抗肿瘤药物与肝脏

常用抗肿瘤药物达40余种。本文重点讨论抗肿瘤药物对肝脏的毒性以及临床应用中的注意事项。一、烷化剂(Alkylating Agents)(一)环磷酰胺(CyclophosphamideCTX)属氯乙烷胺基类。

Adriamycin Thermotherapy through the Hepatic Artery Using VX2 Carcinoma in Rabbit Liver as a Model

OBJECTIVE It has been reported that heating can enhance sensitivity of rabbit VX2 cells to adriamycin and increase the intracellular concentration of adriamycin. This study was designed to evaluate the anti-tumor effect of interventional hyperthermia and interventional thermochemotherapy on VX2 carcinoma in rabbit liver. METHODS VX2 carcinoma cells were surgically implanted into the right liver lobe of 60 male New Zealand white rabbits, which were randomly divided into 4 groups (15 per group). The 4 groups (designated as 1, 2, 3, 4 respectively) were injected with 10 ml of the following via the hepatic artery: physiological saline (37℃); adriamycin (37℃); physiological saline (60℃); adriamycin (60℃). One week later, the tumor volume, serum level of aspartate transaminase (AST) and the survival of the rabbits bearing VX2 were observed and compared among the different treated groups. RESULTS The tumor growth rate in group 4 (ADM 60℃) (0.53±0.21)% was significantly lower than that in group 1 (3.48±1.17)%, in group 2 (1.09±0.26)% and group 3 (3.32±1.28)% (P<0.05, P<0.05, P<0.01, respectively). The days of survival days for group 4 (87.0±2.0) were significantly more than that in group 1 (40.0±3.0). Group 4 showed a significantly higher increase in serum AST compared to group 1 (P<0.05), but without significant differences compared to the other groups (P>0.05). CONCLUSION Adriamycin treatment at 60℃ significantly deceased the tumor growth, prolonged the survival period and resulted in reversible liver damage.

Cytomegalovirus infection in severe ulcerative colitis patients undergoing continuous intravenous cyclosporine treatment in Japan

AIM： TO investigate active cytomegalovirus （CMV） infection following the cydosporine A （CyA） treatment of steroid-refractory ulcerative colitis （UC）. METHODS： Twenty-three patients with severe UC not responding to steroid therapy （male 14, and female 9） enrolled at Nagoya University Hospital from 1999 to 2005. They received continuous intravenous infusion of CyA （average 4 mg/kg per day） for 1 mo. Serum and colonic biopsy samples were collected before CyA treatment and 4 d, 10 d, 20 d, and 30 d after treatment. Patients were evaluated for CMV by using serology （IgM antibody by ELISA）, quantitative real-time PCR for CMV DNA, and histopathological assessment of hematoxylin and eosin （HE）-stained colonic biopsies. CMV infection was indicated by positive results in any test. RESULTS： No patients had active CMV infection before CyA treatment. Eighteen of 23 UC patients treated with CyA were infected with active CMV （IgM antibody in 16/23 patients, 69.6%; CMV DNA in 18/23 patients, 78.2%; and inclusion bodies in 4/23 patients, 17.3%）. There was no difference in the active CMV-infection rate between males and females. Active CMV infection was observed after approximately 8 d of CyA treatment, leading to an exacerbation of colitis. Fifteen of these 18 patients with active CMV infection （83.3%） required surgical treatment because of severe deteriorating colitis. Treatment with ganciclovir rendered surgery avoidable in three patients. CONCLUSION： Our results suggest that active CMV infection in severe UC patients treated with CyA is associated with poor outcome. Further, ganciclovir is useful for treatment of CMV-associated UC after immunosuppressive therapy.

The first report of treatment of liver abscess due to Candida albicans with intra-abscess and intravenous administration of liposomal amphotericin B (Amphotec)

Increasing reports on application and safety of liposomal amphotericin B (Amphotec) in the treatment of deep fungal infections have been described recently. This is the first report that a case of liver abscess due to Candida albicans was completely cured with intra-abscess and intravenous administration of liposomal amphotericin B without recurrence in three-year follow-up period.

