A novel o-nitrobenzyl-based photocleavable antitumor prodrug with the capability of releasing 5-fluorourail一种基于邻硝基苄基的可光致释放5-氟尿嘧啶的新型抗癌前药

An o-nitrobenzyl-based photocleavable antitumor prodrug with a terminal carboxyl group was designed and synthesized.The photolysis properties of the prodrug were investigated by means of1H NMR,HPLC,UV,and MTT methods.The results showed that the toxicity of the anticancer drug was effectively shielded before release.However,the prodrug effectively regained the antitumor capability against cancer cells by release of 5-fluorouracil when it was exposed to ultraviolet irradiation.     

Role of VEGF in the growth and metastasis of a murine bladder carcinoma

Bladder transitional cell carcinoma is the most common form of carcinoma in the urinary system. Although overexpression of VEGF has been identified in tissue, serum,and urine of patients with bladder cancer, the role of VEGF in transitional cell carcinoma of the bladder has not been clearly elucidated. Here, we dissected the effect of VEGF during bladder tumor growth and progression by modifying a BBN (N-butyl-N-(4-hydroxybutyl) nitrosamine) induced mouse bladder transitional cell carcinoma cell line BTT-T739 by stable transfection of antisense VEGF121 cDNA. The transfection resulted in-more than 80% reduction in VEGF production. The growth of the transduced tumor cells in vitro was not affected, however, these cells formed small or no tumors in vivo. Even in the tumors formed, there were minimal vascularization, extensive necrosis and longer latency compared to those formed by parental cells. The permeability of tumor vasrulatuce and metastatic tumor growth were also significantly suppressed in antisense VEGF cDNA transfected cells. In addition, the transfer of anti-angiogenic gene in a rumbination of sFlk-I and ExTek with electroporation can suppress the tumor growth efficiently. Taken together,these results demonstrated that VEGF plays an important role in bladder tumor angiogenesis and angiogenesis plays an important role in bladder tumor growth and metastasis.     

The growth dynamics of tumor subject to both immune surveillance and external therapy intervention

Considering the growth of tumor cells modeled by an enzyme dynamic process under an immune surveillance, we studied in anti-tumor immunotherapy the single-variable growth dynamics of tumor cells subject to a multiplicative noise and an external therapy intervention simultaneously. The law of tumor growth of the above anti-tumor immunotherapy model was revealed through numerical simula- tions to the relevant stochastic dynamic differential equation. Two simulative parameters of therapy, i.e., therapy intensity and therapy duty-cycle, were introduced to characterize a treatment process similar to a tumor clinic therapy. There exists a critical therapy boundary which, in an expo- nent-decaying form, divides the parameter region of therapy into an invalid and a valid treatment zone, respectively. A greater critical therapy duty-cycle is necessary to achieve a valid treatment for a lower therapy intensity while the critical therapy intensity decreases accordingly with an enhancing immunity. A primary clinic observation of the patients with the typical non-hodgekin’s lymphoma was carried out, and there appears a basic agreement between clinic observations and dynamic simulations.     

Soliton pulse compression through cascaded quadratic nonlinearity in difference-frequency generation

Cascaded nonlinearity based soliton pulse compression in the process of femtosecond difference frequency generation is studied theoretically. A set of simplified coupled wave equations under the conditions of large phase mismatch and matched group velocities is obtained, which reveals the physical mechanism of soliton compression in this process. Numerical simulations demonstrate that in the presence of group velocity dispersion and equivalent cross phase modulation, both the pump and the signal pulses can be compressed with a high compression ratio.     

In vitro assay of cytoskeleton nanomechanics as a tool for screening potential anticancer effects of natural plant extract, tubeimoside I on human hepatoma (HepG2) cells

