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Biomedical subjects

G Chen

Publications and source records attributed to G Chen.

949 records · Page 53Linked to original sources
PubMedDate not supplied

Breast cancer resistance protein-mediated topotecan resistance in ovarian cancer cells.

Overexpression of breast cancer resistance protein (BCRP) and mitoxantrone (MX) resistance protein can confer resistance to a variety of cytostatic drugs, such as MX, topotecan (TPT), doxorubicin, and daunorubicin. This study investigates the role of BCRP in resistance of ovarian cancer to TPT treatment. We have developed TPT-resistant human ovarian cancer cell line. Intracellular concentration of fluorescent dye rhodamine 123 (Rh123) was measured by flow cytometry. The expression of several membrane transporter proteins including P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and BCRP were determined by reverse transcription-polymerase chain reaction and Western blotting. The Rh123 concentration in parental cells was approximately three times of those in TPT-resistant cells. In contrast to undetectable level of P-gp messenger RNA (mRNA) and minimal level of MRP1 expression in TPT-resistant cells, overexpression of both the BCRP mRNA and the protein was detected in these cells. Introduction of antisense-phosphorothioate oligonucleotide derived from BCRP mRNA into TPT-resistant cells resulted in a significant increase in the concentration of intracellular Rh123. These results suggested a novel mechanism in which a reduced intracellular drug concentration may be mediated by BCRP gene products in human ovarian cancer cells.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMedDate not supplied

Clearance of [125I]-tumor necrosis factor-alpha from the brain into the blood after intracerebroventricular injection in rats.

To test the hypothesis that brain to blood clearance is a mechanism by which brain inflammation and damage can increase circulating acute phase cytokines, rate of transfer of [125I]-tumor necrosis factor-alpha ([125I]-TNF) from brain to blood was determined. Acid precipitable [125I]-TNF appeared in peripheral blood within 5 min of intracerebroventricular (i.c.v.) injection and was cleared from brain to blood following first order kinetics at a fractional rate of 0.01123 +/- 0.0030/min, a value virtually identical with a previously determined clearance rate of [125I]-IL-6. Area under blood concentration curve compared with that after intravenous injection shows that 31.6 +/- 5.8% of the intracerebral dose reached peripheral blood in 4 h. Elevated ratios of superior sagittal sinus to aortic blood radioactivity concentration at 1 and 3 h (1.48 +/- 0. 26, p = 0.042; 1.95 +/- 0.39, p = 0.026, respectively) indicate that TNF-alpha drains from brain at least in part via the sagittal sinus. Escherichia coli lipopolysaccharide i.c.v. injection increased the rate of brain efflux of TNF-alpha.

Animals↗
PubMedDate not supplied

Radiographic and histologic analyses of stress fracture in rabbit tibias.

Sequential changes in remodeling of the internal structure of the tibia caused by controlled, excessive jumping and running were studied in 20 rabbits. Vascular changes and circulatory disturbances within the cortical bone occurred before osteoclastic resorption. Degeneration and necrosis of osteocytes due to circulatory disturbances also occurred. Periosteal new bone formation, found at and after 12 days of the experiment, was a compensatory reaction to support the tibia weakened by accelerated osteoclastic resorption. Small cracks appeared at the cement line and developed through the neighboring cement line of the haversian systems. At 21 days, incomplete fracture of the tibial cortex was found in two rabbits. Complete fracture through one side of the cortex was seen in one animal at the 50th day of the experiment. In this study, however, most of the tibias did not have visible fracture lines after a period of stressful exercise. This result suggests that most tibias adapt to changes in stress requirements through proper internal remodeling so that a complete fracture does not occur.

Animals↗
PubMedDate not supplied

CYP2C9 Ile359Leu polymorphism, plasma irbesartan concentration and acute blood pressure reductions in response to irbesartan treatment in Chinese hypertensive patients.

