Anti-hepatoma activity of resveratrol in vitro

AIM: To study the anti-tumor effect of resveratrol alone and the synergistic effects of resveratrol with 5-FU on the growth of H22 cells line in vitro. METHODS: The number of cells was measured by MTT method the morphological changes of H22 cells were investigated under microscopy and electron microscopy examination. RESULTS: Resveratrol inhibited the growth of hepatoma cells line H22 in a dose- and time-dependent manner, IC50 of the resveratrol on H22 cells was 6.57mg x L(-1),The synergistic anti-tumor effects of resveratrol with 5-FU increased to a greater extent than for H22 cells treated with 5-FU alone (70.2% vs 28.4%) P<0.05 .Under microscope and electron microscope, characteristics of apoptosis such as typical apoptotic bodies were commonly found in tumor cells in the drug-treated groups. CONCLUSION: Resveratrol can suppresses the growth of H22 cells in vitro,its anti-tumor activity may occur through the induction of apoptosis.     

Effect of resveratrol on cell cycle proteins in murine transplantable liver cancer

AIM: To study the antitumour activity of resveratrol and its effect on the expression of cell cycle proteins including cyclin D1, cyclin B1 and p34cdc2 in transplanted liver cancer of murine. METHODS: Murine transplanted hepatoma H22 model was used to evaluate the in vivo antitumor activity of resveratrol. Following abdominal administration of resveratrol, the change in tumour size was recorded and the protein expression of cyclin D1, cyclin B1 and p34cdc2 in the tumor and adjacent noncancerous liver tissues were measured by immunohistochemistry. RESULTS: Following treatment of H22 tumour bearing mice with resveratrol at 10 or 15 mg/kg bodyweight for 10 days, the growth of murine transplantable liver cancer was inhibited by 36.3% or 49.3%, respectively. The inhibitory effect was significant compared to that in control group (P<0.05). The level of expression of cyclin B1 and p34cdc2 protein was decreased in the transplantable murine hepatoma 22 treated with resveratrol whereas the expression of cyclin D1 protein did not change. CONCLUSION: Resveratrol exhibits anti-tumour activities on murine hepatoma H22. The underlying anti-tumour mechanism of resveratrol might involve the inhibition of the cell cycle progression by decreasing the expression of cyclinB1 and p34cdc2 protein.     

Antitumor efficacy of lidamycin on hepatoma and active moiety of its molecule

AIM: To study the in vitro and in vivo antitumor effect of lidamycin (LDM) on hepatoma and the active moiety of its molecule. METHODS: MTT assay was used to determine the growth inhibition of human hepatoma BEL-7402 cells, SMMC-7721 cells and mouse hepatoma H22 cells. The in vivo therapeutic effects of lidamycin and mitomycin C were determined by transplantable hepatoma 22 (H22) in mice and human hepatoma BEL-7402 xenografts in athymic mice. RESULTS: In terms of IC50 values, the cytotoxicity of LDM was 10 000-fold more potent than that of mitomycin C (MMC) and adriamycin (ADM) in human hepatoma BEL-7402 cells and SMMC-7721 cells. LDM molecule consists of two moieties, an aproprotein (LDP) and an enediyne chromophore (LDC). In terms of IC50 values, the potency of LDC was similar to LDM. However, LDP was 105-fold less potent than LDM and LDC to hepatoma cells. For mouse hepatoma H22 cells, the IC50 value of LDM was 0.025 nmol/L. Given by single intravenous injection at doses of 0.1, 0.05 and 0.025 mg/kg, LDM markedly suppressed the growth of hepatoma 22 in mice by 84.7%, 71.6% and 61.8%, respectively. The therapeutic indexes (TI) of LDM and MMC were 15 and 2.5, respectively. By 2 iv. injections in two experiments, the growth inhibition rates by LDM at doses of 0.1, 0.05, 0.025, 0.00625 and 0.0125 mg/kg were 88.8-89.5%, 81.1-82.5%, 71.2-74.9%, 52.3-59.575%, and 33.3-48.3%, respectively. In comparison, MMC at doses of 5, 2.5, and 1.25 mg/kg inhibited tumor growth by 69.7-73.6%, 54.0-56.5%, and 31.5-52.2%, respectively. Moreover, in human hepatoma BEL-7402 xenografts, the growth inhibition rates by LDM at doses of 0.05 mg/kg ×2 and 0.025 mg/kg ×2 were 68.7% and 27.2%, respectively. However, MMC at the dose of 1.25 mg/kg ×2 showed an inhibition rate of 34.5%. The inhibition rate of tumor growth by LDM was higher than that by MMC at the tolerated dose. CONCLUSION: Both LDM and its chromophore LDC display extremely potent cytotoxicity to hepatoma cells. LDM shows a remarkable therapeutic efficacy against murine and human hepatomas in vivo.     

