• Toxicological Research
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• 제23권1호
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• pp.19-24
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• 2007

We demonstrate that paclitaxel, an antitumor agent derived from yew tree, inhibits LPS- and $IFN-{\gamma}$-induced NF-kB/Rel activation in RAW 264.7 cells. Previously, paclitaxel ($>10{\mu}M$) has been known to induce iNOS gene expression in macrophages. However, in the previous report we described that the pretreatment of macrophages with low concentration of paclitaxel ($0.1{\mu}M$) for 8 h inhibited LPS-induced iNOS gene expression. Pretreatment of RAW 264.7 cells with paclitaxel significantly inhibited NF-kB/Rel transcriptional activation. Electrophoretic mobility shift assay further confirmed that pretreatment of macrophages with paclitaxel inhibited NF-kB/Rel DNA binding. Taxotere, a semisynthetic analog of paclitaxel, also inhibited LPS- and $IFN-{\gamma}$-induced iNOS gene expression. Collectively, these series of experiments indicate that paclitaxel inhibits iNOS gene expression by blocking NF-kB/Rel activation.

• 대한의생명과학회지
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• 제15권1호
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• pp.67-72
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• 2009

Microtubule-interfering agents (MIAs), including paclitaxel, have been attributed in part to interference with microtubule assembly, impairment of mitosis, and changes in cytoskeleton. But the signaling mechanisms that link microtubule disarray to destructive or protective cellular responses are poorly understood. This study investigated the effect of paclitaxel on differentiation such as type II collagen expression and sulfated proteoglycan accumulation in rabbit articular chondrocytes. Paclitaxel caused differentiated chondrocyte phenotype as demonstrated by increment of type II collagen expression and proteoglycan synthesis Paclitaxel treatment stimulated activation of ERK-1/2 and p38 kinase. Inhibition of ERK-1/2 with PD98059 enhanced paclitaxel-induced differentiation, whereas inhibition of p38 kinase with SB203580 suppressed paclitaxel-induced differentiation. Our findings suggest that ERK-1/2 and p38 kinase oppositely regulate paclitaxel-induced differentiation in chondrocytes.

• 한국미생물·생명공학회지
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• 제40권2호
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• pp.157-162
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• 2012

In this study, we have for the first time applied increased surface area fractional precipitation in order to decrease the particle size of the anticancer agent paclitaxel from plant cell cultures. When compared with the case where no surface area increasing material was employed, the addition of ion exchange resin as a surface area increasing material resulted in a considerable decrease in the size of the paclitaxel precipitate. When ion exchange resin was used, the paclitaxel particles were four to five times smaller, having less than a 20 ${\mu}m$ radius, than those obtained in the absence of ion exchange resin. This is presumably because the growth of paclitaxel particles was impeded by the addition of ion exchange resin. The size of the paclitaxel precipitate also depended on the material used to increase the surface area, a result considered to be due to differences in the affinity between the particular ion exchange resin used and the paclitaxel particles. The yield of paclitaxel was significantly improved when ion exchange resin was used as a material to increase surface area. Paclitaxel, with a reduced particle size due to the addition of a surface area increasing material during the fractional precipitation process, is believed to be particularly useful for practical applications of the drug.

• 약학회지
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• 제48권4호
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• pp.226-230
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• 2004

The pharmacokinetics of orally administered paclitlxel (50 mg/kg) was studied in six rabbits after 1hr pretreatment (2.0 mg/kg and 10 mg/kg) of tetramethoxyflavone or coadministration of (2.0 mg/kg, 10 mg/kg and 20 mg/kg) tetramethoxyflavone. The area under the plasma concentration-tine curve (AUC) and plasma concentration of paclitaxe1 coadministered with tetramethoxyflavone (10 mglkg) were increased significantly (p<0.05) compared with control. However, coadministration of tetramethoxyflavone (2 and 20 mg/kg) showed no significant effect on the pharmacokinetic parameters of paclitaxel. Pretreatment with tetramethoxyflavone significantly (p<0.05) increased the plasma concentration of paclitaxel. The area under the plasma concentration-time curve (AUC) and the peak concentration (C$_{max}$) of paclitaxel pretreated with tetramethoxyflavone were increased significantly (p<0.01, p<0.05) compared with control. The terminal half. life of paclitaxel pretreated with tetramethoxyflavone (2 mg/kg and 10 mg/kg) was significantly (p<0.05) prolonged compared with control. Pretreatment with tetramethoxyflavone (2.0 mg/kg, 10 mg/kg) significantly (p<0.01, p<0.05) increased the absolute bioavailability of paclitaxel compared with the control (154∼179%). On the basis of the results, it might be considered that tetramethoxyflavone may inhibit cytochrome P450 or P-glycoprotein efflux pump which are engaged in paclitaxel metabolism, result in increased AUC and t$_{1}$2/ of paclitaxel. However, further study should be conducted to clarify the roles of cytochrome P450 and P-glycoprotein on paclitaxel bioavailability with/or without tetramethoxyflavone. P-glycoprotein on paclitaxel bioavailability with/or without tetramethoxyflavone.

