Antiproliferative, cytotoxic and apoptogenic activity of Indian toad (Bufo melanostictus, Schneider) skin extract on U937 and K562 cells.

The antiproliferative, cytotoxic and apoptogenic activities of Bufo melanostictus (Indian common toad) skin extract (TSE) on U937 and K562 leukemic cell line has been investigated. TSE significantly (P<0.001) reduced the time-dependent cell proliferation and decreased MTT values in U937 and K562 cells. TSE (IC50 doses) suppressed the proliferating cell nuclear antigen expression in both the cells. It was demonstrated that, TSE (IC50 doses) primarily arrested the U937 and K562 cells at G1 phase of the cell cycle. Confocal microscopy showed the altered fragmented nuclei and apoptotic bodies formation in TSE (IC50 doses) treated U937 and K562 cells. Membrane blebbing, cell surface shrinkage and perforation were observed through scanning electron microscope. TSE-induced DNA fragmentation in U937 and K562 cells was reflected in single-cell gel electrophoresis. TSE significantly (P<0.001) increase the length-width ratio of DNA mass as compared to control in comet assay. The flow cytometric analysis of annexin-V binding to the cancer cells further supported the apoptotogenic activity of TSE. The effect of TSE on normal human peripheral blood mononuclear cells viability and cytotoxicity was studied in culture and found to be less cytotoxic than on the U937 and K562 cells. The findings from the present study suggested that TSE might possess potent antineoplastic agent having antiproliferative, cytotoxic and apoptogenic activity against U937 and K562 myeloid leukemic cells.     

化疗药物对轴型皮瓣血运影响的组织学观察

目的探讨抗癌药物动脉灌注后对局部轴型皮瓣血运影响的组织学评价。方法在猪腹部的腹壁上动脉插管灌注抗癌药物,10d后在猪腹部形成以腹壁上血管为蒂的岛状皮瓣,通过对灌注区域轴型血管供养的岛状皮瓣的成活率、光镜、透射电镜及血管铸型透明标本的组织学观察,显示其血管结构及构筑的变化。结果抗癌药物用于局部动脉灌注后,使局部轴型血管支配的血管网有损伤的表现,岛状皮瓣远端的血运显著降低。结论抗癌药物经动脉灌注后可影响局部轴型皮瓣的血运,使皮瓣血供的安全范围缩小,为提高相关修复手术的成功率提供可靠的科学依据。     

赛赓啶对 KBV200细胞多药抗性的逆转作用

研究赛赓啶对KB_V200细胞多药抗性的逆转作用及逆转机制。在KB_V200细胞,采用MTT法,测出赛赓啶对长春新碱、阿霉素和鬼臼乙叉甙耐药的逆转系数分别为5.5,2.0和1.9,而对5-氟尿嘧啶、美法仑的细胞毒性作用无明显影响,表明赛赓啶为多药抗性逆转剂。荧光分光光度法测定表明,赛赓啶可使KB_V200细胞内阿霉素蓄积量增加。流式细胞荧光测定显示赛赓啶可增加罗丹明123的蓄积并减慢其外排。免疫细胞化学及狭缝杂交表明赛赓啶不影响KB_V200细胞的P-糖蛋白染色深度和 mdr1 RNA 表达水平。以上结果提示赛赓啶的多药抗性逆转机制是抑制P-糖蛋白泵的功能。     

Loading anticancer drugs into HDL as well as LDL has little affect on properties of complexes and enhances cytotoxicity to human carcinoma cells

Low density lipoprotein (LDL) has been found to represent a suitable carrier for cytotoxic drugs that may target them to cancer. This study investigated whether very low density lipoprotein (VLDL), LDL and high density lipoprotein (HDL) can be used to effectively incorporate four cytotoxic drugs, 5-fluorouracil (5-FU), 5-iododeoxyuridine (IUdR), doxorubicin (Dox) and vindesine; characterized the complexes; and examined the effect of incorporation on drug cytotoxicity against HeLa cervical and MCF-7 breast carcinoma cells. Significant drug loading was achieved into all three classes of lipoproteins, consistent with the sizes and hydrophobicity of the drugs. The relative loading efficiency was found to be vindesine>IUdR>Dox>5-FU for all three classes of lipoproteins. As shown by electron microscopy (EM), drug incorporation did not affect the size or morphology of the lipoproteins. Differential scanning calorimetry (DSC) showed that drug loading did not significantly change the thermal transition temperature of core lipids in the lipoproteins. The transition enthalpy was changed only for LDL–Dox and LDL–vindesine. The drugs remained stable in the lipoproteins as determined by high performance liquid chromatography (HPLC). EM, DSC and HPLC data suggest that drugs were incorporated into lipoproteins without disrupting their integrity and drugs remained in their stable forms inside lipoproteins. Compared with free drugs in cytotoxicity assays, the IC₅₀ values of LDL– and HDL–drug complexes were significantly lower (2.4- to 8.6-fold for LDL complexes and 2.5- to 23-fold for HDL complexes). All free or lipoprotein-bound drug formulations were comparably more cytotoxic against MCF-7 than HeLa cells. Upregulating the lipoprotein receptors enhanced, and downregulating them inhibited, the cytotoxicity, indicating the mechanistic involvement of lipoprotein receptor pathways. Complexes of all four drugs with VLDL, in contrast to LDL and HDL, had the same cytotoxicity as the four corresponding free drugs. Our results suggest that further studies are required of the potential of HDL to be a cancer targeting drug carrier.     