CpG oligodeoxynucleotides inhibit tumor growth and reverse the immunosuppression caused by the therapy with 5-fluorouracil in murine hepatoma

AIM: To investigate the effect of CpG-containing oligodeoxynucleotides (CpG ODN) alone or in combination with the chemotherapeutic agent 5-fluorouracil (5-FU) on tumor growth and whether CpG ODN can reverse the immunosuppression caused by the chemotherapy with 5-FU in murine hepatoma model. METHODS: Hepatoma model was established by subcutaneous inoculation with hepatoma-22 (H22) cells into the right flank of BALB/c mice. Mice with tumor were treated by peritumoral injection of CpG ODN alone or in combination with subcutaneous injection of 5-FU. Tumor size was quantified regularly. Serum levels of IL-12 and IFN-γ in mice were assayed by enzyme-linked immunosorbent assay (ELISA). The lytic capacity of splenic NK cells was tested by lactate dehydrogenase release assay. RESULTS: Peritumoral injection of CpG ODN alone or in combination with subcutaneous injection of 5-FU, and the treatment with 5-FU alone all led to significant inhibition of hepatoma growth. The mean tumor volumes fell by 46.66% in mice injected with CpG ODN, 68.34% in the 5-FU treated mice, and 70.23% in mice treated with the combination of CpG ODN and 5-FU than in controls. There was no significant difference in tumor size between 5-FU treated mice and mice treated with the combination of 5-FU and CpG ODN (P&gt;0.05). The serum levels of IL-12 and IFN-γ of mice treated with CpG ODN alone (IL-12: 464.50&#177;24.37 pg/mL; IFN-γ: 134.20&#177;25.76 pg/mL) or with the co-administration of CpG ODN and 5-FU (IL-12: 335.83&#177;28.74 pg/mL; IFN-γ: 111.00&#177;5.33 pg/mL) were significantly higher than that of controls (IL-12: 237.50&#177;45.31 pg/mL; IFN-γ: 56.75&#177;8.22 pg/mL). The production of IL-12 and IFN-γ was suppressed moderately in 5-FU-treated mice (IL-12:166.67&#177;53.22 pg/mL, 53.33&#177;16.98 pg/mL) compared to control mice (P&gt;0.05), whereas the combination of CpG ODN and 5-FU significantly increased the serum levels of IL-12 and IFN-γ compared to 5-FU alone (P&lt;0.05). The NK cell killing activity in CpG ODN treated mice (44.04&#177;1.38%) or the mice treated with CpG ODN combined with 5-FU (30.67&#177;1.28%) was significantly potentiated compared to controls (19.22&#177;0.95%, P&lt;0.05). The co-administration of CpG ODN and 5-FU also significantly enhanced the lytic activity of NK cells when compared with the treatment with 5-FU alone (12.03&#177;1.42%, P&lt;0.05). CONCLUSION: The present data suggests that CpG ODN used as single therapeutic agent triggers anti-tumor immune response to inhibit the growth of implanted hepatoma and reverses the immunosuppression caused by the chemotherapy with 5-FU.     