Cytoskeleton nanomechanics characterizes cancer cell’s physical behaviors such as how it spread and invade. For anticancer drug, cytoskeleton nanomechanics may be a target to inhibit invasiveness and metastasis of cancer cells. Therefore, in vitro assay of cytoskeleton nanomechanics may be used to evaluate the effects of potential anticancer drug on various cancer types. Here, we investigated the effects of tubeimoside I (TBMS I) on human hepatoma (HepG2) cells by using optical magnetic twisting cytometry, a well-established technique for measuring nanomechanics of the Factin cytoskeleton. TBMS I is a natural compound extracted from a traditional Chinese herbal medicine, and is reported with antitumor effect. In this study, we demonstrated that the cytoskeleton stiffness (G) of HepG2 cells was affected by TBMS I. G′ exhibited a typical power law with respect to the loading frequency (f), i.e. G~f . The magnitude of G′ and the value of exponent (α) of the HepG2 cells decreased consistently with the increase of concentration for TBMS I exposure. In addition, the HepG2 cells responded to TBMS I much faster than the normal liver (L-02) cells. Such alteration of cytoskeleton nanomechanics induced by TBMS I was reported for the first time, which was further corroborated by assays of Factin cytoskeleton structure and cell migration. Taken together, these results suggest that in vitro assay of cytoskeleton nanomechanics may have a great potential as an additional tool in screening of anticancer drug candidates.     

Apoptosis induced by （DIPP-L-Leu）2-L-Lys-OCH3 in K562 cells

Apoptosis as a mechanism of deleting cells from tissues plays an important role in physiological and varieties of pathological situations, especially cancer conditions. In order to search for tumor cells apoptosis inducers, the inhibition effects on K562 cells of N-phosphoryl dipeptide methyl esters were studied by MTT assays, and (DIPP-L-Leu)2-L-Lys-OCH3 was the compound which had the best activity. From the studies of the typical apoptotic morphologic changes, DNA agarose gel electrophoresis, and flow cytometry analysis, it could be concluded that (DIPP-L-Leu)2-L-Lys-OCH3 could induce apoptosis of K562 cells in a dose-dependent manner, and the IC50 was 22.66 μmol/L according to MTT assays.     

CD8<Superscript>+</Superscript> T cell response mediates the therapeutic effects of oncolytic adenovirus in an immunocompetent mouse model

The role of anti-tumor immune responses in oncolytic adenoviral therapy has not been well studied due to lack of efficacious tu- mor model in immunocompetent mice.Here,we evaluated the contributions of immune components to the therapeutic effects of oncolytic adenoviruse in an immunocompetent murine tumor model permissive for infection and replication of adenovirus.We found that CD8+T cells were critical mediator for antitumor efficacy by oncolytic adenovirus.Intratumoral viral therapy induced intensive infiltration of CD8+T cells in tumor,increased tumor-specific IFN-?(interferon-?)production and CTL(cytotoxic T lymphocyte)activity of lymphocytes,and generated a long-term tumor-specific immune memory.Boosting CD8+T cell responses by agonistic anti-4-1BB(cluster differentiation 137,CD137)antibody showed synergistic anticancer effects with oncolytic viro- therapy.Our results provide insight into antitumor mechanisms of oncolytic adenovirus in addition to their direct oncolytic effect.     

Inhibition of PKB/Akt activity involved in apigenininduced apoptosis in human gastric carcinoma cells

Apigenin is a flavonoid widely distributed in fruits and vegetables. It possesses growth inhibitory properties against numerous cancer cell lines. However,the molecular mechanism(s) by which api-genin elicits its effects have not been fully elucidated. Here we studied whether apigenin inhibits growth and induces apoptosis in human gastric carcinoma cells. We showed that the flavonoid inhibited growth of the cells and caused apoptosis,as evidenced by DNA Ladder,cleavage of pro-caspase-3 in a time-dependent manner. Induction of apoptosis was dependent on inhibition of the PKB/Akt activity. We found that while apigenin had no effect on the expression of Akt and Bad,it inhibited specific phosphorylation of the two proteins that are associated with pro-survival mechanisms. We propose that this important flavonoid induces apoptosis in gastric cancer cells by inhibiting Akt activity. Since Akt is often activated in cancers,our findings may have clinical implications.     

