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目的探讨重组腺相关病毒(rAAV)介导促凋亡因子Smac/DIABLO是否能提高恶性黑色素瘤细胞对丝裂霉素(MMC)的敏感性。方法将携有目的基因的rAAV加入到培养液中转染肿瘤细胞,荧光显微镜观察绿色荧光蛋白(EGFP)的表达,RT-PCR检测Smac/DIABLO基因的表达,MTT法测定肿瘤细胞增殖,流式细胞术测定肿瘤细胞的凋亡;动物在体实验测定抗肿瘤效果。结果 rAAV转染96h后几乎所有细胞表达明亮的黄绿色荧光。RT-PCR检测发现转染48h后目的基因Smac/DIABLO稳定表达。MTT检测显示rAAV-hTERT/Smac/DIABLO+MMC对肿瘤细胞的抑制率最高(P<0.05)。流式细胞检测结果显示,rAAV-hTERT/Smac/DIABLO+MMC组肿瘤细胞的凋亡率明显高于生理盐水(HBSS)组、MMC组和rAAV-hTERT/Smac/DIABLO组(P<0.01)。动物实验结果表明,rAAV-hTERT/Smac/DIABLO+MMC有非常强的抑制肿瘤作用,其抗癌效果优于HBSS、MMC、rAAV-hTERT/EGFP和rAAV-hTERT/Smac/DIABL组。结论 rAAV-hTE...

目的观察外源性p27Kip1作用于兔眼滤过术后的效果,研究其对术后结膜瘢痕形成的抑制作用。方法根据GenBank人p27基因序列设计引物,制备腺病毒介导Ad-p27并验证其正确性。兔眼滤过术中结膜下注射Ad-p27、丝裂霉素C(MMC)和PBS,术后28d内测定眼压、观察眼前节的动态变化及并发症,依照Krofeld评分法进行滤过泡评分。结果 Ad-p27作用后28d内维持低眼压的状态,术后3d眼压下降达峰值7.68mmHg。Ad-p27降眼压程度与MMC相似,与PBS比较术后7d(P<0.05)、14d(P<0.01)、21d(P<0.01)和28d(P<0.05)眼压存在显著性差异。Ad-p27作用后14d内滤过泡弥漫性隆起,28d有囊性泡形成。Ad-p27组与PBS组比较,滤过泡评分在7d(P<0.01)、14d(P<0.01)和21d(P<0.05)有显著性差异。Ad-p27组术后21d前房恢复正常,而PBS组术后14d恢复正常。Ad-p27作用偶有前房渗出、前房出血等并发症。结论 Ad-p27通过抑制手术区瘢痕形成保持滤过道通畅,降低眼压。

Aim： To investigate the efficacy of mitomycin C （MMC） in combination with curcumin in suppressing human breast cancer in vitro and in vivo. Methods： Human breast cancer MCF-7 cells were used. Cell viability was measured using MTT assay. The cell cycle phase was detected with flow cytometric analysis. Cell cycle-associated proteins were examined using Western blot analysis. MCF-7 breast cancer xenografts were established to monitor tumor growth and cell cycle-associated protein expression. Results： Curcumin inhibited MCF-7 breast cancer cell viability in a concentration-dependent manner （IC50 value=40 pmol/L）. Similarly, MMC inhibited the cell viability with an IC50 value of 5 μmol/L. Combined treatment of MMC and curcumin showed a synergistic antiproliferative effect. In the presence of curcumin （40 pmol/L）, the IC50 value of MMC was reduced to 5 μmol/L. In MCF-7 xenografts, combined administration of curcumin （100 mg/kg） and MMC （1-2 mg/kg） for 4 weeks produced significantly greater inhibition on tumor growth than either treatment alone. The combined treatment resulted in significantly greater G1 arrest than MMC or curcumin alone. Moreover, the cell cycle arrest was associated with inhibition of cyclin D1, cyclin E, cyclin A, cyclin-dependent kinase 2 （CDK2） and CDK4, along with the induction of the cell cycle inhibitor p21 and p27 both in MCF-7 cells and in MCF-7 xenografts. These proteins were regulated through p38 MAPK pathway. Conclusion： The results suggest that the combination of MMC and curcumin inhibits MCF-7 cell proliferation and cell cycle progression in vitro and in vivo via the p38 MAPK pathway.