Antitumor and immunomodulatory activity of resveratrol onexperimentally implanted tumor of H22 in Balb／c mice

AIM: To study the antitumor and immunomodulatory activity of resveratrol on experimentally implanted tumor of H22 in Balb/c miceMETHODS: The cytotoxicity of peritoneal macrophages (M φ ) against H22 cells was measured by the radioactivity of [3H]TdR assay, mice with H22 tumor were injected with different concentrations of resveratrol, and the inhibitory rates were calculated and IgG contents were determined by single immunodiffusion method. the plaque forming cell (PFC) was measured by improved Cunningham method, the levels of serum tumor necrosis factor-α (TNF-α) were measured by cytotoxic assay against L929 cells.implanted tumor of H22 in mice. The inhibitory rates were 31.5 %, 45.6 % and 48.7 %, respectively (P＜0.05), which could raise the level of serum IgG and PFC response to production of serum TNF-α in mice H22 tumor. However,the effect of resveratrol was insignificant (P ＞0.05).CONCLUSION: Resveratrol could inhibit the growth of H22tumor in Balb/c mice. The antitumor effect of resveratrol might be related to directly inhibiting the growth of H22cells and indirectly inhibiting its potential effect on nonspecific host immunomodulatory activity.     

Role of the Fas/FasL pathway in combination therapy with interferon-alpha and fluorouracil against hepatocellular carcinoma in vitro

BACKGROUND/AIMS: Several studies have reported the efficacy of combination therapy of interferon (IFN) alpha and 5-fluorouracil (5-FU) for hepatocellular carcinoma (HCC). However, the mechanism underlying the clinical anti-tumor effects of this treatment is not well understood. The aim of this study was to determine the role of Fas/FasL signaling in the anti-tumor effect of this combination therapy. METHODS AND RESULTS: We used six human hepatoma cell lines, three of which are known Fas-expressing cells. Growth of Fas-positive hepatoma cell lines was inhibited by an agonistic anti-Fas antibody in a dose-dependent manner, and these effects were enhanced by IFNalpha or 5-FU alone, but even more so by combination therapy using both agents. Annexin-V assay implicated apoptosis as the main mechanism underlying these growth inhibitory effects, although changes in Fas expression regulated by IFNalpha and/or 5-FU did not correlate with increased apoptosis. Caspase-3 activation was exclusively increased by IFNalpha/5-FU combination treatment, which was compatible with enhancement of the synergistic apoptotic effect, and other caspases and apoptotic factors (FLIP, BCL-xl, and Bax) were also regulated by IFNalpha/5-FU. 51Cr-release assay revealed that pretreatment with IFN activated cytotoxicity of peripheral blood mononuclear cells (PBMCs) against HCC cells. The largest interaction was observed when both PBMC and HCC cells were pretreated with the combination of IFNalpha/5-FU. These cytotoxicities were markedly inhibited by a neutralizing anti-Fas antibody. CONCLUSIONS: Our results indicated that IFNalpha/5-FU combination treatment enhances the induction of apoptosis and the cytotoxic effect of PBMCs via the Fas/FasL pathway. The Fas/FasL pathway seems, at least in part, to contribute to the anti-tumor effects of IFNalpha/5-FU against HCCs.     

Involvement of immune response in anti-tumor effects of Staphylococcus Aureus Filtrate Preparation

Purpose Staphylococcus Aureus Filtrate Preparation (SAFP) is a preparation of low-virulence strain of Staphylococcus aureus. In our study, we aimed to determine the anti-tumor activity of SAFP in vivo and explore the potential mechanism. Methods Our study evaluated the anti-tumor activity of SAFP in four cancer cell models in vivo and determined its up-regulatory effects on mice immune system in vivo. Results It showed that 7.2 ng/10 g SAFP could inhibit the progression of murine hepatoma H22 and sarcoma S180, and the tumor inhibition rates achieved 48.1 and 35.7%, respectively. In human non-small cell lung cancer A549 and hepatoma BEL7402 xenograft athymic mice models, T/C of 7.2 ng/10 g SAFP group reached 41.0% in A549 model and 21.0% in BEL7402 model. Meanwhile, SAFP also significantly increased the proliferation of cultured mice splenocytes to 162.1%, and 7.2 ng/kg SAFP significantly (P < 0.001) raised the activity of NK cells, elevated the serum level of IL-2, TNF-α and IFN-γ in mice. Conclusion SAFP exhibited high efficiency in inhibiting the growth of cancer cells in a dose-dependent manner, which possibly attributed to its regulatory effects of immune system.     

