阿霉素为主的化疗方案治疗非霍奇金淋巴瘤40例

目的：评价水剂阿霉素与粉剂阿霉素在临床疗效和安全性方面的差异。方法：在40例非霍奇金淋巴瘤（NHL）患者中，采用统一方案CHOP（环磷酰胺，阿霉素，长春新碱和泼尼松）。其中治疗组20例患者用水剂阿霉素，对照组20例患者用粉剂阿霉素。结果：治疗组有效率为85％，对照组有效率为80％，本研究表明二者在疗效及不良反应方面无差异。结论：水剂阿霉素在临床应用中是安全和有效的。     

吡喃阿霉素米托蒽醌治疗非霍奇金淋巴瘤

目的 观察以吡喃阿霉素为主的CTOP方案治疗非霍奇金淋巴瘤的疗效，并与以米托蒽醌为主的CMOP方案进行比较。方法 THP方案组治疗NHL26例，21d一个周期；MIT方案组治疗NHL25例，21d一个周期。结果 初发患者以THP为主方案治疗后有效率为81．81％，复发或难治患者的有效率为53．33％；MIT方案组治疗初发患者的有效率为75．00％，复发或难治患者的有效率为33．33％。THP及MIT治疗非霍奇金淋巴瘤的疗效无差异（P〉0．05）。结论 THP是治疗非霍奇金淋巴瘤的高效低毒的化疗药物。     

Miscibility analysis of particulate solid dispersions prepared by electrospray deposition

Physical characteristics of solid dispersions were investigated using carbamazepine (CBZ) and prednisolone (PDN) as model drugs, and poly(vinyl pyrrolidone) and Eudragit as polymeric excipients. Electrospray method provided particulate formulations, of which the particle size was typically in the order of micrometers, when the polymer concentration of the solution used for the preparation was below 2% (w/v). Decrease of the solution concentration and flow rate resulted in a decrease in the particle diameter, as theoretically expected. Also, the particle size could be reduced to 400 nm by increasing the conductivity of the solution by the addition of salts. When poly(vinyl pyrrolidone) K90 was used as an excipient, CBZ was homogeneously loaded up to ca. 40%, and if a greater amount was added, the excess CBZ was separated as a pure crystalline phase. PDN was homogeneously loaded up to ca. 60%. However, in contrast to CBZ, excess PDN maintained the amorphous state, even when a greater amount was added. The separated excess PDN phase was crystallized in the heating process during thermal analysis. In addition to the thermodynamic factor, there seems to be a dynamic factor to separate drug phase from the excipient phase, depending on their molecular weight and miscibility during the electrospray deposition process. The mechanism for particle formation by electrospray deposition is discussed with emphasis on the miscibility between drug and excipient.     

An update on the pharmacological management of post-herpetic neuralgia and painful diabetic neuropathy

Neuropathic pain is a persistent pain condition that develops secondary to nerve injury. The two most common types of peripheral neuropathic pain are post-herpetic neuralgia (PHN) and painful diabetic neuropathy (PDN). Amitriptyline, nortriptyline, desipramine and imipramine are TCAs that have been shown to be effective for the symptomatic relief of PHN and PDN. Serotonin noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine have been shown to be very promising for the treatment of PDN with fewer adverse effects than TCAs. Selective serotonin reuptake inhibitors (SSRIs) were shown in a number of studies to have some efficacy in relieving PDN-related pain, yet other studies of the SSRIs have demonstrated conflicting outcomes. Most of the older antiepileptic studies were performed in patients with PDN; consequently, little is known about the efficacy of these drugs in patients with PHN. Carbamazepine, phenytoin and valproic acid were shown to be effective in ameliorating PDN-related pain. Other antiepileptic agents, including lamotrigine, oxcarbazepine and topiramate, have demonstrated some beneficial effects for the treatment of PDN, although they were also found to be ineffective in some PDN studies. alpha2delta Ligands such as gabapentin and pregabalin have been proven to be effective for the treatment of PHN and PDN in a number of large placebo-controlled trials. These drugs are useful not only in relieving pain but also in improving quality of life. Although the use of opioids for the treatment of neuropathic pain is controversial, a number of studies support the efficacy and safety of opioids in the treatment of neuropathic pain. Of these, oxycodone and tramadol have been shown to be superior to placebo for the treatment of PHN and PDN. A number of small studies have shown that dextromethorphan was effective in patients with PDN but not in patients with PHN. Topical agents such as lidocaine 5% patches and topical capsaicin are useful in ameliorating pain in patients with PHN but these agents are unsatisfactory for use as a sole agent. Although a number of drug treatments are available for the symptomatic relief of neuropathic pain symptoms, these agents do not provide satisfactory relief in all patients. For these patients, other treatment alternatives such as combination drug therapy that produces pain relief via distinctly different mechanisms may be successful. The purpose of this review is to compare the efficacy and limitations of currently available pharmacological treatments for the symptomatic relief of PHN and PDN, and to discuss the potential of combination therapy in PHN and PDN.     