• Biomolecules & Therapeutics
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• 제22권1호
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• pp.68-72
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• 2014

When chemotherapy is administered during pregnancy, it is important to consider the fetus chemotherapy exposure, because it may lead to fetal consequences. Paclitaxel has become widely used in the metastatic and adjuvant settings for woman with cancer including breast and ovarian cancer. Therefore, we attempted to clarify the transport mechanisms of paclitaxel through blood-placenta barrier using rat conditionally immortalized syncytiotrophoblast cell lines (TR-TBTs). The uptake of paclitaxel was time- and temperature-dependent. Paclitaxel was eliminated about 50% from the cells within 30 min. The uptake of paclitaxel was saturable with $K_m$ of $168{\mu}M$ and $371{\mu}M$ in TR-TBT 18d-1 and TR-TBT 18d-2, respectively. [$^3H$]Paclitaxel uptake was markedly inhibited by cyclosporine and verapamil, well-known substrates of P-glycoprotein (P-gp) transporter. However, several MRP substrates and organic anions had no effect on [$^3H$]paclitaxel uptake in TR-TBT cells. These results suggest that P-gp may be involved in paclitaxel transport at the placenta. TR-TBT cells expressed mRNA of P-gp. These findings are important for therapy of breast and ovarian cancer of pregnant women, and should be useful data in elucidating teratogenicity of paclitaxel during pregnancy.

• 약학회지
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• 제47권2호
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• pp.98-103
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• 2003

The purpose of this study was to investigate the effect of flavone (20 mg/kg) on the pharmacokinetic parameters and the bioavailability of paclitaxel (40 mg/kg) orally coadministered in rats. The plasma concentration of paclitaxel in combination with flavone was increased significantly (coadministration p＜0.05, pretreatment p＜0.0l) compared to that of control. Area under the plasma concentration-time curve (AVC) of paclitaxel with flavone was significantly (coadministration p＜0.05, pretreatment p＜0.0l) higher than that of control. Peak concentration (Cmax) of paclitaxel with flavone were significantly increased (coadministration p＜0.05, pretreatment p＜0.01) compared to that of control. Time to peak concentration (Tmax) of paclitaxel with flavone decreased significantly (p＜0.05) than that of control. The total body clearance (CLt) and elimination rate constant ($\beta$) of paclitaxel with flavone were significantly reduced (p＜0.05) compared to those of control. Half-life (t$_{1}$2/) of paclitaxel with flavone was significantly prolonged (p＜0.05) compared to that of control. Based on these results, it might be concluded that flavone may enhance bioavailability of paclitaxel through the inhibition of cytochrome P450 and P-glycoprotein, which are engaged in paclitaxel absorption and metabolism in liver and gastrogintestinal mucosa, respectively.

• Radiation Oncology Journal
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• 제17권1호
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• pp.57-64
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• 1999

목적 : Paclitaxel(Taxol)은 미소관의 집합을 촉진시키고 분해를 방지하여 세포주기 중 유사분열을 정지시킴으로써 방사선조사와 병용할 경우 방사선감작제로서의 가능성이 있다. 흰쥐의 대장점막에서 paclitaxel이 방사선의 효과에 미치는 영향을 파악하기 위하여 본 실험을 시도하였다. 대상 및 방법 :실험군은 세군으로 나누어 paclitaxel 단독군은 paciltaxel 10mg/kg을 복강내 1회 주입하였고, 방사조사 단독군은 8Gy를 전복부에 단일조사하였으며, paclitaxel과 방사선 병용군은 paclitaxel(10mg/kg)을 복강내 주입 후 24시간에 방사선조사 단독군과 동일한 방법으로 조사하였다. 실험완료 후 대장점막에서 유사분열수, apoptosis와 기타 점막의 변화를 시간별로(6시간$\~$5일) 비교관찰하였다. 결과 : Paclitaxel 주입시 대장점막에서 유사분열의 빈도는 증가되지 않았고 apoptosis는 주입 후 24시간에 관찰할 수 있었으며, 소수포형성, 비정형성 및 배상세포의 감소는 paclitaxel 주입 후 6시간부터 3일까지 심하게 보였다. 방사선 조사 단독시 apoptosis는 6시간과 24시간에 관찰할 수 있었으며, 대장점막의 소수포형성, 비정형성 잊 배상세포의 감소는 24시간에 보이기 시작하여 3일에 심하게 보였다. Paclltaxel 주입 후 24시간에 방사선조사하여 apoptosls는 3일에 나타났으며 소수포형성, 비정형성 및 배상세포의 감소는 6시간부터 3일까지 나타났다. Paclitaxel과 방사선의 병용군에서 방사선조사 단독군에 비하여 apoptosis는 증가되지 않았으나, 소수포형성, 비정형성 및 배상세포의 감소는 6시간과 24시간에 증가되었으며(P<0.05), 이것은 방사선과 paclitaxel의 각각의 세포독성의 첨가효과가 있었다. 결론 : 흰쥐 대장에서 paclitaxel은 유사분열에 영향을 미치지 않았으나, 방사선조사에 의한 세포손상과 동일한 변화로 apoptosis, 소수포형성, 비정형성 및 배상세포의 감소를 유발하였다. Paclitaxel과 방사선조사 병용군에서 대장점막에 소수포형성, 비정형성 및 배상세포 감소가 방사선조사 단독군에 비하여 현저히 증가되어 paclitaxel은 방사선에 대하여 첨가효과가 있었다.