磁处理水对抗癌药物的解毒作用

我们的实验发现，磁处理水对环磷酰胺等五种抗癌药物的毒性具有不同程度的缓解作用，能增加小鼠的存活率，能降低药物引起的白细胞减少。对目前癌化疗中使用率最高的环磷酰胺，其作用最明显。     

ATP生物发光法检测卵巢癌细胞对化疗药物的敏感性

目的 探讨ＡＴＰ生物发光法药物敏感试验在卵巢癌中的应用的可行性。方法 以ＡＴＰ生物发光法检测卵巢癌ＨＯ－８９１０细胞对１１种常用化疗药物的敏感性,并与ＭＴＴ法相比较。结果 ＡＴＰ浓度、细胞浓度的对数与发光强度（ＲＬＵ）的对数值之间有较好的线性关系,并存在直线回归关系。两种方法测定的抑制率基本符合,但ＡＴＰ法测定的抑制率数值大,变异系数小,结果稳定。结论 ＡＴＰ生物发光法是一种高度敏感的化疗药物敏感     

白血病化疗药物研究

白血病是一类血液系统的恶性肿瘤，发病机制复杂，涉及到染色体易位、融合基因及融合蛋白的形成、基因拷贝数的改变、癌基因的活化、抑癌基因的失活等。针对不同白血病，从药物作用的分子机制分类综述国内外抗白血病药物的发展及治疗现状。     

抗肿瘤药物的治疗监测

大多数抗肿瘤药具有治疗指数低、毒性大、药动学参数个体差异大的特性，临床需进行治疗药物监测，以达到个体化给药。但治疗药物监测最基本的条件——量效关系，对大多数肿瘤药而言只是量毒关系，基于提高临床疗效的治疗药物监测除少数药物外目前尚不可行。     

Preclinical pharmacology of the natural product anticancer agent 10-hydroxycamptothecin, an inhibitor of topoisomerase I

Purpose: 10-Hydroxycamptothecin (HCPT) is an indole alkaloid isolated from a Chinese tree, Camptotheca acuminata, and has a wide spectrum of anticancer activity in vitro and in vivo mainly through inhibitory effects on topoisomerase I. HCPT has been shown to be more potent and less toxic than camptothecin and has recently undergone clinical trials. To determine how HCPT might be best used as an anticancer agent, preclinical studies of the pharmacokinetics, tissue distribution, metabolism and elimination of HCPT in rats were undertaken. Methods: HCPT was administered to rats by i.v. bolus injection at doses of 1, 3, and 10 mg/kg body weight. HCPT (lactone and carboxylate) and its metabolites in plasma, urine, feces, and various tissues were quantitated by reversed-phase HPLC. Pharmacokinetic parameters were then estimated. Results: Following i.v. administration at doses of 3 or 10 mg/kg, the plasma concentration-time profile for lactone HCPT could be best described by a three-compartment model, with terminal elimination half-lives of 140.4 and 428.6 min, respectively. A two-compartment model was used to fit the plasma concentration-time curve at 1 mg/kg, with a terminal elimination half-life of 30.5 min. Carboxylate HCPT had a longer half-life than the lactone form of HCPT. During the initial 6 h after dosing, urinary excretion was the major route of elimination, and fecal excretion became the major route of elimination thereafter. HCPT was widely distributed to various tissues including the enterohepatic system, kidney, and bone marrow. The lactone form of HCPT was detectable in various tissues examined up to 72 h after dosing at all the three test doses. HCPT glucuronides were present in plasma, urine, feces and various tissues. No significant toxicity was observed at doses of 1 or 3 mg/kg. Polyuria and hematuria were observed only during the initial 3 h after dosing at 10 mg/kg. Conclusions: Prolonged elimination of HCPT in vivo may have a significant impact on its therapeutic effects. HCPT is metabolized to its carboxylate form and glucuronides. Dose-dependent toxicity was observed with i.v. administration of HCPT. The results of this study should be useful in the design of future human trials with this anticancer drug. Received: 6 September 1996 / Accepted: 15 July 1997     

得康口服液对小鼠艾氏腹水瘤的抑制作用

为了研究祖国医学治疗肿瘤的方法，根据中医理论，用１０种中药制成得康口服液，并对其抗癌作用进行研究。实验结果表明，服用得康口服液的荷艾氏腹水瘤小鼠的平均生存为（１８．１±６．１）ｄ，生命延长率为６４．５％。服药组与对照组相比，经统计学处理（Ｐ＜０．０１），表明得康口服液对小鼠艾氏腹水瘤有显著抑制作用