Our previous study demonstrated that the CYP2C9*3 gene variant was significantly associated with elevated plasma irbesartan concentration and blood pressure decline, assessed by a 4-week follow-up and revisit following daily administration of irbesartan. We conducted a further analysis to examine the acute effects of the CYP2C9 polymorphism on plasma concentration and blood pressure through remeasurement 6 h after administration of irbesartan. We used an extreme-sampling approach by selecting individuals from the top and bottom deciles of blood pressure response residuals to irbesartan from the previous study population in Anhui, Taihu, and Dongzhi Counties, in China. A total of 196 subjects were available for the analysis. Pre- and posttreatment systolic and diastolic blood pressures (SBP and DBP), and venous blood samples (0.5, 2, and 6 h following the first treatment) were collected from each individual. Plasma irbesartan concentrations were determined by a standard HPLC/fluorescence method. The observed frequencies were 97.7% for CYP2C9*1 (Ile359) and 2.3% for CYP2C9*3 (Leu359). Subjects with the CYP2C9*1/CYP2C9*3 genotype had significantly higher plasma irbesartan concentrations when compared with those with the CYP2C9*1/CYP2C9*1 genotype (beta +/- SE = 81 +/- 36) and greater DBP response (beta +/- SE = 5.6 +/- 2.5 mmHg) at the 6-h time point after adjusting for important confounders. Our finding suggests that the CYP2C9*3 gene variant significantly alters the plasma concentration and acute DBP response at the 6-h point following irbesartan treatment in Chinese hypertensive patients.

Administration, Oral↗
PubMedDate not supplied

Laser in situ keratomileusis enhancement after radial keratotomy.

PURPOSE: To present results of laser in situ keratomileusis (LASIK) enhancement after radial keratotomy (RK). METHODS: Sixteen eyes of 10 patients were treated with LASIK for residual myopia and hyperopia after RK. Mean preoperative spherical equivalent refraction was -3.14+/-3.04 D (range, -6.675 to +6.00 D). Best spectacle-corrected visual acuity was 20/20 in 9 eyes, 20/25 in 6 eyes, and 20/30 in 1 eye. Uncorrected visual acuity was better than 20/40 in only 2 eyes. Patients were followed at 1 day, 1 week, 1, 3, and 6 months, and 1 year. Mean follow-up was 8.3 months (range, 1 to 17 mo). RESULTS: All eyes received one LASIK enhancement. Mean final spherical equivalent refraction was +0.16+/-0.68 D (range, -1.00 to +1.75 D). No eyes experienced any visual loss. Five eyes gained 1 line of best spectacle-corrected visual acuity. Uncorrected visual acuity was 20/20 in 9 eyes, 20/25 in 6 eyes, and 20/30 in 1 eye. Two eyes of one patient had the previous RK incisions open. CONCLUSION: LASIK was an effective treatment for correction of residual myopia and hyperopia after RK.

Adult↗
PubMedDate not supplied

Augmentation of cisplatin (DDP) cytotoxicity in vivo by DL-buthionine sulfoximine (BSO) in DDP-sensitive and-resistant rat ovarian tumors and its relation to DNA interstrand cross links.

DDP treatment (1.2 mg/kg x 5) prolonged the mean survival time (MST) of rats bearing an experimental ovarian tumor (0-342) from 16.4 to 51.1 days, with one of ten rats surviving more than 90 days. Administration of D,L - buthionine sulfoximine (BSO) (24 and 2 h prior to DDP, respectively) before the last two doses of DDP had no significant effect on DDP therapeutic activity, while daily combination of DDP with BSO (BSO 2 h prior to DDP) throughout the treatment significantly increased MST to 69 days (p less than 0.05, vs. DDP alone), with three of ten rats surviving more than 90 days. In the DDP resistant counterpart (0-342/DDP), on the other hand, DDP alone showed only a slight increase of MST (11.6 days in DDP group vs. 10.7 days in control group), addition of BSO to DDP treatment further prolonged MST to 13.3 days (p less than 0.01 vs. DDP alone). The formation of DNA interstrand cross links (DNA-ISCL) was found to be higher in 0-342 than in 0-342/DDP cells in vitro with a maximum at 24 h following 1 h exposure to DDP. BSO depleted the intracellular GSH level in a dose - and time - dependent manner in the two cell lines. Pretreatment with BSO resulted in a 7.4% increase in DNA-ISCL by DDP in 0-342 cells but a 39% increase in 0-342/DDP cells, which may partially account for chemosensitization of BSO to DDP in vivo. Our result that the chemosensitizing effect of BSO, through depletion of cellular GSH, is more significant in the DDP sensitive O-342 tumor than in its DDP resistant subline in vivo underlines that BSO should be used as a chemosensitizer in combination with DDP at the beginning of chemotherapy for clinical trial.

