| Background:Malignant ascites is a manifestation of end stage events in cancers and associated with a poor prognosis. Except in breast and ovarian cancer, the median survival time is ranged from1to4months. Massive ascites can low down the quality of life of patients. The intent of therapy is palliative and improvement of quality of life. Intraperitoneal chemotherapy is an important and effective regional method to treat malignnant ascites. Pestieau et al used a rat model to compare the pharmacokinetics and tissue adsorption of pemetrexed after administration by the intraperitoneal and intravenous route. And then suggested a notable superiority of intraperitoneal administration in local treatment.Objective:To evaluate the effect of intraperitoneal administration of pemetrexed on murine hepatoma H22ascites-bearing mice and its mechanism.Methods:Nighty male Kunming mice model of ascites were established by i.p. injection2×106H22cells, divided into5groups (18per group)at random after24h inoculation:control group (normal saline); PEM low dose group(pemetrexed, lOmg/kg/day); PEM middle dose group (pemetrexed,50mg/kg/day); PEM high dose group (pemetrexed,90mg/kg/day); DDP group (cisplatin,0.6mg/kg/day). Mice were treated with i.p. injection of each drug on day1-10(i.p., qd×10).The body-weights, abdomen circumference and behavior of the mice were measured every day before treatment. Eight mice of each group were sacrificed and surveyed ascites volumes on the11th day. Also, H22cells in ascites were checked the cell cycles and early apoptosis, late apoptosis/necrosis rates by flow Cytometry to explore the mechanism. The rest mice were checked the survival days, and calculate the life-prolonging rate.Result:1. Ascites volume was collected on day11after sacrificing eight mice of each group. Mean volume of ascites in the control group was (17.85±2.56) ml. Compared with the control group, PEM middle (10.93±3.05), high dose (8.08±2.22), and cisplatin (7.30±2.32) group was statistically significant (p<0.01).Unfortunately, the PEM low dose group (15.05±3.95) was not statistically significant (p>0.05). There was no difference between PEM high dose group and DDP group (P>0.05)2. The majority of control group mice occurred metastasis in gastrointestinal,mesentery,liver, and lung. And each treatment group could reduce the rate of metastasis.3. The mean survival days of PEM low, middle,high dose group, and DDP group were(14.30±2.26),(15.70±1.89),(20.10±5.90),(19.1±3.21), prolonged compared with the mean survival days of the control group(13.20±1.93). Life-prolonging rate were8.33%,18.94%,52.27%,44.70%. Especially,the most significant were PEM middle, high dose group, DDP group (p<0.01). There was no difference between PEM high dose group and DDP group.(P>0.05)4. Twenty-four hours of last administration, H22cells S and G2/M phase in PEM low, middle, high dose group were (44.77±2.30,41.49±3.94);(51.59±6.34,22.80±5.08);(57.09±9.84,27.78±10.90); respectively.Compared with the control group (22.95±5.13,61.62±6.52), there were statistically significant(p<0.01). There was no difference between DDP group (30.47±9.53,58.94±13.95) and control group (P>0.05)5. Twenty-four hours of last administration, the early apoptosis and late apoptosis/necrosis rates of H22cells in PEM low, middle,high dose group, and DDP group were(1.81±0.76,10.39±4.56);(3.63±1.19,11.44±1.29);(8.85±1.86,14.21±2.63);(7.68±2.17,13.93±2.53), respectively. Compared with the control group(0.73±0.23,5.56±1.61), there were statistically significant(p<0.01). There was no difference between PEM high dose group and DDP group (P>0.05)Conclusion:1.Intraperitoneal pemetrexed can control and inhibit the generation of ascites in H22ascites-bearing mice, and improve of the quality of animal’s life.2.Intraperitoneal pemetrexed in H22ascites-bearing mice can reduce the rates of metastasis, specially in mesentery and liver.3.Intraperitoneal pemetrexed significant prolonged on the average survival time in H22ascites-bearing mice.4.Pemetrexed altered the cell cycle phase distribution in H22cells,mainly arrested in S phase,and G2/M phase development were greatly inhibited.5.Pemetrexed caused H22cells death via apoptosis and necrosis in vivo.In a word,Intraperitoneal pemetrexed administration on murine hepatoma H22ascites-bearing mice has good therapeutic effect, and also safe after supplement folic acid in KM mice. The mechanism might be related to arrest murine hepatoma H22cells in S phase, inhibit G2/M phase cell and induce them to apoptosis and necrosis. |
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