Effect of Quercetin on Breeding and Apoptosis of Cervical Cancer HeLa Cell and on Growth of Transplanted Tumor in Nude Mice

Effect of quercetin on HeLa cell system of cervical cancer was studied by methods of MTT and Annexin V-FITC/PI. The results show that quercetin has functions of inhibiting breeding of HeLa cells and inducing apoptosis of the cells. The total apoptosis rate is positively proportional to reaction duration and concentration of quercetin used. The maximum apoptosis rate being （88.76±2.35）% was obtained when the concentration was 50.0 μmol/L and the cells were treated with quercetin for 72 hours. Based on establishing a model of tumor of cervical cancer transplanted into nude mice, quercetin of different concentrations was injected into abdominal cavity of nude mice and situation of tumor growth was reviewed. The result showed that with quercetin concent＇ration increasing from 0 to 100.0 μmol/L, the transplantation volume and weight of the tumors decreased from （279.59±70.58） mm^3 and （0.145±0.019） g to （128.72±36.12） mm^3 and （0.089± 0.019） g respectively, while apoptosis rate of the transplanted tumor increased from （9.63±1.85）% to （34,98±0.47）%, which proved that quercetin inhibited increment of volume and weight of transplanted tumor in nude mice bodies.     

脉冲电场作用下Hela细胞穿孔率研究

以宫颈癌Hela细胞为实验对象，利用自制脉冲电源和台盼蓝染色法计数，针对不同的电脉冲参数作用于Hela细胞上，研究了细胞可逆和不可逆电穿孔的场强阈值范围，重点研究了脉冲个数、脉冲宽度和电场强度对细胞不可逆穿孔率的影响，并选择了优化的参数组合。实验发现，在固定脉冲宽度50 μs和20个脉冲个数不变的情况下，Hela细胞出现可逆电穿孔（存活）的场强阈值范围分别为500～750 \begin{document}$ \mathrm{V}/\mathrm{c}\mathrm{m} $\end{document}，出现不可逆电穿孔（死亡）的场强阈值范围为750～1 000 \begin{document}$ \mathrm{V}/\mathrm{c}\mathrm{m} $\end{document}。在对电脉冲参数优化组合的实验中，Hela细胞的不可逆穿孔率随着脉冲个数、脉冲宽度和脉冲场强的增加而增加，最终趋于饱和。宜选择场强1 500 \begin{document}$ \mathrm{V}/\mathrm{c}\mathrm{m} $\end{document}、脉宽60 μs和70个脉冲的参数组合，不可逆穿孔率为93.42%。     

红景天苷对荷瘤小鼠抗肿瘤活性和免疫功能的研究

研究红景天苷抗肿瘤活性及其提高免疫功能的机制。用胃腺癌BGC-823在BALB/c小鼠建立皮下肿瘤模型,分别用大、中、小剂量红景天苷灌胃,以环磷酰胺(CTX)为阳性对照组,连续给药12d后处死小鼠,称小鼠体质量、瘤重,计算脾脏系数,同时测定脾淋巴细胞转化率和IL-2活性。各剂量红景天苷给药组均能显著提高小鼠的体质量,且能明显抑制荷瘤小鼠肿瘤生长,以大、中剂量组比较明显,而环磷酰胺组体质量明显下降(P<0.05)。各红景天苷给药组均能提高脾脏系数和脾脏细胞功能,增加脾淋巴细胞转化率和IL-2活性,以大剂量给药组作用最明显,而环磷酰胺阳性对照组的体液免疫功能则显著下降。红景天苷能明显抑制BGC-823肿瘤的生长,同时能增加小鼠体质量,提高治疗肿瘤的药物耐受性,改善体液免疫功能而发挥抗癌作用,高效低毒,可与化疗药物合用提高其疗效。     

胡桃楸树皮抗肿瘤有效成分对H22荷瘤小鼠T细胞亚群的影响

 为测定胡桃楸树皮提取物(HT)抗肿瘤有效成分对H₂₂荷瘤小鼠T细胞亚群的影响,将昆明小鼠随机分为HT高剂量组、HT低剂量组、阳性药环磷酰胺组、模型组和正常组,采用接种法复制H₂₂肿瘤移植模型。利用荧光标记抗体-流式细胞术检测HT对建立的H₂₂荷瘤小鼠模型外周血中CD4⁺/CD8⁺细胞亚群比值变化; ELISA法检测CD4⁺细胞所分泌细胞因子IL-4和IFN-γ的含量,以测定Th1/Th2细胞亚群比例。结果显示,与阳性药注射用环磷酰胺(CTX)相比,HT高、低剂量组能显著降低机体CD8⁺亚群比例(P<0.01),HT低剂量组可明显提高CD4⁺/CD8⁺比值(P<0.05)。HT高、低剂量组的IL-4含量显著低于阳性药CTX组(P<0.001),明显低于模型组(P<0.05)。HT高剂量组的IFN-γ/IL-4水平明显高于阳性药CTX组(P<0.05)。研究表明,胡桃楸树皮提取物具有明显的抑瘤作用,能保护胸腺和脾脏,能减轻荷瘤机体的T细胞免疫功能的损伤。     

