Ultrastructural observations on the vincristine-induced neuronal crystalloid inclusion in young rats

Summary Vincristine-induced crystalloid inclusions were examined in the neurons and neuronal processes of young rats by the electron microscope (EM) equipped with a tilting stage. Using a computer system that reproduces three-dimensional organization, an optical transformation method was applied to the microtubules and neurofilaments in an attempt to clarify the morphological appearance and internal pattern of crystalloid inclusions. The dimensional models obtained were compared with actual EM photographs, and the characteristic ultrastructural component and morphology were drawn out.Basically, a crystalloid inclusion is composed of four strands of intermediate 10 nm neurofilaments connected to one another by four side-arms producing a circular profile on a transverse section. These four side-arms seemed to arise from nodules within the filaments at regular intervals simulating a bead-like appearance. These data did not significantly differ from those obtained from EM images. Characteristically, these crystalloid inclusions began to appear 6 h after the administration of 10^–3 M vincristine sulfate and persisted up to a period of 6 days. Beyond that, however, these inclusions were no longer demonstrable suggesting a transient state. This was in contrast to neurofibrillary tangles which appeared to be permanent changes.     

Increased cation transport inmdr1-gene-expressing K562 cells

Cation-transport properties were compared in a human leukemic cell line (K562) and its vincristineselected,mdr1-gene-expressing sublines (K562/Vcr30 and K562/Vcr150) by the capacity of the cells to accumulate the potassium analogue thallium (²⁰¹Tl). Determination of the time course of thallium accumulation in the absence and presence of ouabain, an inhibitor of sodium-potassium adenosine triphosphatase (ATPase), showed that the initial (at 20 min) rate of ouabain-resistant uptake was about 70% higher in the K562/Vcr30 cells than in the parental line. The maximal rate (V_max) of ouabain-resistant uptake was 78 mmol/h for K562 cells and 115 mmol/h for K562/Vcr30 cells, and the Michaelis constant (K _m) was 0.37 and 0.18 mmol, respectively. Bumetanide (50 M), a specific inhibitor of ouabain-resistant Na–K–Cl cotransport, inhibited the elevated²⁰¹TI uptake in K562/Vcr150 cells but had no effect on cellular vincristine accumulation. Incubation with different multidrug resistance (MDR)-reversing agents (verapamil as well as cyclosporin A and its analogue PSC833) had no significant effect on²⁰¹Tl uptake. Membrane depolarization by an elevation of the potassium concentration in the incubation medium did not affect vincristine accumulation in any cell line, which indicated that the changed drug-transport properties inmdr1-gene-expressing cells were not due to membrane hyperpolarization. It was concluded that P-glycoprotein-positive cells have a more efficient ouabain-resistant cation-transport mechanism than to cells without P-glycoprotein. A functional relationship between this phenomenon and MDR was not identified.     

动脉插管化疗治疗中晚期膀胱肿瘤(附11例报告)

目的探讨动脉插管化疗对于中晚期膀胱肿瘤的治疗效果。方法对１１例由于年龄大、体质差、发现较晚、不能耐受麻醉和手术的中晚期膀胱肿瘤患者，采用了动脉插管化疗。结果１１例患者治疗后平均存活时间为２６．２±１３．１个月，１年生存率为８１．８％，总有效率为９０．９％，不良反应轻微。结论动脉插管化疗是目前治疗中晚期膀胱肿瘤的一种较好方法。     

耐长春新碱视网膜母细胞瘤细胞株的建立

目的：研究视网膜母细胞瘤获得性多药耐药现象，探讨其产生机制。方法：利用长春新碱(vincristree，VCR)对人视网膜母细胞瘤细胞系HXO-RB₄₄细胞在体外进行浓度递增法逐步诱导实验，建立一株耐长春新碱视网膜母细胞瘤细胞亚株HXO—RB/VCR。并对其细胞生长，药物含量，药物敏感性与放射性敏感性进行检测。 结果：该耐药细胞株HXO—RB/VCR细胞对长春酰胺、丝裂霉素C、阿霉素、足叶乙甙、顺铂、卡铂等有交叉耐受，对卡氮芥、氟尿嘧啶无明显抗药性，而对氨甲喋呤的敏感性反而增加。对⁶⁰ Coγ射线有轻度耐受性。细胞内药物含量测定显示：耐药细胞内长春新碱浓度明显低于敏感细胞，钙通道阻断剂异博定可使细胞内VCR浓度增加，部分逆转其耐药性。 结论：VCR可诱导视网膜母细胞瘤产生多药耐药和轻度放射耐受，获得性多药耐药作用可被异博定逆转。 （中华眼底病杂志，1997，13：6-9）     

Characterization of tetrandrine,a potent inhibitor of P-glycoprotein-mediated multidrug resistance