Safety and efficacy of meso-2,3-dimercaptosuccinic acid (DMSA) in children with elevated blood lead concentrations

OBJECTIVE: To evaluate the safety and efficacy of meso-2,3-dimercaptosuccinic acid in the treatment of children with lead toxicity. DESIGN: This was an open-label study in 59 children 12-65-months old, with pretreatment whole-blood lead levels of 25-66 microg/dL, who received 116, 26-28 day courses of oral dimer-captosuccinic acid, while residing either in the Pediatric Clinical Research Unit of the Johns Hopkins Hospital or in lead-safe housing during the outpatient portion of the study. RESULTS: All, who completed the study, showed sharp decreases in blood lead concentration during therapy, but 2-3 weeks following completion of drug therapy, blood lead concentration rebounded to an average of 58% (23 microg Pb/dL of whole blood) of their average pretreatment blood lead concentration (40 microg Pb/dL of whole blood). There were no adverse reactions attributable to dimercaptosuccinic acid; however, 2 of the 59 patients were reexposed to defective lead paint and experienced sharp increases in blood lead concentration while on therapy. In one instance, the child's blood lead concentration increased from 20 to 90 microg Pb/dL whole blood in 1 week. Other unexpected events were discussed in the text. CONCLUSIONS: Dimercaptosuccinic acid is apparently safe and does mobilize lead into the urine, but not the essential metals, zinc and copper. Reexposure is always a danger; therefore, all children, while on therapy, should be monitored for their blood lead concentration at weekly intervals during and immediately after therapy. No conclusions can be drawn from this study regarding long-term beneficial effects, if any, of this drug on late neurocognitive outcome.     

Modulation by prednisolone of calcium handling in skeletal muscle cells.

1. Increased calcium (Ca2+) influx has been incriminated as a potential pathological mechanism in the chronic skeletal muscle degeneration exhibited by Duchenne muscular dystrophy (DMD) patients. We have studied the influence of the glucocorticoid alpha-methylprednisolone (PDN), the only drug known to have a beneficial effect on the degenerative course of DMD, on Ca2+ handling in the C2 skeletal muscle cell line. 2. PDN, when added 3 days (when myoblasts start to fuse into myotubes) after cell seeding, led to a 2 to 4 fold decrease in cellular Ca2+ uptake. This decrease was independent of the extracellular Ca2+ concentration applied to cells. The effect took at least 24 h in order to become established (PDN of 10(-5) M) and took longer for lower PDN concentrations (EC50 of ca. 10(-6) M at day 5, 10(-6.5) M at day 7 and 10(-7.5) M at day 9 in culture). 3. Cellular calcium accumulation was also decreased in PDN-treated myotubes exposed to 45Ca(2+)-containing medium for 1 to 6 days. 4. No effect of PDN was seen on 45Ca2+ efflux; a decrease in the amount of 45Ca2+ released was observed due to the reduction of cellular 45Ca2+ loading. 5. PDN treatment led to an approximately 2 fold decrease in basal cytosolic Ca2+ concentration. 6. Three antioxidant drugs (lazaroids), previously shown to enhance in vitro skeletal muscle cell differentiation to the same extent as PDN, induced a similar decrease in Ca2+ influx. 7. Our results suggest that long-term incubation of C2 cells with PDN leads to a decrease of the size of the cellular Ca2+ pools and to reduced resting cytosolic Ca2+ levels. Part of the beneficial effect of PDN in DMD patients could be attributed to a reduction of Ca2+ influx and of the size of Ca2+ pools in dystrophic muscle fibres.     

