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.     

增强剂量CHOP方案治疗非霍奇金淋巴瘤51例

〔目的〕探讨增强剂量CHOP方案治疗非霍奇金淋巴瘤的临床完全缓解率和3年生存率及骨髓抑制等情况。（方法）对51例非霍奇金淋巴瘤患者进行增强剂量CHOP方案治疗及良好的支持治疗并长期、定期治疗及随访。（结果）全组完全缓解率为784％；3年生存率为779％。（结论）增强剂量CHOP方案与传统CHOP方案相比在完全缓解率和3年生存率上有明显提高，而其骨髓抑制等毒副反应未见明显增加。     

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。     

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.     

长春新碱载体红细胞体内代谢分布的初步研究

目的：初步探讨长春新碱载体红细胞在小鼠体内的分布代谢情况。方法i昆明种小鼠腋窝皮下接种S180肉瘤细胞建立荷瘤小鼠模型，将荷瘤小鼠随机分为长春新碱、长春新碱载药红细胞2组，经尾静脉分别注射长春新碱200ug及长春新碱载药红细胞（浓度1cg／L）。注射后0、1、2、3、4、24、48及72h取小鼠血液、肝脏及肿瘤组织，用高效液相色谱法测定其中药物浓度，计算半衰期。结果：长春新碱进入体内后血浆浓度迅速增高，其代谢速率也很快，48h后完全测不出，半衰期1．53h。长春新碱载药红细胞在血浆中浓度稳定而持久，72h仍可测出，药物半衰期达4．1h，是前者的2．68倍。载药红细胞在肝脏及肿瘤中的浓度和稳定性均高于游离药物，且随着时间延长，这种优势越来越大。结论：载药红细胞延缓药物释放，延长药物作用时间；增强了药物向肝脏及肿瘤的靶向聚集，减少不良反应。为临床肿瘤治疗提供新思路和可行方法。     

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.     

甲基莲心碱对长春新碱抑制人胃癌细胞增殖作用的影响

目的：观察甲基莲心碱（Nef）在体外对长春新碱抑制人胃癌细胞增殖及诱导人胃癌细胞凋亡的影响。方法：采用MTT比色法、软琼脂克隆形成法检测药物的细胞毒性作用,并用流式细胞术、AO/EB荧光双染色法测定Nef对长春新碱诱导人胃癌细胞凋亡的影响。结果：2.5、5、10μmol/LNef能增强长春新碱对人胃癌细胞（SGC7901）增殖的抑制作用;10μmol/LNef能增强长春新碱（0.1、0.5、2、4μg/ml）诱导SGC7901细胞凋亡。结论：甲基莲心碱能增强长春新碱抑制人胃癌细胞增殖及诱导人胃癌细胞凋亡,为一种低毒高效的化疗增敏剂。     

潘生丁增强抗肿瘤药物作用的体外实验研究

为观察潘生丁与临床常用抗肿瘤药物阿霉素（ＡＤＭ）、长春新碱（ＶＣＲ）及足叶乙甙（ＶＰ－１６）联合应用的价值，我们选用人肺癌细胞株Ａ５４９进行体外细胞毒试验。可以看到：当阿霉素浓度为０．５μｇ／ｍｌ时，对Ａ５４９的抑制率为２９．７６％，加入０．５～１０μｇ／ｍｌ潘生丁时，其细胞生长抑制率提高了１３．２７％～３１．４２％，对长春新碱、足叶乙甙来说，当加入不同浓度潘生丁（０．５～１０μｇ／ｍｌ）时，其细胞生长抑制率分别提高了１８．４３％～４３．２１％及１６．１３％～２９．４７％。以上试验结果表明：潘生丁具有增强某些抗肿瘤药物（ＡＤＭ、ＶＰ－１６、ＶＣＲ）对肺癌细胞株Ａ５４９的细胞毒作用。     

Chemotherapy-induced peripheral neuropathy

The induction of peripheral neuropathy is a common factor in limiting therapy with chemotherapeutic drugs. Little is known about the mechanisms responsible for the development of neuropathy. Depending on the substance used, a pure sensory and painful neuropathy (with cisplatin, oxaliplatin, carboplatin) or a mixed sensorimotor neuropathy with or without involvement of the autonomic nervous system (with vincristine, taxol, suramin) can ensue. Neurotoxicity depends on the total cumulative dose and the type of drug used. In individual cases neuropathy can evolve even after a single drug application. A general predisposition for developing a chemotherapy-induced neuropathy has been observed in nerves previously damaged by diabetes mellitus, alcohol or inherited neuropathy. The recovery from symptoms is often incomplete and a long period of regeneration is required to restore function. Up to now, no drug is available to reliably prevent or cure chemotherapy-induced neuropathy. Received: 15 November 2000, Received in revised form: 12 April 2001, Accepted: 19 April 2001