新的肿瘤化疗药物

新的肿瘤化疗药物可以分为四组:相对地被证明有临床价值的药物;在少数病例中提示有临床效果的药物;处于第一期临床研究的药物和很可能临床有效但尚处于临床前研究的药物。属于第一类的有阿霉素(Adriamycin)、5—(3,3—二甲基—1—三氮烯)—咪唑—4—酰胺(DTIC)、博莱霉素、天门冬酰胺酶、1,3—双—(2—氯乙基)—1亚硝基脲(BCNU)和1—(2—氯乙基)—3—环己基—1—亚硝基脲(CCNU)。

SIRT1 suppresses PMA and ionomycin-induced ICAM-1 expression in endothelial cells

Intercellular adhesion molecule-1 （ICAM-1） plays an important role in the recruitment of leukocytes to the endothelium, which causes inflammation and initiation of atherosclerosis. We have previously shown that endothelium-specific over-expression of class III deacetylase SIRT1 decreases atherosclerosis. We therefore addressed the hypothesis that SIRT1 suppresses ICAM-1 expression in the endothelial cells. Here, we found that expression of SIRT1 and ICAM-1 was significantly induced by PMA and ionomycin （PMA/Io） in human umbilical vein endothelial cells （HUVECs）. Adenovirus-mediated over-expression of SIRT1 significantly inhibited PMA/Io-induced ICAM-1 expression （RNAi） resulted in increased expression of ICAM-1 in HUVECs in HUVECs. Knockdown of SIRT1 by RNA interference Luciferase report assay showed that over-expression of SIRT1 suppressed ICAM-1 promoter activity both in basic and in PMA/Io-induced conditions. We further found that SIRT1 was involved in transcription complex binding on the ICAM-1 promoter by chromatin immunoprecipitation （CHIP） assays. Furthermore, SIRT1 RNAi increased NF-~：B p65 binding ability to the ICAM-1 promoter by ChIP assays. Overall, these data suggests that SIRT1 inhibits ICAM-1 expression in endothelial cells, which may contribute to its anti-atherosclerosis effect.

Mithramycin inhibits intimal hyperplasia of vein grafts after transplantation of the jugular vein to the abdomainal aorta in rats

Objective: The intimal hyperplasia caused by migration and proliferation of the smooth muscle cells play a most important role in the stenosis of the vein grafts. This study is to explore how the C myc oncogene and its protein contribute to the intimal hyperplasia after the jugular vein is transplanted to the abdominal aorta and to assess the effect of Mithramycin on the intimal hyperplasia. Methods: In 60 Wistar rats, a 0.8 cm segment of the right jugular vein graft was interposed at the level of the abdominal aorta. The experiment group received Mithramycin (150 μg/kg IP) 1 h before and after the operation. The control group received normal saline, specimens of vein graft at 2 and 6 h postoperatively were subjected respectively to in situ hybridization. The vein grafts 4 weeks after operation were perfusion fixed. The specimens were stained with hemotoxylin eosin and the computer morphologic analysis system was used to evaluate the degree of intimal thickening. Immunohistochemistry studies of muscle specific α actin, C myc protein and 5 Bromodeoxyuridine were performed. Results: The areas of neointimal and the ratios of neointimal to medial area were significantly smaller and lower in the Mithramycin treated than in the control rats (P< 0.05 ). The 5 Brdu labeling rate between the two groups were also different significantly (P< 0.05 ). Muscle specific α actin showed that the smooth muscle cells formed the most area of myointimal hyperplasia. Steady state C myc mRNA level was increased from 2 h to 6 h postoperatively. The positive rate of the placebo treated group was higher significantly than that of the Mithramycin treated group (P< 0.05 ). Conclusions: Mithramycin may effectively inhibits transcription of C myc in proliferating vascular smooth muscle cells and could be useful in the prevention of restenosis after vascularization. These results support the hypothesis that systemic administration of Mithramycin might immediately prevent intimal proliferation.