5-FU,folinic acid and cisplatin (LV5FU2-P) for unresectable pancreatic cancer

AIM: To prospectively evaluate efficacy and tolerance of the 5-fluorouracil + folinic acid + cisplatin (LV5FU2-P) combination in the treatment of unresectable pancreatic carcinoma. PATIENTS AND METHODS: Between March 1998 and June 2000, 35 patients, mean age 61 years (37-75), with advanced (n=2) or metastatic (n=33) pancreatic cancer and initial performance status (WHO) of 0 (n=9), 1 (n=14) or 2 (n=12) were enrolled in the study. Two consecutive groups of patients were treated twice monthly, the first group (n=19) received the LV5FU2 regimen: a 2 hour-infusion of leucovorin 200 mg/m(2), 5-FU bolus 400 mg/m(2), followed by 22-hour continuous infusion of 5-FU 600 mg/m(2) on 2 consecutive days and cisplatin 50 mg/m(2) on day 2. The second group (n=16) received a simplified schedule with bolus leucovorin 40 mg/m(2), 5-FU bolus 400 mg/m(2) on day 1, followed by 5-FU 2400 mg/m(2) 48-hour infusion and cisplatin 50 mg/m(2) on day 2. Clinical symptoms and performance status were monitored together with weight changes. Tumor assessment was performed every 2 months. RESULTS: Three patients (9%) exhibited grade 4 neutropenia and grade 3 toxicity occurred in 31% of the patients (neutropenia: n=3, thrombocytopenia: n=1, vomiting: n=3, mucositis: n=3, diarrhea: n=1). There were no treatment-related deaths. Objective response was observed in 10 patients (29%, 95% confidence interval: 20-40%) including one complete response. Median progression-free survival and overall survival were 4.5 and 9 months, respectively. Six-months and 1-year survival rates were 70% and 25%, respectively. Weight gain was observed in 40% of the patients and performance status improved in 50%. CONCLUSION: LV5FU2-P regimen is active and well tolerated. It should be compared to gemcitabine as a first line therapy in advanced and metastatic pancreatic cancer.     

Hepatic resection followed by IFN-alpha and 5-FU for advanced hepatocellular carcinoma with tumor thrombus in the major portal branch

BACKGROUND/AIMS: The prognosis of hepatocellular carcinoma (HCC) invading the major branches of the portal vein (Vp3) is extremely poor. Recently, we reported the efficacy of combination therapy with subcutaneous interferon (IFN)-alpha and intra-arterial 5-FU for intractable HCC with Vp3. In this study, this therapy was applied for resectable advanced HCC (Vp3) as a postoperative adjuvant. METHODOLOGY: Patients with HCC and tumor thrombi either in the major or first branch of portal vein were included (n=30). Fifteen consecutive patients with HCC and Vp3 were treated with at least 3 cycles of a combination therapy consisting of continuous arterial infusion of 5-FU (300 mg/mm3/day, 5 days/week, for the initial 2 weeks) and subcutaneous injection of IFN (5 MIU, 3 times/week, 4 weeks) as a postoperative adjuvant therapy following hepatic resection. Another 15 patients who underwent hepatic resection with no IFN/5-FU chemotherapy acted as controls. RESULTS: The results were as follows in the IFN/5-FU adjuvant treatment group; disease-free survival (n=11, 5-55 months), survival with recurrence (n=2, 9, 48 months), cancer death (n=1, 18 months), death from other causes but no recurrence (n=l, 22 months). The 1-year survival rate was 100% in patients treated with IFN/5-FU, and 41% in those without IFN/5-FU historical controls (n=15). There was a significant difference in disease-free and overall survival rates between the two groups (p = 0.0033 and 0.0031). CONCLUSIONS: Combination therapy with subcutaneous IFN and intra-arterial perfusion of 5-FU seems to be a promising postoperative adjuvant treatment modality for resectable HCC with Vp3.     