Effect of rifampicin on haem and bilirubin metabolism in man.

Haem and bilirubin metabolism was studied in seven healthy volunteers during 4 weeks treatment with rifampicin 600 mg at night. The serum unconjugated bilirubin concentration increased 2-3 fold in the first 24 h of treatment (P less than 0.01) and subsequently fell to below pretreatment values (P less than 0.05) during the third and fourth weeks of rifampicin therapy. In each subject, the activity in leucocytes of delta-aminolaevulinic acid (ALA) synthase increased and that of protoporphyrinogen (proto) oxidase decreased during the first week of therapy. The mean ALA synthase activity was most markedly increased on day 4 being seven-fold its pretreatment value (P less than 0.01), and the mean proto oxidase activity most depressed on day 2 at 50% its pretreatment value (P less than 0.02). There was increased urinary excretion of porphobilinogen (PBG) during the first week of therapy and increased excretion of porphyrins and PBG during the third week of treatment. The increase in ALA synthase activity and haem precursor excretion can be explained by the combination of increased haem demand for haemoprotein induction and partial block in haem synthesis due to reduced proto oxidase activity.     

三氧化二砷对胃癌细胞SGC7901多药耐药的逆转作用及其机制

研究三氧化二砷(arsenic trioxide，As₂O₃)对胃癌细胞多药耐药的逆转作用及其机制。逐渐递增长春新碱(VCR)的浓度诱导胃癌细胞株SGC7901产生多药耐药性(SGC7901/VCR)。MTT法测定药物对肿瘤细胞的杀伤作用；Western blotting检测肿瘤细胞内P-糖蛋白(P-gp)、谷胱甘肽S-转移酶(GST-s)表达。结果表明，胃癌SGC7901/VCR细胞对长春新碱(VCR)、5-氟尿嘧啶(5-Fu)及表阿霉素的耐药倍数分别为16.56倍、2.69倍及13.05倍。经As₂O₃预处理24 h后，长春新碱、5-氟尿嘧啶及表阿霉素对SGC7901/VCR的耐药倍数显著下降(P<0.05)。SGC7901/VCR在静息时细胞内P-gp、GST-s蛋白表达显著高于SGC7901。而As₂O₃可使SGC7901/VCR细胞内P-gp、GST-s蛋白表达显著下降，但是对SGC7901无明显作用。从而证实As₂O₃部分逆转SGC7901/VCR的耐药性，其机制可能与P-gp、GST-s蛋白表达降低有关。     

Adverse effects during the treatment with pegylated interferon and ribavirin in children with chronic hepatitis C

PURPOSE: Administration of pegylated interferon-alpha (IFN-alpha) and ribavirin in adults with chronic hepatitis C (CHC) is a recommended therapeutic standard. Nevertheless, this therapeutic regimen rises numerous controversies. The aim of this study was to analyze adverse effects during the treatment with pegylated IFN-alpha and ribavirin in children with CHC. METHODS: Study group comprised 30 children with CHC, age 8-19 years (mean 13,6 years), 9 girls and 21 boys. All patients were administered two medication therapy with pegylated IFN-alpha-2b in the dose of 1.5 microg/kg of body weight 1x/week subcutaneously and daily oral ribavirin 15 mg/kg of bodyweight for 48 weeks. Blood samples were taken at baseline and every 4 weeks during the whole treatment and 24 weeks of follow-up period. Panel of test included: cellular blood count and smear, ALT activity, bilirubin level. Patients complaints were noticed during every visit. Thyroid hormones and antibodies were checked every 3 months. Children were divided into group A that responded to treatment and group B-nonresponders. RESULTS: Abnormalities in laboratory tests (white blood cells, neutrophils, haemoglobin) were observed mainly during first weeks of treatment. Mean bilirubin level and platelets were normal. Mean ALT normalized during the treatment. After 12-16 weeks of the therapy somatic adverse effects decreased significantly. CONCLUSIONS: Administration of pegylated IFN-alpha and ribavirin in children with CHC is related to characteristic adverse effects. Periodical dose reduction was necessary. Although side effects and subjective patient complaints were present, children attended school without difficulties. Constant monitoring is required during the whole treatment.     