Animals↗
PubMedDate not supplied

Ability of m-chloroperoxybenzoic acid to induce the ornithine decarboxylase marker of skin tumor promotion and inhibition of this response by gallotannins, oligomeric proanthocyanidins, and their monomeric units in mouse epidermis in vivo.

m-Chloroperoxybenzoic acid (CPBA) was tested for its ability to induce the ornithine decarboxylase (ODC) marker of skin tumor promotion. In contrast to benzoyl peroxide, dicumyl peroxide, and 2-butanol peroxide, 5 mg of CPBA applied twice at a 72-h interval induce ODC activity at least as much as 3 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA). ODC induction peaks 36 h after a single CPBA treatment but is maximal 5 h after two applications of CPBA at a 48-h interval. The ODC-inducing activity of CPBA is dose dependent and sustained after chronic treatment. In contrast to TPA, two CPBA treatments at 12-24 h intervals produce no refractory state against ODC induction. The mechanism of ODC induction by CPBA is iron dependent. Various hydrolyzable tannins, condensed tannins (CTs) and their monomeric units remarkably inhibit the ODC response to multiple CPBA treatments. At 12 mg, gallic acid, Aleppo gall tannic acid (TA), catechin, and loblolly pine bark CT inhibit the most CPBA-induced ODC activity. Aleppo gall TA is even effective when applied several hours before CPBA. The tumor-promoting activity of CPBA and its inhibition by plant tannins remain to be evaluated.

Animals↗
PubMedDate not supplied

Increased poly(ADP-ribose) formation in cisplatin-resistant rat ovarian tumor cells.

Poly(ADP-ribose) polymerase (PARP) is well known for its involvement in DNA repair, although the underlying mechanisms remain unclear. Poly(ADP-ribose) is synthesized on nuclear proteins in response to DNA damage and consequently implicated in the toxicity of various xenobiotics, including anticancer agents. The metabolism of poly(ADP-ribose) in cisplatin (DDP)-sensitive (O342) and -resistant (O-342/DDP) rat ovarian tumor cells was investigated to explore its possible roles in DDP resistance. The poly(ADP-ribose) synthesis assayed as [3H]-NAD incorporation was higher by up to two-fold in the resistant O-342/DDP cells, when compared with that of its DDP-sensitive subline O-342. Furthermore, this difference still existed even in the presence of saturating concentrations of a double-stranded octameric deoxynucleotide that stimulates the enzyme directly, indicating a higher maximal poly(ADP-ribosyl)ation capacity of the resistant cells. In addition, acute treatment of O-342 cells with DDP also stimulated the polymer synthesis by up to 1.6-fold, which was totally suppressed by inclusion of 2.5 mM 3AB in the post-exposure incubation. Western blot analysis, however, failed to reveal higher levels of the enzyme proteins in the resistant cells. A higher level of endogenous DNA single strand breaks was also detected in both intact and permeabilized cells of O-342/DDP line. Taken together, these results demonstrate that the DDP resistance phenotype in these rat ovarian tumor cells is accompanied by a higher cellular poly(ADP-ribosyl)ation capacity, which may be linked with DDP resistance by enhancing the repair of DDP-inflicted DNA damage.

Animals↗
PubMedDate not supplied

Collateral sensitivity to thaliblastine and/or hyperthermia exhibited by a rat ovarian tumor cell line selected for resistance to cisplatin.

Drug resistance severely limits the effectiveness of clinical cancer chemotherapy. Employment of drugs other than the selected compounds with different mechanisms of action may provide a potential way to improve the therapeutic effects. Thaliblastine (TBL), a natural compound, showed a 2-fold higher cytotoxicity in a cisplatin (DDP) resistant rat ovarian tumor cell line (0-342/DDP) than in its parental sensitive line (0-342), as determined by an antiproliferation assay with 24 h continuous exposure. This phenomenon was also observed following 2 h pulse exposure if combined with heat treatment (40 degrees C). Further escalation of the temperature to 43 degrees C alone brought about 74.7 +/- 17.0% growth inhibition in the sensitive and 97.2 +/- 1.8% in the resistant line. Under this condition, the ID50 of TBL was again only half as much in 0-342/DDP cells as in the parental cells (12 vs 24 micrograms/ml) when compared to the hyperthermic treatment alone. In a colony formation assay with 2 h pulse exposure, the hypersensitivity of the resistant cells to DDP and/or heat was further confirmed. Alkaline elution showed that 24 h continuous treatment with TBL induced DNA single-strand breaks (SSB) in a dose-dependent manner in 0-342/DDP cells, whereas there was almost no DNA-SSB production by TBL in the sensitive line, possibly in part accounting for the hypersensitivity of the DDP resistant cells to TBL. The heat treatment (40 degrees C for 2 h) induced SSB in both lines, which was further enhanced by combination with TBL. This damage was repaired in part in 0-342 but almost completely in 0-342/DDP line after cells grew in drug-free medium for 48 h following the exposure, indicating that resistant cells can more efficiently repair DNA damage by either TBL or hyperthermia. Altogether, these results suggest that TBL may have potential to be used clinically as an alternative in the treatment of cisplatin-resistant malignancies with hyperthermia.