灵芝黄芪复配物提高环磷酰胺对荷瘤小鼠的疗效

研究灵芝(Ganoderma lucidum)黄芪(Astragalus)复配物对环磷酰胺(cyclophosphamide,CTX)治疗的荷瘤小鼠肿瘤和免疫功能的影响.建立小鼠S180肉瘤模型,每日灌胃低、中、高剂量的灵芝黄芪复配物,并配合腹腔注射CTX.连续处理小鼠2周后,分析抑瘤效应,测定小鼠脾指数、胸腺指数、外周血白细胞(white blood cell,WBC)数和红细胞(red blood cell,RBC)数等免疫指标.同单CTX治疗组相比,中、高剂量的灵芝黄芪复配物能显著加强CTX对小鼠S180肉瘤的抑制作用(P<0.01),明显改善CTX引起的小鼠胸腺萎缩(P<0.01)和白细胞减少症状(P<0.05,P<0.01).灵芝黄芪复配物对CTX的抑瘤治疗具有明显的增效减毒作用,其效果堪比于单味中药灵芝提取物辅助CTX的抑瘤疗效,可大大降低单味灵芝提取物的治疗成本,经济价值可观.     

化胃舒颗粒体内抗肿瘤作用的实验研究

摘要: 目的探讨化胃舒颗粒对小鼠移植性肿瘤的抑制作用。方法以S180 肉瘤和H22 肝癌作为实验瘤株,观察化胃 舒颗粒对S180 小鼠肉瘤的抑瘤率及对H22 肿瘤小鼠生存期的影响。采用小鼠移植性肿瘤S180 实体瘤模型,观察化胃舒 颗粒与环磷酰胺( CTX) 联用对S180 实体瘤小鼠的白细胞数及抑瘤率的影响。结果化胃舒颗粒能阻止S180 肿瘤生长, 小鼠肿瘤抑制率在30%以上; 化胃舒颗粒能明显延长H22 肿瘤小鼠的生存时间; 化胃舒颗粒能抑制由环磷酰胺( CTX) 引 起的S180 实体瘤小鼠血液中白细胞总数的减少,从而增强环磷酰胺( CTX) 的抑瘤作用。结论化胃舒颗粒对S180 肉瘤 和H22 肝癌荷瘤小鼠有明显的抗肿瘤作用,与环磷酰胺( CTX) 合用有显著的减毒增效作用。     

~(131)I标记抗人结肠癌单克隆抗体MC_3对裸鼠载人肠癌的放射免疫显像和导向治疗研究

用~(131)I标记的抗人结肠癌单克隆抗体(McAbMC_3)对裸鼠载人肠癌进行放射免疫显像诊断和实验性治疗研究。结果显示:体外标记抗体特异性结合率分别为37.5％和32.1％。裸鼠体内在48~120h的ECT照相可见在肿瘤部位均有放射性的特异性浓聚,其摄取量随时间延长逐渐增加,肿瘤显影清晰,显像的合适时间为96～120h。而给予非特异性的~(131)I-NMIgG后肿瘤部位来见放射性浓聚,而呈全身均匀性分布。120h肿瘤组织与肝脏及正常肠组织的比值分别为3.61和9.81,肿瘤定位指数为4.26。实验治疗显示与对照相比~(131)I-MC_3对肿瘤有明显的抑制生长作用,治疗后第14天肿瘤抑制率为90.14％,与~(131)I-NMIgG对照组比较差异极显著(P<0.01)。治疗后第32天裸鼠血清CEA含量与~(131)I-NMIgG组比较差异显著(P<0.05)。病理组织学检查结果显示治疗后8天注射~(131)I-MC_3裸鼠肿瘤呈大片坏死,仅局部肿瘤边缘尚存少数完整的肿瘤细胞,而其它正常组织、器官未见明显辐射损伤。提示McAbMC_3用于肠癌的诊断和导向治疗可能有良好的前景。     