Different kinetics of immunologic recovery using nelfinavir or lopinavir/ritonavir-based regimens in children with perinatal HIV-1 infection

The choice to include the optimal protease inhibitor (PI) in highly active antiretroviral therapy (HAART) regimens in children with perinatal HIV-1 infection is still under debate. Virologic and immunologic outcomes of three different regimens in an observational paediatric cohort were compared. Data from 12 saquinavir-, 18 nelfinavir-, and 10 lopinavir/ritonavir-treated children were analyzed after 4 and 24 weeks of therapy. Immunologic and virologic outcomes were compared using multivariate analysis adjusting the results for age, baseline CD4+ T-lymphocyte count and baseline viral load. Saquinavir-treated children displayed significant reduction in viral load at week 24 (but not at week 4) and no increase in CD4+ T-lymphocyte count, indicating a poor advantage in using this drug. Lopinavir/ritonavir-treated children presented lower viral loads than nelfinavir-treated children at week 4 (P=0.020) and week 24 (P<0.0001). Virologic failure occurred in 6/18 (33.3%) nelfinavir-treated children but in no child receiving lopinavir/ritonavir (P=0.013). An undetectable viral load was achieved in 9/10 (90.0%) lopinavir/ritonavir- vs. 3/18 (16.6%) nelfinavir-treated children (P<0.0001). No significant difference in CD4+ T-lymphocyte count was observed between lopinavir/ritonavir- and nelfinavir-treated children at weeks 4 and 24. However, a different kinetic of the immunologic recovery was observed. Lopinavir/ritonavir-treated children displayed higher CD4+ T-lymphocyte counts than saquinavir-treated children since the first month of therapy (week 4: P=0.042; week 24: P= 0.029) while nelfinavir-treated children took 24 weeks to reach such an outcome (P=0.034). Since lopinavir/ritonavir-based regimen controls viral replication more efficiently and restores CD4+ T-lymphocyte count more quickly than saquinavir- or nelfinavir-based HAART, it may be considered when a salvage therapy or a rapid increase in CD4+ T-lymphocytes is necessary.     

Modulation by verapamil of vincristine pharmacokinetics and toxicity in mice bearing human tumor xenografts

The effect of the calcium channel blocker verapamil (VRP) on the accumulation and retention of vincristine (VCR) has been examined in mice bearing xenografts of human rhabdomyosarcomas. The tumors were Rh18, moderately sensitive to VCR, and its subline, Rh18/VCR3, selected in vivo for primary resistance to VCR. Administration of VRP by i.p. bolus at dose levels above 75 mg/kg was limited by acute lethality. At this dose, the maximal concentration in plasma was 24 microM, with rapid elimination such that plasma concentrations reported to modulate resistance in vitro (approximately 5-10 microM) were maintained for less than 60 min. To sustain a 10 microM plasma concentration, mice were infused with VRP at 6.25 mg/kg/hr (150 mg/kg/day) for up to 7 days using osmotic pumps implanted in the peritoneal cavity. Steady-state plasma levels were greater than or equal to 10 microM for at least 96 hr, and this schedule demonstrated minimal toxicity. Administration of VCR 20 hr after the start of VRP infusion produced significant lethality, requiring an 8-fold reduction in the VCR dose. Pharmacokinetic studies showed that VRP markedly increased the uptake and retention of VCR in small intestine, liver and kidney of mice. In small intestine, 8-fold greater levels of VCR were determined 24 hr after VCR administration, and this was associated with in increase in T1/2 for elimination from 350 to 913 min. HPLC analysis of extracts from small intestine showed that greater than 90% of the radiolabel eluted with VCR or 4-desacetyl-VCR. Modulation of VCR retention was also related to the dose of VCR administered. The VRP-sensitive efflux pathway appeared more effective in certain tissues only at higher concentrations of VCR. In contrast, VRP did not alter significantly the uptake and retention of VCR in either the parent or VCR-resistant human xenografts. The data demonstrated that, in the mouse, VRP modulates the uptake and retention of VCR in several tissues, and this may indicate that drug efflux mediated by a VRP-sensitive mechanism (e.g. GP-170, associated with the multiple drug resistance phenotype) has a protective function against xenobiotics in these tissues.     