Animals↗
PubMedDate not supplied

Effects of thaliblastine on cytotoxicity and DNA damage in drug-sensitive and -resistant rat ovarian tumor cells treated with cisplatin.

Combination effects of cisplatin (DDP) and thaliblastine (TBL) in DDP-sensitive (0-342) and -resistant (0-342/DDP) rat ovarian tumor cells were investigated. TBL alone, at either 40 or 80 micrograms/ml, exerted higher cytotoxicity in the DDP-resistant 0-342/DDP cells than in the parental sensitive 0-342 cells in growth inhibition assay (% inhibitions: 12.5 and 42.8 in 0-342 cells vs. 37.5 and 66.1 in 0-342/DDP cells, at 40 and 80 micrograms/ml of TBL, respectively). TBL at 40 micrograms/ml showed an additive effect with DDP in the sensitive cells, while a synergistic cytotoxicity was observed in the resistant subline when the two drugs were used in combination, as exhibited by either % inhibition or cell viability. At 80 micrograms/ml of TBL, however, the combination effects were less than additive (infraadditive) in both lines, but still this treatment was more cytotoxic in 0-342/DDP cells. Alkaline elution assay showed that DDP induced higher DNA interstrand crosslings (ISCL) in 0-342 cells, while TBL produced DNA single strand breaks (SSB) in a dose-dependent manner in the resistant line but not in the sensitive cells. Combination of these two compounds resulted in a dramatic increase of DNA-SSB in 0-342/DDP cells. It is tentatively concluded that TBL might have some potential in combination with DDP to conquer the resistance in clinical use, which may result from its selective SSB-inducing activity in the resistant cells.

Animals↗
PubMedDate not supplied

Differential interactions of Pgp inhibitor thaliblastine with adriamycin, etoposide, taxol and anthrapyrazole CI941 in sensitive and multidrug-resistant human MCF-7 breast cancer cells.

The reversing effect of p-glycoprotein (Pgp) inhibitors on the multidrug resistance (MDR) phenotype is well established in a variety of MDR cell lines. The interactions of these inhibitors with individual MDR drugs in the respective parental lines, however, is less documented. This kind of information is not only essential for understanding of the outcome of clinical trials for MDR modulation in heterogeneous tumor populations but also important for evaluating of new Pgp blockers. Interaction of the Pgp inhibitor, thaliblastine (TBL), with several MDR drugs was therefore investigated in sensitive human breast cancer cell line (MCF-7) as well as adriamycin (AdR) selected MDR subline MCF/AdR. While the resistance to anthrapyrazole CI941 was completely overcome by simultaneous exposure to TBL (8 microM) in a 48 h exposure MTT assay compared with MCF-7 cells exposed to the same combination, only partial reversal was achieved in the case of AdR and etoposide (VP-16), but 240-fold hypersensitivity (or collateral sensitivity) was obtained in the MCF/AdR cells treated with taxol plus TBL, with IC50s of 0.10 +/- 0.03 microM and 24.6 +/- 5.0 microM in the resistant and sensitive cell lines, respectively. In the parental MCF-7 cells, on the other hand, no change of AdR cytotoxicity by simultaneous exposure to TBL was observed. There was an enhancement of CI941 cytotoxicity but an antagonism against taxol and VP-16 obtained upon addition of TBL to the treatment with the drugs in the MCF-7 parental cell line. Our results demonstrate that while TBL can overcome the resistance to each of the MDR drugs studied in MCF/AdR cells, albeit to a different extent varying from the partial reversal to the hypersensitivity, TBL co-exposure does not uniformly increase the cytotoxicity of these drugs in the parental MCF-7 cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