• The Korean Journal of Nuclear Medicine
• /
• v.37 no.3
• /
• pp.178-189
• /
• 2003

Purpose: Cellular uptakes of $^{99m}Tc-sestamibi(MIBI)\;and\;\;^{99m}Tc-tetrofosmin$ into cancer cell lines expressing multidrug resistance(MDR) were investigated and compared. The effects of verapamil and cyclosporin A, well-known multidrug resistant reversing agents, on cellular uptakes of both tracers were also compared. Materials and Methods: Doxorubicin-resistant HCT15/CL02 human colorectal cell and doxorubicin-resistant K562(Adr) and vincristine-resistant K562(Vcr) human leukemic cells were studied. RT-PCR analysis was used for the detection of mdr1 mRNA expression. MDR-reversal effects with verapamil and cyclosporine A were evaluated at different drug concentrations after incubation with MIBI and tetrofosmin for 1, 15, 30, 45 and 60 min, using single-cell suspensions at $1{\times}10^6cells/ml$ incubated at $37^{\circ}C$. Radioactivity in supernatants and pellets were measured with gamma well counter. Results: The cellular uptakes of MIBI and tetrofosmin in K562(Adr) and K562(Vcr) were lower than those of parental K562 cell. In HCT15/CL02 cells and K562(Adr) cells, there were no significant difference in cellular uptakes of both tracers, but cellular uptake of MIBI was higher than that of tetrofosmin in K562(Vcr) cells. Coincubation with verapamil resulted in a increase In cellular uptakes of MIBI and tetrofosmin. Verapamil increased cellular uptakes of MIBI and tetrofosmin by HCT15/CL02 cell by 11.9- and 6.8-fold, by K562(Adr) cell by 14.3- and 8-fold and by K562(Vcr) cell by 7- and 5.7-fold in maximum, respectively. Cyciosporin A increased cellular uptakes of MIBI and tetrofosmin by HCT15/CL02 cell by 10- and 2.4-fold, by K562(Adr) cell by 44- and 13-fold and by K562(Vcr) cell by 18.8- and 11.8-fold in maximum, respectively Conclusion: Taking together, MIBI and tetrofosmin are considered as suitable radiopharmaceuticals for defecting multidrug resistance. However, MIBI seems to be a better tracer than tetrofosmin for evaluating MDR reversal effect of the modulators. Since cellular uptakes of both tracers might differ in different cell types, further experiments regarding differences in cellular uptakes between cell types should be explored.

• Proceedings of the Korean Society of Veterinary Clinics Conference
• /
• 2008.05a
• /
• pp.80-80
• /
• 2008

• Tuberculosis and Respiratory Diseases
• /
• v.50 no.6
• /
• pp.686-692
• /
• 2001

Background : Outbreaks of multidrug-resistant tuberculosis(MDR-TB) are caused by the low rate of treatment response due to limitation in number of available drugs and high rates of adverse drug side-effects. This study analysed the risk factors for MDR-TB patients, who did not respond to treatment, with an aim to improve the rate of treatment response. Methods : Retrospective study of 111 MDR-TB patients at National Mokpo Tuberculosis Hospital from Jan. 1996 to Dec. 1998 was made. The patients were separated into two groups ; group I comprised of patients who were treated successfully and group II comprised of those were not treated successfully. In order to analyze the risk factors for treatment failure, differences between the two groups were compared and the confidence limit regarding the results were tested using an independent t-test. chi-square test and a Fisher's exact test. Results : The treatment failure rate of MDR-TB patients was 32% (36 patients), and treatment success rate 68%(75 patients). This study found no significant difference between two groups in terms of age, sex, family history, extent of the disease on the chest X-ray, the number of sensitive drugs in the treatment regimen, and the number of sensitive bactericidal drugs in the treatment regimen (p>0.05). However, a past history of pulmonary tuberculosis, cavitary lesions on the chest X-ray, the number of treatments, the number of resistant drugs and the number of drugs used showed a significant difference(p<0.05). Conclusion : The rate of treatment failure in MDR-TB was increased by a past history of pulmonary tuberculosis, cavitary lesions on the chest X-ray, the number of treatments, the number of resistant drugs and the number of drugs used. For improving the treatment response of MDR-TB, every effort should be made to reduce the drug resistance caused by failure of the first treatment.