白芷生物碱对小鼠U14宫颈癌抗肿瘤活性作用的研究

白芷生物碱(AAD)作为天然药物,生物活性强,具有防癌、抗突变及抑制酪氨酸酶等作用,是天然抗氧化剂.但迄今为止,关于AAD对宫颈癌治疗的研究,国内外一直未见相关报道.本研究以U14移植性实体瘤小鼠为模型,将其分为阴性对照组、环磷酰胺(CTX)阳性对照组、AAD低、高剂量组.采用HE染色法、免疫组织化学SP法,对AAD抗宫颈癌作用进行了研究.通过对白芷生物碱的提取,得白色结晶,得率为2％,经鉴定为白芷生物碱且含量为0.16 mg/g.动物体内试验表明,AAD能有效地抑制U14荷瘤鼠瘤体生长,对肿瘤细胞内突变型P53和Ki-67相关蛋白表达量降低.本文初步地研究了AAD抗宫颈癌的作用及其机理,为AAD治疗宫颈癌提供了重要的科学依据和理论基础.     

Development of a nano-immunomodulator encapsulating R837 and caffeine for combined radio-/immunotherapy against orthotopic breast cancer

Immunotherapy is an ascendant approach in cancer treatment. It shows more pronounced effects on killing cancer cells in a specific manner in particular against metastasis more than traditional techniques, such as chemotherapy or surgery. However, tumor immunosuppression limits the response of the immune system to cancer development. In this study, we developed a lipid-based nanocarrier doubly loaded with imiquimod (R837), a toll-like receptor 7 agonist, and caffeine, an adenosine receptor antagonist. This R837/caffeine loaded nanocarrier served as a nano-immunomodulator (RC-nIM) for combination treatment with radiotherapy (RT) against orthotopic breast cancer. RT-induced immunogenic cell death facilitated the production of tumor antigen and elicited the immune response in corporation with R837-medaited activation of antigen-presenting cells (APCs) while RC-nIMs being adopted. Additionally, caffeine, an adenosine analog, can successfully compete with adenosine in the tumor. The tumor-bearing mice that received RT together with RC-nIMs experienced the best antitumor effects and exhibited higher levels of T cells and APCs within the tumor; the growth of secondary tumors was also limited. This work serves as a proof-of-concept study for the development of a new immunotherapy strategy against cancer.     

仙芦抗癌胶囊抗肿瘤作用及其作用机制研究

通过观察仙芦抗癌胶囊对S180A和H22荷瘤小鼠瘤重和生存时间的影响,观察其体内抗肿瘤作用.采用荧光探针DPH法,观察仙芦抗癌胶囊对S180A和H22荷瘤小鼠红细胞膜流动性的影响.实验结果发现仙芦抗癌胶囊(1g/kg,0 5g/kg,0 25g/kg)对S180A小鼠的瘤体生长有显著的抑制作用.仙芦抗癌胶囊(1g/kg,0 5g/kg)对H22小鼠的生存时间有显著的延长作用.仙芦抗癌胶囊高、中、低剂量(1g/kg,0 5g/kg,0 25g/kg)均能够升高S180小鼠红细胞膜流动性.仙芦抗癌胶囊高、中剂量(1g/kg,0 5g/kg)均能够降低H22小鼠红细胞膜流动性,而低剂量组无明显作用.因此仙芦抗癌胶囊对S180A和H22都有显著的抑制作用,抗肿瘤作用机制与其恢复荷瘤小鼠红细胞膜流动性有关.     

半枝莲多糖对小鼠S180肉瘤抑制作用的研究

探讨半枝莲多糖对体内S180肉瘤肿瘤抑制作用及相关机制.采用动物移植性肿瘤实验观察半枝莲多糖对小鼠体内肿瘤细胞生长的影响,ELISA法检测对荷瘤小鼠外周血血清中白细胞介素-2和干扰素-α质量浓度的影响.结果显示,半枝莲多糖对S180肉瘤生长的抑制率以中剂量为佳;各剂量组均对脾脏指数有显著性差异,能够提高S180荷瘤小鼠外周血血清中白细胞介素-2及干扰素-α的质量浓度,但中剂量最为显著,表明半枝莲多糖在小鼠体内具有抑制S180肉瘤的作用.