Achievement of target cyclosporine concentrations as a predictor of severe acute graft versus host disease in children undergoing hematopoietic stem cell transplantation and receiving cyclosporine and methotrexate prophylaxis

This study evaluates our institution's target trough cyclosporine (CSA) concentrations as predictors of severe acute graft versus host disease (aGvHD) in children receiving either matched related or unrelated hematopoietic stem cell transplantation (HSCT). The outcomes of 87 consecutive children who underwent allogeneic HSCT and received CSA and methotrexate as prophylaxis against aGvHD between October 1, 1999 and September 30, 2002 were retrospectively evaluated. The proportion of time that each patient maintained a whole blood CSA concentration within or above the initial target range (105-155 ng/mL or 155-210 ng/mL) was calculated for each of the following time periods: in each week after HSCT from day 0 to +28; in the week preceding engraftment; and in the week preceding the onset of aGvHD. Patients were prospectively evaluated twice weekly for the presence and severity of aGvHD by senior attending physicians. The relationship between potential predictors and the development of severe aGvHD was examined using univariate logistic regression. The main variables of interest were the proportion of time that therapeutic or supratherapeutic CSA concentrations were maintained; median CSA concentrations; the number of methotrexate doses received; and the use of folinic acid rescue. Mean follow-up time was 3.0+/-1.9 years among children who survived beyond day +100. Three variables were significantly associated with the development of severe aGvHD on univariate analysis: initial CSA target concentration [odds ratio (OR), 0.24; P=0.03], proportion of time the target CSA concentration was achieved during the second week after transplant (OR, 0.16; P=0.02), and proportion of time the target CSA concentration was achieved during the week before engraftment (OR, 0.22; P=0.0489). Multivariable analysis demonstrated an inverse relationship between the median CSA concentration during the week before engraftment and the development of severe aGvHD (OR, 0.99; P=0.045). These results suggest that achievement of our CSA target concentrations is important to aGvHD outcomes.     

A study of the clinical efficacy of azelastine in patients with extrinsic asthma, and its effect on airway responsiveness.

1. The effect of 4.4 mg azelastine administered orally on airway responsiveness, skin prick testing, daily peak expiratory flow rates and symptoms of asthma was compared with placebo in a 7 week double-blind, parallel group study of 24 patients with extrinsic asthma. The study was in two parts: a 2 week assessment period, during which all patients received placebo tablets but recorded daily peak flow rates (PEFRs) and symptoms, preceding the 7 week double-blind comparison. 2. Azelastine, 4.4 mg, significantly decreased airway responsiveness to histamine compared with placebo both after a single dose (P less than 0.001), and following 7 weeks continuous treatment (P less than 0.02). Airway responsiveness to methacholine was not altered by administration of azelastine compared with placebo. 3. Skin prick test weal diameters to both allergen and histamine were significantly reduced after both a single dose and following 7 weeks continuous therapy treatment with azelastine. 4. There was a significant improvement in both the mean of the morning and the evening peak flow rates recorded during the last week compared with the first week of the study in the group receiving 4.4 mg of azelastine twice daily compared with placebo. Scores for wheeze were significantly reduced during the final 3 weeks of the study in patients receiving azelastine compared both with those receiving placebo and with the first week of the study (P less than 0.05, P less than 0.01). Consumption of inhaled bronchodilators fell significantly during the study in the group receiving azelastine therapy (P less than 0.05); no such fall occurred in the placebo treated patients. 5. A bitter metallic taste was reported by 58% of patients who received azelastine therapy.     