• Proceedings of the PSK Conference
• /
• 2002.10a
• /
• pp.251.3-252
• /
• 2002

The present study was performed to compare the cardiovascular adverse effects of verapamil. KR30031 and their each optical isomers, and also to measure their ability to overcome multidrug resistance (MDR). R-isomer of KR30031 (R-KR30031) was equipotent with S-isomer of KR30031 (S-KR30031) and 25 fold less potent than R-isomer of verapamil (R-verapamil) in relaxing the aorta isolated from rat (EC50: 11.8, 10.2 and 0.46 ${\mu}$M, respectively). (omitted)

• Journal of Integrative Natural Science
• /
• v.5 no.3
• /
• pp.190-194
• /
• 2012

Human P-gp is one of the protein responsible for the multidrug resistance (MDR) develpment. MDR is a major cause of the cancer chemotherapy. In this paper, we performed homology modeling, docking study of papayriferic acid into the P-gp nucleotide binding domain (NBD2). For human P-gp, X-ray crystal structure is not known yet. We developed homology model for human NBD2 using HlyB ABC transporter structure (PDB code: 1XEF, resolution 2.5 ${\AA}$). Docking study was performed using Autodock. Docking result was analyzed, which shows that ligand docks into steroid binding site and interacts through hydrophobic and hydrophilic interactions.

• Journal of Pharmaceutical Investigation
• /
• v.37 no.6
• /
• pp.369-376
• /
• 2007

Cyclosporine (CsA) and tacrolimus (FK506) have a narrow therapeutic range, and their pharmacokinetic (PK) characteristic varies among individual. They are also substrates for cytochrome P450 (CYP) 3A4, 3A5 genes, and P-glycoprotein, the product of the multidrug resistance 1 (MDR1). The aims were to investigate the relationship between CYP3A and MDR1 genotypes and their PK parameters among healthy subjects. We investigated the genotype for CYP3A and MDR1 gene in human using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. After oral administration of CsA and FK506 (100 mg and 1 mg, respectively), whole blood samples were taken up to 24 hours. Blood CsA and FK506 concentrations were measured by LC/MS/MS. Each PK parameters were compared using Kruskal-Wallis test according to the CYP3A and MDR1 genotype. We found that the values of AVC for CsA were significantly different among CYP3A5 and MDR1 exon 26 (C3435T) genotypes (P=0.037 and P=0.049). On the other hand, the AUC for FK506 was significantly different only among CYP3A5 genotypes (P=0.013). The results clearly demonstrate the effects of CYP3A5 and MDR1 exon 26 on Cys and FK506 disposition.

• Asian Pacific Journal of Cancer Prevention
• /
• v.17 no.4
• /
• pp.2311-2314
• /
• 2016

Pistagremic acid (PA) is a bioactive triterpenoid isolated from various parts of Pistacia integerrima plants. The aim of this research was to investigate PA for reversion of multidrug resistant (MDR) mediated by P-glycoprotein using rhodamine-123 exclusion study on a multidrug resistant human ABCB1 (ATP-binding cassette, sub-family B, member 1) gene-transfected mouse T-lymphoma cell line in vitro. Results were similar to those with verapamil as a positive control. Docking studies of PA and standard Rhodamine123 were carried out against a P-gp crystal structure which showed satisfactory results. Actually, PA cannot bind exactly where co-crystallized ligand of P-gp is already present. However, the docking study predicted that if a compound gives a lesser score then it may have some potency. The docking scores of PA and Rhodamine were similar. Therefore, we can conclude that there are certain important chemical features of PA which are responsible for the inhibiting potency of P-gp.