• 약학회지
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• 제48권1호
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• pp.1-5
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• 2004

The purpose of this study was to investigate the effect of coadministration and 3 days-pretreatmemt of niledipine (2, 10 mg/kg) on the pharmacokinetic parameters and bioavailability of paclitaxel (50 mg/kg) after oral administration in rats. Coadministration of nifedipine with paclitaxel did alter the $C_{max}$ (115${\pm}$29 ng/ml without nifedipine; 135${\pm}$35 ng/ml with nifedipine (10 mg/kg): p<0.05) and AUC (188${\pm}$459 ng/mlㆍhr with-out nifedipine; 2546${\pm}$642 ng/mlㆍhr with nifedipine; p<0.05). Three days treatment of nifedipine on the prior to paclitaxel administration increased the $t_{1/2}$ 〔9.90${\pm}$2.47 hr without nifedipine; 12.37${\pm}$3.12 hr with nifedipine (2 mg/kg): 12.83${\pm}$3.32 hr with nifedipine (10 mg/ml); p<0.05] and AUC [1833${\pm}$459 ng/mlㆍhr without nifedipine; 2663${\pm}$648 ng/mlㆍhr with nifedipine (2 mg/kg): 3006${\pm}$734 ng/mlㆍhr with nifedipine (10 mg/ml): p <0.05]. Drug interaction between nifedipine and paclitaxel decreased the elimination rate constant and increased the oral bioavailability of paclitaxel. On the basis of the results of this study, it might be considered that nifedip ine may inhibit cytochrome P450, which are engaged in paclitaxel metabolism, result in increased $t_{1/2}$ and AUC of paclitaxel. However, further study should be conducted to clarify the roles of cytochrome P450 and P-glycoprotein on paclitaxel bio-availability wit/or without nifedipine.

• 대한의생명과학회지
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• 제15권2호
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• pp.141-146
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• 2009

Paclitaxel, an antimicrotubule agent, binds to beta-tubulin in the microtubule and stabilizes the polymer, thereby repressing dynamic instability. Here, we have demonstrated that microtubule cytoskeletal architecture involved in regulation of the COX-2 expression in chondrocyte treated with paclitaxel. Paclitaxel enhanced COX-2 expression and prostaglandin E2 production, as indicated by the Western blot analysis, reverse transcriptase PCR(RT-PCR) and immunofluorescence staining, and $PGE_2$ assay, respectively. In our previous data have shown that paclitaxel treatment stimulated activation of ERK-1/2 and p38 kinase(Im et al., 2009). SB203580, an inhibitor of p38 kinase, blocked the induction of COX-2 expression by paclitaxel. Also PD98059, an inhibitor of ERK-1/2 kinase was blocked the induced COX-2 expression. These results indicate that activation of ERK-1/2 and p38 kinase is required for COX-2 expression induced by paclitaxel in rabbit articular chondrocytes.

• 한국임상약학회지
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• 제13권2호
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• pp.91-96
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• 2003

Paclitaxel과 cephalosporines(제 1세대인 ceftezole sodium과 cephradine, 제2세대인 cefamandole sodium과 cefmetazole sodium, 제3세대인 cefoperazone sodium과 cefotaxime sodium 그러고 제4세대인 cefepime hydrochloride)을 $5\%$포도당주사액 그리고 $0.9\%$ 염화나트륨주사액과 함께 Y-Site 장치를 써서 환자에게 주입할 때 paclitaxel의 안정성에 관하여 연구하였다. Paclitaxel 0.3 mg/ml 및 1.2 mg/ml과 cephalosporines 20 mg/m을 각각 1 : 1로 혼합한 후 0, 1, 2, 4, 12시간 시점에서 paclitaxel의 농도를 HPLC로 분석하였다. 방해물질에 의한 분석오차를 줄이기 위해 분석법을 여러 상태에서 확인하였으며, 각 농도에서 3차례씩 실험하였고 각 샘플은 2차례 반복하여 HPLC로 분석하였다. 분석전에 각 시료의 투명도, 색의 변화, 침전상태 및 pH를 검사하였다. Paclitaxel 0.3 mg/ml 및 1.2 mg/ml와 cephalosporines 20 mg/ml를 각각 혼합하였을 때 12시간 동안 안정하였으며, 주사액의 혼탁이나 색의 변화 및 침전은 나타나지 않았으며 pH도 변하지 않았다.