Effects of vincristine on the bile flow in male albino rats

Bile secretion is an important function served by the liver. The microtubular system integrity plays a key role in hepatic transport and excretion of several of bile constituents including phospholipids & cholesterol as well as detoxified xenobiotics. Furthermore, an alteration in bile secretion has been proposed as an important cause of enteritis, also a complication of microtubular inhibitors like Vincristine (VCR) that may occur following treatment as an anti cancer drug. The study aims to study the effects of microtubule inhibitor VCR on bile flow and bile composition in rats. For this purpose, male albino rats were studied. One group of five rats was infused with single IV dose of VCR (@1 mg/kg and the other received equal volume of IV vehicular fluid. For bile samples, animals were cannulated, bile flow examined at different time intervals before and after drug administration. Biliary composition studied at second hour post i/v administration. Single dose VCR treatment showed significant rise in the baseline excretion of bile in animals studied during first 2 hrs, although, there was a mild reduction in the biliary flow rate after few hours. Biliary total cholesterol was decreased and cation concentrations increased significantly in the second hour post VCR. The results indicate that the exposure of rats to VCR induces early alterations in biliary secretion. This study may prove useful for the purpose of understanding enteritis in patients undergoing chemotherapy.     

ZNF300基因在肝癌耐药细胞HepG2/VCR中的表达及功能初探

目的建立人肝癌HepG2/VCR耐药细胞株,检测ZNF300基因在HepG2/VCR中的表达并初步分析其在肝癌多药耐药(MDR)中发挥的功能。方法采用体外低浓度梯度递增的诱导方法建立长春新碱(VCR)获得性HepG2/VCR耐药细胞株。MTT法检测确定HepG2/VCR耐药细胞株对VCR的耐药性,用Western blot方法检测人锌指蛋白ZNF300基因编码的ZNF300及多药耐药基因编码的P糖蛋白(P-gp)在HepG2和HepG2/VCR细胞中的表达差异;在HepG2/VCR细胞中转染ZNF300基因正向或反向cDNA质粒后,MTT法检测VCR对耐药细胞IC50值的变化,Westernblot方法检测细胞内P-gp表达的影响。结果 MTT检测确认HepG2/VCR耐药细胞构建成功,Western blot检测发现耐药细胞中ZNF300及P-gp的表达相对于HepG2细胞明显增高。在HepG2/VCR细胞中转染正向ZNF300 cDNA质粒后,MTT和Western blot检测发现ZNF300过表达可使VCR对耐药细胞的IC50值增高,并使细胞内P-gp表达上调;在转染反向cDNA质粒Knockdown ZNF300基因表达后得到相反的结果。结论 ZNF300基因在HepG2/VCR耐药细胞中表达明显增高,并能通过上调耐药蛋白P-gp的表达促进肝癌细胞耐药性,可以作为逆转肝癌多药耐药的分子作用靶点。     

Effect of PSC 833, a P-glycoprotein modulator, on the disposition of vincristine and digoxin in rats.

PSC 833 has been used to overcome the phenomenon of multidrug resistance by inhibiting the P-glycoprotein (P-gp)-mediated efflux of antitumor drugs from tumor cells. Because P-gp expressed in several normal tissues may affect the disposition of its substrates, we examined the dose-dependent effect of PSC 833 on the disposition of vincristine (VCR) and digoxin (DGX) in rats. One-tenth milligram per kilogram PSC 833 was sufficient to significantly reduce the biliary excretion clearance of DGX from 3.0 ml/min/kg to 0.5 ml/min/kg, whereas 3 mg/kg PSC 833 was needed to significantly reduce the biliary excretion clearance of VCR from 36 ml/min/kg to 9 ml/min/kg. Three milligrams per kilogram PSC 833 significantly reduced the renal clearance of VCR by 30% but did not affect that of DGX significantly. The tissue-to-plasma DGX concentration ratio in the brain at 6 h after administration (0.34 versus 1.64), but not that of VCR at 2 h (1.07 versus 1.37), was significantly increased by PSC 833, 3 mg/kg. The differential effect of PSC 833 on the disposition of VCR and DGX may be ascribed to the different degree of contribution of P-gp to the disposition of these ligands.     