Multidrug resistance (MDR) is one of the main obstacles in tumor chemotherapy. A promising approach to solving this problem is to utilize a nontoxic and potent modulator able to reverse MDR, which in combination with anticancer drugs increases the anticancer effect. Experiments were carried out to examine the potential of tetrandrine (Tet) as a MDR-reversing agent. Survival of cells incubated with Tet at 2.5 mol/l for 72 h was over 90%. Tet at 2.5 mol/l almost completely reversed resistance to vincristine (VCR) in KBv200 cells. Tet at a concentration as low as 0.625 mol/l produced a 7.6-fold reversal of MDR, but showed no effect on the sensitivity of drug-sensitive KB cells in vitro. In the KBv200 cell xenograft model in nude mice, neither Tet nor VCR inhibited tumor growth. However, VCR and Tet combined inhibited tumor growth by 45.7%, 61.2% and 55.7% in three independent experimental settings. In the KB cell xenograft model in nude mice, Tet did not inhibit tumor growth, but VCR and the combination of VCR and Tet inhibited tumor growth by 40.6% and 41.6%, respectively. Mechanism studies showed that Tet inhibited [³H]azidopine photoaffinity labeling of P-gp and increased accumulation of VCR in MDR KBv200 cells in a concentration-dependent manner. The results suggest that Tet is a potent MDR-reversing agent in vitro and in vivo. Its mechanism of action is via directly binding to P-gp and increasing intracellular VCR accumulation.Abbreviations DMSO Dimethyl sulfoxide - FBS Fetal bovine serum - MDR Multidrug resistance - MTT 3-(4,5-Dimethylthiazol-yl)-2,5-diphenyltetrazolium bromide - PBS Phosphate-buffered saline - P-gp P-glycoprotein - SDS Sodium dodecyl sulfate - Tet Tetrandrine - VCR Vincristine     

甲钴胺防治长春新碱神经毒性临床观察

目的：观察甲钴胺防治长春新碱神经毒性的近期疗效。方法：入选54例患者随机分为A、B两组,两组化疗方案均为含长春新碱1 mg/m2的化疗方案,21 d为1周期。A组（试验组）采用甲钴胺＋化疗,B组（对照组）单用化疗。A组在用长春新碱之前口服甲钴胺片0.5 mg/次,每日3次,第1~7 d,所有患者完成4周期化疗后评价疗效。结果：可评价病例54例,A组28例,发生神经毒性1级4例、2级2例、3级1例,总发生率25.0%。B组26例,发生神经毒性1级9例、2级4例、3级4例,总发生率65.4%。两组比较,差异有统计学意义（P〈0.05）。结论：甲钴胺能降低长春新碱神经毒性的发生率,值得临床推广应用。     

长春新碱脂质体介导的肿瘤化疗研究现状

长春新碱是一种广谱抗癌药,广泛应用于肿瘤联合化疗,但由于严重的神经毒性和组织刺激性等不良反应,其临床应用受到限制。长春新碱利用脂质体作为药物载体,可有效提高药物剂量,延长半衰期并降低药物的毒性,显示出良好的疗效和可耐受的不良反应,具有广阔的应用前景。本文就长春新碱脂质体介导的肿瘤化疗研究的现状予以综述。     

The neuroprotective effect of tropisetron on vincristine-induced neurotoxicity

Vincristine (VCR) peripheral neuropathy is a dose-limiting side effect. Several studies have shown that tropisetron, a 5-HT₃ receptor antagonist, exerts anti-inflammatory and immunomodulatory properties. Current study was designed to investigate a suppressive effect of tropisetron on VCR-induced neuropathy and whether this effect exerts through the 5-HT₃ receptor or not.Neuropathy was induced in rats by administration of vincristine (0.5 mg/kg, 3 intraperitoneal injections on alternate days) and in treatment group, tropisetron (3 mg/kg); m-chlorophenylbiguanide (mCPBG), a selective 5-HT₃ receptor agonist (15 mg/kg); tropisetron (3 mg/kg) plus mCPBG (15 mg/kg); granisetron, another selective 5-HT₃ receptor antagonist (3 mg/kg) were administered intraperitoneally 1 h prior to vincristine injection. Hot plate, open field tests (total distance moved, mean velocity and percentage of total duration of the movement) and motor nerve conduction velocity (MNCV) were performed to evaluate the sensory and motor neuropathy. Further, plasma levels of tumor necrosis factor-alpha (TNF-α) and interleukin-2 (IL-2) and the level of TNF-α in sciatic nerve were assessed as well as histological examination.In only VCR-treated rats hot plate latencies were significantly increased, total distance moved, mean velocity, total duration of the movement and sciatic MNCV significantly decreased compared with control. In tropisetron and tropisetron plus mCPBG groups, one injection of tropisetron prior to each VCR injection robustly diminished TNF-α and IL-2 levels, and also prevented mixed sensory-motor neuropathy, as indicated by less mortality rate, better general conditions, behavioral and electrophysiological studies. Moreover, pathological evidence confirmed the results obtained from other findings. But granisetron and mCPBG had no significant effect on the mentioned parameters.In conclusion, these studies demonstrate that tropisetron significantly suppressed VCR-induced neuropathy and could be a neuroprotective agent for prevention of VCR-induced neuropathy via a receptor-independent pathway.     

Potentiation of PIEZO2 mechanically-activated currents in sensory neurons mediates vincristine-induced mechanical hypersensitivity

Vincristine,a widely used chemotherapeutic agent for treating different cancer,often induces severe peripheral neuropathic pain.A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia.However,mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood.In the present study,we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2channel-depen...     

长春新碱联合白介素11治疗难治性特发性血小板减少性紫癜疗效观察

目的探讨长春新碱联合重组人白介素11治疗难治性血小板减少性紫癜的疗效方法.方法通过分析我院2006年3月~2011年2月间符合23例难治性血小板减少性紫癜的临床资料,采用长春新碱联合重组人白介素11进行治疗.结果显效8例,良9例,进步2例,无效4例,总有效率达73.9%(17/23).结论长春新碱联合重组人白介素11治疗难治性ITP疗效切实可行,不良反应小.