Vitamin K2 has growth inhibition effect against hepatocellular carcinoma cell lines but does not enhance anti-tumor effect of combination treatment of interferon-alpha and fluorouracil in vitro.

Several studies have recently reported the efficacy of combination therapy of interferon (IFN) alpha and 5-fluorouracil (5-FU) for hepatocellular carcinoma (HCC). However, the clinical effect of this treatment was not complete. The new therapeutic modality should be necessary to rise up this clinical response rate. Recently, the anti-tumor effect of Vitamin K2 has been reported in terms of decreased recurrence rate of HCC patients. The aim of this study was to explore the additive or synergistic effect of Vitamin K2 to combined therapy of interferon (IFN) alpha and 5-fluorouracil (5-FU) against hepatocellular carcinoma (HCCs). The study was conducted using three hepatoma cell lines (PLC/PRF/5, Hep3B and HepG2). The 3-(4-5-dimethylthiazol-2-yl)-2, 5-dyphenyl tetrazolium bromide (MTT) assay (48h) revealed anti-tumor effect of IFNalpha and 5-FU. Cell growth assay (3-7 days) showed growth inhibitory effect of Vitamin K2 on three cell lines after day 5. But additional effect of combination treatment of Vitamin K2 and IFNalpha/5-FU was not observed in any time course from 48h to 7 days. Cell cycles were assessed with flowcytometry. Although either Vitamin K2 or IFNalpha/5-FU alone has the influence to the cell cycles, no significant change was shown in the combination of Vitamin K2 and IFNalpha/5-FU. In conclusion, Vitamin K2 itself has potentially growth inhibitory effect for HCC cell lines, but does not enhance the anti-tumor effect of IFNalpha and 5-FU.     

苦参碱联合5-氟尿嘧啶对人胃癌裸鼠移植瘤的抑制作用

目的　研究苦参碱和5 -氟尿嘧啶(5- FU)联用对人胃腺癌SGC 7901裸鼠移植瘤的抑制作用及骨髓毒性作用。方法　将42只Balb/c小鼠分为阴性对照组(12 只)、5- FU组(6 只)、苦参碱A组(50 mg/kg,6只)、苦参碱B组(100 mg/kg,6只)、联合用药A组(苦参碱50 mg/kg+5 -FU,6只)和联合用药B组(苦参碱100 mg/kg+5 -FU,6只)。观察苦参碱和5 -FU联合用药对胃癌裸鼠移植瘤的抑制作用,计算出相对肿瘤体积(RTV)和肿瘤抑制率(IR);取裸鼠骨髓,计数有核细胞数并进行骨髓集落培养。结果　联合用药B 组抑瘤作用为70. 4%,与其他各组相比疗效明显升高,差异有统计学意义(P<0.01)。与联合用药A组相比,联合用药B组抑瘤作用亦显著增强(P<0.05)。联合用药组对骨髓的抑制作用与5 FU组相比差异无统计学意义(P>0.05)。骨髓集落培养后,与对照组相比,用药组骨髓集落明显生长旺盛。结论　苦参碱和5 -FU联用对人胃癌裸鼠移植瘤的抑制作用明显优于两者单独应用;联合用药对裸鼠骨髓增殖期造血细胞抑制作用有所加重,但不损伤静止期骨髓干细胞。     