Enteral absorption of sulfasomidine depending on age (author's transl)

After intravenous and oral application of 25 mg 6-(sulfanilamido)-2,4-dimethyl-pyrimidine (sulfasomidin)/kg body-weight to 29 newborns, 8 infants and 9 older children the completeness and rate of absorption were determined. Sulfasomidine was completely absorbed in newborns (mean value 95.7%) as well as in older children (mean value 94.4%). Concerning the rate of absorption there were age-dependent differences. Using the Bateman function for the kinetic model of intestinal absorption the rate constant of invasion k1 was significantly lower in the first week of life compared to that in older children. In agreement with these data the time tmax of the maximum serum concentration was significantly prolonged in newborns compared to that of older children.     

SB203580, a specific inhibitor of p38-MAPK pathway, is a new reversal agent of P-glycoprotein-mediated multidrug resistance.

P-glycoprotein (P-gp) is the plasma membrane transport pump responsible for efflux of chemotherapeutic agents from cells and is one of the systems that secures multidrug resistance (MDR) of neoplastic cells. In the present study, drug sensitive L1210 and multidrug resistant L1210/VCR (characterized by overexpression of P-gp) mouse leukemic cell lines were used as an experimental model. We have found that SB203580, a specific inhibitor of p38-MAPK pathway, significantly reduced the degree of the vincristine resistance in L1210/VCR cells. This phenomenon was accompanied by a decrease in the LC(50) value of vincristine from 3.203+/-0.521 to 0.557+/-0.082 microM. The LC(50) value of sensitive cells for vincristine was about 0.011 microM. The effect of SB203580 on L1210/VCR cells was associated with significantly increased intracellular accumulation of [3H]-vincristine in the concentration dependent manner. Prolonged exposure of resistant cells to 30 microM SB203580 did neither significantly influence the gene expression of P-gp, nor change the protein levels of p38-MAPK. Western blot analysis revealed that the MDR phenotype in L1210/VCR cells was associated with increased level and activity of cytosolic p38-MAPK. In resistant cells, the enhanced phosphorylation of both, p38-MAPK and ATF-2 (endogenous substrate for p38-MAPK) was found as well. In conclusion we could remark that SB203580, an inhibitor of p38 kinase pathway, reversed the MDR resistance of L1210/VCR cells. MDR phenotype of these cells is connected with increased levels and activities of p38-MAPK. These findings point to the possible involvement of the p38-MAPK pathway in the modulation of P-gp mediated multidrug resistance in the L1210/VCR mouse leukemic cell line. However, the mechanisms of SB203580 action should be further investigated.     

苦参碱和氧化苦参碱对胃癌细胞株SGC7901/VCR耐药性的作用

目的研究苦参碱和氧化苦参碱对人胃癌细胞株SGC7901/VCR耐药性的作用。方法以SGC7901/VCR为研究对象,用SRB法测定苦参碱和氧化苦参碱对SGC7901/VCR耐药细胞的增殖抑制率,计算IC50和IC10,并进一步计算其耐药倍数和逆转倍数。流式细胞术检测罗丹明123的荧光强度变化。结果苦参碱和氧化苦参碱对SGC7901/VCR均存在抑制作用,且呈剂量依赖。VCR耐药倍数为33.4倍;0.78 mg/ml苦参碱逆转倍数为1.92倍;0.71 mg/ml氧化苦参碱逆转倍数为3.39倍;细胞内罗丹明123浓度较明显增加(P<0.01)。结论低毒浓度的苦参碱和氧化苦参碱对人胃癌耐药细胞株SGC7901/VCR具有一定的耐药逆转作用,且氧化苦参碱优于苦参碱。