• Journal of Life Science
• /
• v.26 no.7
• /
• pp.826-834
• /
• 2016

The present investigation was undertaken to examine the effectiveness of the combination treatment of an Hsp90 inhibitor and a SIRT1 inhibitor on suppressing the growth of chemo-resistant human cancer cells. We showed that inhibition of SIRT1 effectively potentiated the cytotoxicity of 17-allylamino-17-demethoxygeldanamycin (17-AAG) and reversed Hsp90 inhibitor resistance in multidrug-resistant (MDR) human ovarian HeyA8-MDR cells. Amurensin G, a potent natural SIRT1 inhibitor, enhanced Hsp90 inhibitor-mediated abrogation of the Hsp90 chaperone function and accelerated degradation of mutated p53 (mut p53), an Hsp90 client protein, by up-regulation of ubiquitin ligase CHIP. Knock-down of CHIP significantly attenuated amurensin G-induced mut p53 degradation. Down-regulation of mut p53 reduced the expression of heat shock factor1 (HSF1)/heat shock proteins (Hsps), a major cause of Hsp90 inhibitor resistance, which led to sensitization of the MDR cells to the Hsp90 inhibitor by the SIRT1 inhibitor. Amurensin G potentiated cytotoxicity of the Hsp90 inhibitor in HeyA8-MDR cells through suppression of 17-AAG-induced Hsp70 and Hsp27 induction via down-regulation of mut p53/HSF1, and it caused activation of PARP and inhibition of Bcl-2. Our data suggests that SIRT1 inhibitors could be used to sensitize MDR cells to Hsp90 inhibitors, possibly through suppression of the mut p53/HSF1-dependent pathway, and a novel mut p53-directed action of SIRT1 inhibition could effectively prevent mut p53 accumulation in MDR cells.

• Pediatric Infection and Vaccine
• /
• v.30 no.1
• /
• pp.47-54
• /
• 2023

With the widespread use of broad-spectrum antibiotics in clinical practice, the emergence of multidrug-resistant (MDR) gram-negative bacteria has become a global problem. The MDR Pseudomonas aeruginosa infection is especially difficult to treat and increases mortality in critically ill patients. Ceftolozane-tazobactam (Zerbaxa^TM) is a fifth-generation cephalosporin and beta-lactamase inhibitor that has proved to be effective for treating complicated urinary tract infections and complicated intra-abdominal infections caused by MDR P. aeruginosa. Herein, we report the first case of pediatric hematologic cancer in Korea that was successfully treated for MDR P. aeruginosa bacteremia with Ceftolozane-tazobactam.

• Journal of Pharmaceutical Investigation
• /
• v.35 no.4
• /
• pp.249-254
• /
• 2005

Multidrug resistance (MDR) of cancer cells is, at least in part, associated with the overexpression of P-glycoprotein (P-gp). Many studies have demonstrated that natural compounds obtained from fruits, vegetables, teas and medicinal plants may modulate P-gp activity. The objective of the present investigation was to examine the effect of seven natural compounds on the P-gp activity in human uterine sarcoma cell line, MES-SA/DX5. Daunomycin uptake was significantly increased by biochanin A and silymarin (p<0.0001) whereas it was reduced by morin (p<0.01). The efflux of daunomycin from the cells was significantly inhibited by biochanin A, morin, cephalotaxine, berberine (p<0.05) and silymarin (p<0.0001). Biochanin A, berberine and silymarin significantly decreased $IC_{50}$ value of daunomycin (p<0.05) while morin increased it (p<0.05). These results suggest that some natural compounds such as biochanin A and silymarin may inhibit P-gp function and can be developed as MDR reversing agents to improve the efficacy of chemotherapeutic drugs when administered concomitantly.