复方斑蝥胶囊联合化学治疗对转移性结直肠癌的疗效观察

目的 观察复方斑蝥胶囊联合奥沙利铂(L-OHP)、5-氟尿嘧啶/亚叶酸钙(5-FU/CF)组成的FOLFOX4方案治疗转移性结直肠癌的临床疗效及不良反应.方法 收集2006年4月至2008年10月收治的无手术指征的转移性结直肠癌患者107例,随机分为复方斑蝥胶囊联合FOLFOX4方案组(联合治疗组)54例和FOLFOX4方案组53例.联合治疗组给予L-OHP 85mg/m2,第1天静脉滴注2 h,同时或之后予CF 200 mg/m2,静脉滴注2 h,续5-FU 400 mg/m2静脉推注,600 mg/m2持续静脉滴注22 h,次目重复,CF与5-FU每2周重复一次,同时予以复方斑蝥胶囊口服750 mg,每天2次.FOLFOX4方案组患者单纯接受FOLFOX4方案化学治疗.结果 联合治疗组和FOLFOX4方案组有效率分别为44.4%和37.7%,两组间差异无统计学意义(P=0.481).联合治疗组的中位无进展时间(TTP)为11.6个月,FOLFOX4方案组为7.9个月,两组间差异有统计学意义(P=0.020).生活质量评价,联合治疗组的改善率为57.4%,FOLFOX4方案组为32.1%,两组间差异有统计学意义(P=0.008).两组不良反应主要表现为消化道反应、神经系统毒性、脱发和骨髓抑制.联合治疗组Ⅲ/Ⅳ度粒细胞减少发生率为37.0%,FOLFOX4方案组为58.5%,两组间差异有统计学意义(P=0.043).结论 复方斑蝥胶囊联合FOLFOX4方案一线治疗转移性结直肠癌能协同增效,能提高患者TTP及改善患者生活质量,降低粒细胞减少发生.     

Effect of O-4-ethoxyl-butyl-berbamine in combination with pegylated liposomal doxorubicin on advanced hepatoma in mice

AIM: To study the synergistic effects of calmodulin (CaM) antagonist O-4-ethoxyl-butyl-berbamine (EBB) and pegylated liposomal doxorubicin (PLD) on hepatoma-22 (H(22)) in vivo. METHODS: Hepatoma model was established in 50 Balb/c mice by inoculating H(22) cells (2.5 x 10(6)) subcutaneously into the right backs of the mice. These mice were divided into 5 groups, and treated with saline only, PLD only, doxorubicin (Dox) only, PLD plus EBB and Dox plus EBB, respectively. In the treatment groups, mice were given 5 intravenous of PLD or Dox on days 0, 3, 6, 9 and 12. The first dosage of PLD or Dox was 4.5 mg/kg, the other 4 injections was 1 mg/kg. EBB (5 mg/kg) was coadministered with PLD or Dox in the corresponding groups. The effect of drugs on the life spans of hepatoma-bearing mice and tumor response to the drugs were recorded. Dox levels in the hepatoma cells were measured by a fluorescence assay. Light microscopy was performed to determine the histopathological changes in the major organs of these tumor-bearing mice. The MTT method was used to analyze the effect of Dox or PLD alone, Dox in combination with EBB, or PLD in combination with EBB on the growth of H(22) cells in an in vitro experiment. RESULTS: EBB (5 mg/kg) significantly augmented the antitumor activity of Dox or PLD, remarkably prolonged the median survival time. The median survival time was 18.2 d for control group, but 89.2 d for PLD+EBB group and 70.1 d for Dox+EBB group, respectively. However, Dox alone did not show any remarkable antitumor activity, and the median survival time was just 29.7 d. Addition of EBB to Dox or PLD significantly increased the level of Dox in H(22) cells in vivo. Moreover, EBB diminished liver toxicity of Dox and PLD. In vitro, EBB reduced the IC50 value of Dox or PLD on H(22) cells from 0.050+/-0.006 mg/L and 0.054+/-0.004 mg/L to 0.012+/-0.002 mg/L and 0.013+/-0.002 mg/L, respectively (P<0.01). CONCLUSION: EBB and liposomization could improve the therapeutic efficacy of Dox in liver cancer, while decreasing its liver toxicity.     

