebo: 1.58+/-0.29 vs. 2.39+/-0.27, p<0.05). There was no significant difference in the mean area of internal elastic lamina, external elastic lamina and mean luminal area between groups. In 2nd set experiment, the mean neointimal area (placebo: 0.29+/-0.03mm2, mid-dose: 0.16+/-0.02mm2: p<0.005), the mean area of internal elastic lamina and external elastic lamina were significantly less in mid-dose group than in placebo group. The mean ratio of neointima to medial area was significantly less in mid-dose group(1.58+/-0.29) than in placebo group (2.39+/-0.27) (p<0.05). CONCLUSION: LB30057 inhibits SMC proliferation in a dose dependent manner. Prolonged 14-day oral administration of LB30057 is effective in reducing the neointimal hyperplasia in rat carotid balloon injury model.
Administration, Oral ; Animals ; Cell Culture Techniques ; Cell Proliferation* ; Hyperplasia* ; Muscle, Smooth, Vascular* ; Neointima ; Phenobarbital ; Rats* ; Thrombin* ; Thymidine

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

OBJECTIVETo investigate the effects of total alkaloids of Tripterygium hypoglaucum Hutch (THH) on the tk gene of mouse lymphoma cells.

METHODL5178Y cells were infected with total alkaloids of THH with different concentrations and put into single-cell wells at different time phases. Then the numbers of positive wells were counted and the cell plating efficiency, relative suspension growth and mutation frequency were determined.

RESULTTotal alkaloids of THH (0.1-2.0 g x L(-1)) induced tk locus mutation with mutation frequency 2-9 times higher than that of spontaneous mutation frequency of L5178Y cells. There were two different phenotypes of mutation colonies, large colony and small colony, but the main colony was large colony. This phenomenon might be related with the mutagenesis of THH.

CONCLUSIONTotal alkaloids of THH can exert toxicity and mutagenic effects on tk gene in L5178Y cells, and there may be range limit in gene mutation.

Alkaloids ; administration & dosage ; isolation & purification ; toxicity ; Animals ; Cell Line, Tumor ; Cell Survival ; drug effects ; Dose-Response Relationship, Drug ; Leukemia L5178 ; enzymology ; genetics ; pathology ; Mice ; Mutagens ; administration & dosage ; isolation & purification ; toxicity ; Plants, Medicinal ; chemistry ; Point Mutation ; Thymidine Kinase ; genetics ; Tripterygium ; chemistry

The tissue distribution of DNA-PLGA-NP was investigated by the technique of gamma scintigraphy. The results showed that 30 min after mouse caudal vein injection of 32P-DNA-PLGA-NP, the ratio of radioactivity in liver against total radioactivity is higher than 70%, which is 1.4 fold the ratio after caudal vein injection of 32P-DNA, and that 2 h after subcutaneous injection of 32P-DNA-PLGA-NP 2 h, the ratio of the radioactivity in liver against total radioactivity is also higher than 70%, reaching a 1.6 fold increase when compared with the ratio after subcutaneous injection of 32P-DNA.
Animals ; DNA ; administration & dosage ; pharmacokinetics ; Drug Carriers ; Injections, Intravenous ; Injections, Subcutaneous ; Lactic Acid ; Mice ; Particle Size ; Plasmids ; administration & dosage ; genetics ; pharmacokinetics ; Polyglycolic Acid ; Polymers ; Thymidine Kinase ; genetics ; Tissue Distribution

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

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

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

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

OBJECTIVECalcium Glucarate (Cag), Ca salt of D-glucaric acid is a naturally occurring non-toxic compound present in fruits, vegetables and seeds of some plants, and suppress tumor growth in different models. Due to lack of knowledge about its mode of action its uses are limited in cancer chemotherapy thus the objective of the study was to study the mechanism of action of Cag on mouse skin tumorigenesis.

METHODSWe have estimated effect of Cag on DMBA induced mouse skin tumor development following complete carcinogenesis protocol. We measured, epidermal transglutaminase activity (TG), a marker of cell differentiation after DMBA and/or Cag treatment and [3H] thymidine incorporation into DNA as a marker for cell proliferation.

RESULTSTopical application of Cag suppressed the DMBA induced mouse skin tumor development. Topical application of Cag significantly modifies the critical events of proliferation and differentiation TG activity was found to be reduced after DMBA treatment. Reduction of the TG activity was dependent on the dose of DMBA and duration of DMBA exposure. Topical application of Cag significantly alleviated DMBA induced inhibition of TG. DMBA also caused stimulation of DNA synthesis in epidermis, which was inhibited by Cag.

CONCLUSIONCag inhibits DMBA induced mouse skin tumor development. Since stimulation of DNA synthesis reflects proliferation and induction of TG represents differentiation, the antitumorigenic effect of Cag is considered to be possibly due to stimulation of differentiation and suppression of proliferation.

9,10-Dimethyl-1,2-benzanthracene ; toxicity ; Administration, Topical ; Animals ; Anticarcinogenic Agents ; therapeutic use ; Carcinogens ; toxicity ; Cell Division ; drug effects ; DNA ; biosynthesis ; Enzyme Inhibitors ; toxicity ; Female ; Glucaric Acid ; therapeutic use ; Mice ; Skin Neoplasms ; chemically induced ; enzymology ; prevention & control ; Thymidine ; metabolism ; Transglutaminases ; metabolism

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