目的:评估余甘子提取物(PE)对丝裂霉素C(MMC)和顺铂(cDDP)抗癌活性及其遗传毒性副作用的影响。创新点:首次发现PE能减弱MMC和cDDP对人正常结肠上皮细胞基因组的损伤以及降低基因组受损细胞的克隆形成能力和克隆异质性。方法:人结肠癌Colo205细胞和人正常结肠上皮NCM460细胞分别经PE、PE+MMC组合或PE+cDDP组合处理72 h。细胞增殖用台盼蓝拒染法和克隆形成法测定,遗传毒性用胞质分裂阻断微核分析法(CBMN)测定。结论:结果显示,PE可以显著增强MMC和cDDP的抗Colo205细胞增殖能力(图1)。同时,PE显著降低MMC和cDDP诱导的NCM460细胞基因组不稳定现象,包括降低微核、核质桥和核芽(表1和图2)以及多核化细胞(图3)。此外,PE显著降低经MMC和cDDP处理的NCM460细胞克隆性扩增能力,并降低克隆的异质性(图4)。综上所述,PE不仅能增强MMC和cDDP的抗癌能力,还可能具有减弱它们诱发正常细胞恶性转变的潜力。

Although the local application of mitomycin C may prevent epidural adhesion after laminectomy, mitomycin C can induce neurotoxicity in optic and acoustic nerves at high concentrations. To determine the safe concentration range for mitomycin C, cotton pads soaked with mitomycin C at different concentrations （0.1, 0.3, 0.5, and 0.7 mg/mL） were immediately applied for 5 minutes to the operation area of rats that had undergone laminectomy at L1. Rat sciatic nerves, instead of dorsal nerves, were used in this study. The results showed that mitomycin C at 0.1-0.5 mg/mL did not damage the structure and function of the sciatic nerve, while at 0.7 mg/mL, mitomycin C signiifcantly reduced the thickness of the sciatic nerve myelin sheath compared with lower concen-trations, though no functional change was found. These experimental ifndings indicate that the local application of mitomycin C at low concentrations is safe to prevent scar adhesion following laminectomy, but that mitomycin C at high concentrations （＆gt;0.7 mg/mL） has potential safety risks to peripheral nerve structures.

The existence of cancer stem cells, stem-like cancer cells (SLCCs), or tumor-initiating cells is considered as the cause of tumor formation and recurrence, indicating the importance of studying novel therapy that targets SLCCs. The origin of SLCCs is controversial because of two competing hypotheses: SLCCs are either transformed from tissue adult stem cells or dedifferentiated from transformed progenitor cells. Our previous research demonstrates that SLCCs are inducible by increasing genomic instability in cancer cells. In this study, to block the emergence of SLCCs, aminoethyl isothiourea (AET), a compound that clears free radicals and is used to protect patients from radioactive exposure, was used as an agent that maintains genomic stability in combination with mitomycin C (MMC), a commonly used chemotherapeutic drug that damages DNA. Using a rabbit tumor model with VX2 hepatic carcinoma, we found that MMC alone increased lung metastases and disadvantaged survival outcome, but the combination of MMC and AET reversed this effect and even prolonged overall survival. Moreover, in a VX2 xenograft model by immunocompromised mice, MMC alone enriched tumor-initiating cells, but the administration of MMC in combination with AET eliminated tumor cells effectively. Furthermore, MMC alone enhanced genomic instability, but MMC combined with AET attenuated the extent of genomic instability in primary VX2 tumor tissue. Taken together, our data suggest that the genomic protector AET can inhibit the induction of SLCCs, and this combination treatment by AET and cytotoxic agents should be considered as a promising strategy for future clinical evaluation.

Aim： To evaluate the genetic instability of 11 fertile and 25 infertile men. Methods： The methodology of sister chromatid exchanges （SCEs） was applied to cultures of peripheral blood lymphocytes, and the levels of SCEss were analyzed as a quantitative index of genotoxicity, along with the values of the mitotic index （MI） and the proliferation rate index （PRI） as qualitative indices of cytotoxicity and cytostaticity, respectively. The genotoxic and antineoplastic agent, mitomycin C （MMC）, and caffeine （CAF） - both well-known inhibitors of DNA repair mechanism - were used in an attempt to induce chromosomal instability in infertile men, so as to more easily detect the probable underlying damage on DNA. Results： Our experiments illustrated that infertile men, compared with fertile ones, demonstrated a statistically significant DNA instability in peripheral blood lymphocytes after being exposed simultaneously to MMC and CAF. Conclusion： The current study showed vividly that there was genetic instability in infertile men which probably contributes to the development of an impaired reproductive capacity. （Asian JAndro12006 Mar; 8： 199-204）