Effects of short term treatment with pentagastrin, proglumide, tamoxifen given separately or together with 5-fluorouracil on the growth in the murine transplantable Colon 38 cancer

It is well known that 5-fluorouracil (5-FU) is the most effective drug in the treatment of colon cancer, however the positive response is small, only about 20%. On the other hand, it has been postulated that the growth of colon cancer depends on many growth factors, such as gastrin and estrogens. The search for new substances increasing the antitumor effect of 5-FU has lasted for many years. The aim of the present study was to examine the effects of pentagastrin (PEN, syntetic gastrin analogue), proglumide (PRO, a blocker of gastrin receptor) and tamoxifen (TAM, a partial estrogen antagonist) given separately or together with 5-FU on proliferation, apoptosis, necrosis and proliferation/apoptosis (P/A) ratio in the murine transplantable Colon 38 cancer. The male mice were implanted with a suspension of Colon 38 cells. After 7 days, the animals were treated with PEN (250 microg/kg b.w., twice daily), PRO (100 mg/kg. b.w., twice daily), TAM (10 microg/animal) separately or together with 5-FU (60 mg/kg b.w., once) for 2 days. The incorporation of bromodeoxyuridine (BrdU) into cell nuclei was used as an index of cell proliferation (labeling index--LI). The in situ labeling of nuclear DNA fragmentation according to TUNEL method was considered as an apoptotic index (AI). It was found that 5-FU increased the apoptosis, unexpectedly increased the LI and decreased the P/A ratio when compared to control. Both PEN and PRO increased the apoptosis and in the case of PRO decreased P/A ratio when compared to control. TAM did not affect any of the examined parameters. All of the investigated substances modify the 5-FU action: PEN and PRO on AI and LI and TAM on AI and P/A ratio. Necrosis was observed in 3 tumors treated with PEN + 5-FU, in 2 tumors of PRO + 5-FU group and in 1 tumor of group with 5-FU and with PEN. Further studies are needed to elucidate if those modification of 5-FU action by the examined substances will be useful in the inhibition of the growth of Colon 38 cancer.     

Therapeutic intervention in a rat model of adult respiratory distress syndrome: II. Lipoxygenase pathway inhibition

The present study was designed to investigate the role of 5-lipoxygenase (5LO) metabolites in an endotoxin (LPS)-induced model of the adult respiratory distress syndrome (ARDS) in the rat. The therapeutic value of two 5LO inhibitors and a specific LTB4 and a LTD4 receptor antagonist were examined. Rats were treated 1 hr prior to administration of aerosolized LPS. Rats were either unexposed (n = 11), or pretreated with vehicle sham (n = 63), 50 mg/kg phenidone t.i.d. (n = 7, n = 10 for assessment of mortality), 30 mg/kg SK&F 103842 b.i.d. (n = 6), 50 mg/kg SK&F 106203 t.i.d. (n = 11), or 5 mg/kg SK&F 107324 b.i.d. (n = 6) 1 hr prior to the administration of aerosolized endotoxin (LPS, 7 mg/kg) or phosphate-buffered saline (PBS, n = 22). Twenty-four hours later, blood samples were collected for hematologic evaluation and after wet lung weight was determined, broncho-alveolar lavage (BAL) was performed to measure cells counts and total protein (TP). 5LO inhibition and LTD4 receptor antagonism reduced LPS-induced mortality to zero compared to 35% in rats pretreated with vehicle sham. Pretreatment with the LTD4 receptor antagonist attenuated the LPS-induced increased in wet/dry lung weight (W/D) whereas 5LO inhibition reduced TP increases. Both 5LO inhibition and LTD4 receptor antagonism attenuated the LPS-induced BAL erythrocyte increase. The LPS-induced thrombocytopenia was attenuated by phenidone, the 5LO receptor antagonist. We conclude that the increased microvascular permeability was associated with the formation of 5LO products since 5LO inhibition lessened the severity of the LPS-induced increase in W/D and TP.(ABSTRACT TRUNCATED AT 250 WORDS)     

片仔癀对人结肠癌SW480细胞株的抑制作用研究

目的探究片仔癀对人结肠癌SW480细胞株的抑制效果。 方法通过对人结肠癌SW480细胞株常规体外培养,随机设定空白组、5-氟尿嘧啶（5-FU）组和不同浓度片仔癀组,分别采用对应药物干预24 h、48 h、72 h,并通过细胞增殖活力检测法（MTT法）和荧光显微镜观察其抑制效果。采用人结肠癌SW480细胞株建立结肠癌小鼠模型,把造模成功的150只小鼠随机分为模型组,5-FU组和片仔癀低、中、高剂量组,每组30只;分别以不同剂量药物外敷3 d,通过抑瘤率和原位凋亡检测（TUNEL法）解释抑制效果。 结果1 mg/mL、2 mg/mL、3 mg/mL浓度片仔癀对人结肠癌SW480细胞体外抑制率最高,为70.05%、71.39%、70.12%,与5-FU组比较差异具有统计学意义（χ²=4.49,4.97,4.52;均P<0.05）。4 mg/mL片仔癀抑制率为67.39%,与5-FU组比较差异无统计学意义（χ²=3.57,P>0.05）;荧光显微镜显示5-FU组与片仔癀各组人结肠癌SW480细胞株数量均显示不同程度的减少、体积变小、折光性差、细胞悬浮及脱落死亡。片仔癀高、中、低剂量组对人结肠癌SW480细胞的体内抑瘤率分别为51%、39%、23%,其中高、中剂量组与5-FU组比较差异无统计学意义（χ²=0.05,0.49;均P>0.05）,低剂量组与之比较差异有统计学意义（χ²=4.09,P<0.05）;荧光显微镜显示片仔癀各剂量组和5-FU组对人结肠癌SW480细胞均有不同程度的凋亡反应。 结论片仔癀外用对人结肠癌SW480细胞生长有明显的抑制作用,高、中剂量体内抑制作用与5-Fu相近,优于低剂量,临床可考虑采用高剂量可能取得更佳效果,体外抑制作用上显示则优于5-Fu,但剂量差异影响不大。     

Different effects of sequential combinations ofN-methylformamide with 5-fluorouracil on human colon carcinoma cells growing in nude mice

Summary The effects of the combination ofN-methylformamide (NMF) with 5-fluorouracil (5-FU) on tumor growth and morphological features of human colon carcinoma cells (HT29) implanted in nude mice were assessed. Both agents were administered i.p. at tolerable doses: 5-FU at 19 mg/kg for 5 days and NMF at 200 mg/ kg for 12 days. Four main schedules were tested: 5-FU alone, NMF alone, NMF followed by 5-FU and 5-FU followed by NMF. The last sequence was the most effective, as compared with the other treatment regimens. In particular, the 5-FU NMF combination induced a tumor inhibition of about 75% at the end of the treatments (17th day) versus an inhibition of 23%–43% in the other schedules. Morphological observations, carried out by light and electron microscopy, indicated a possible relationship between the presence of structural changes and tumor growth inhibition. The results of this study renew interest in the use of NMF in sequential combination confirming sequence as a critical factor for the optimal combination of NMF and 5-FU.Abbreviations 5-FU 5-fluorouracil - NMF N-methylformamide - DMF N,N-dimethylformamide - cisplatin cis-diamminedichloroplatinum - m _T/m _c tumor weight inhibition - t _T-t _c tumor growth delay This work was supported by grants from the Italian National Research Council, contract 89.03979.CT04; Ministero della Sanità; Istituto Oncologico Romagnolo n 90152.1     

白黎芦醇对舒尼替尼诱导肾损伤的作用及机制研究

目的:探究白黎芦醇对舒尼替尼诱导肾损伤的作用及机制.方法:选择WKY大鼠30只随机分为3组:对照组(n=10),舒尼替尼组(n=10),舒尼替尼+白藜芦醇组(n=10).舒尼替尼组给予舒尼替尼[15 mg/(kg·d)]灌胃28 d,建立舒尼替尼肾损伤大鼠模型.舒尼替尼+白藜芦醇组于建模前7 d给予大鼠白藜芦醇[100...