الفهرس 
Acknowledgments.Only 14 pages are availabe for public view
 |  | from | 158 |  |  |
| | | from | 158 | | |
Abstract
This study was conducted to investigate the effect of dietary protein quality on ovarian cancer growth and its synergism with an anticancer drug, using murine ovarian cancer models. During the period of January 2014 to April 2016, the animal experiments were conducted at Kyoto university, Kyoto, japan, using ovarian cancer cell line (HM-1) and (ID-8) injected into immunocompetent B6C3F1 and C57BL/6 mice and all procedures was approved by the Kyoto University Animal Research Committee. br The different types of dietary protein had different effects on the growth of ovarian cancer in mice. Overall, our current study is the first to illustrate the detrimental effects of a high dietary protein on ovarian cancer progression. we found that high animal protein promotes an aggressive growth pattern of ovarian tumor spread in the syngeneic OC bearing mice. A high tumor burden was observed at most organ sites in high animal protein fed mice along with a wider spread to the abdominal adipose tissue compared to the high plant protein fed mice. The plasma and ascitic fluid of high animal protein fed mice displayed increased levels of growth, inflammatory factors which provide a tumor promoting environment, while the high plant protein fed mice showed an inverse profile, which correlated with the tumor growth seen in the respective groups. br We first generated two ovarian cancer models; the 1ST is the subcutaneous model (SC), -#119;-#104;-#101;-#114;-#101; the ovarian cancer cells were injected on the back of the mice and hence tumor initiation and growth was evident and easily followed and measured two times per week using digital ruler. The 2ND one is the intraperitoneal model (IP); -#119;-#104;-#101;-#114;-#101; the ovarian cancer cells were injected into peritoneal cavity whish is the real environment of the ovarian cancer. In later model mice body weight and abdominal circumference were measured weekly. br The experiments were conducted in each model separately; starting with SC model to examine effect of protein diet on ovarian cancer as regard initial growth and then IP model was used to examine the proliferation, ascites formation and metastasis of the ovarian cancer. During the experiment we established two sequence of event as regard tumor injection and diet intervention; -#119;-#104;-#101;-#114;-#101; mice was fed with the special protein diet before injection of ovarian tumor cells and that was called pre-implantation model in contrast to post-implantation model; -#119;-#104;-#101;-#114;-#101; the mice was shifted to special protein diet after the ovarian tumor has reached certain seize. br In SC model; four groups of mice were, which were fed high (20%) or low (10%) animal based protein or plant based protein diet, respectively. br We studied effect of Rapamycin; well known m-TOR inhibitor in combination with diet on ovarian cancer growth, we also injected cisplatin into the mice intraperitoneally and observed tumor size, body weight and survival. Different rates of tumor growth were confirmed, at the end of each experiment mice were scarified, blood and ascites were collected for analysis of insulin, IGF-1 and other factors, and by immunohistochemistry; expression of level of eukaryotic initiation factor 4E-binding protein 1 (p-4EBP1) activity; important downstream of mTOR pathway, and indicator of proliferation using Ki-67 index were examined. br Interestingly, our study had found a link between quantity as well quality of dietary protein intake and increased risk of ovarian cancer. The inhibition of tumor growth of the subcutaneously implanted cancers were observed in -#111;-#114;-#100;-#101;-#114; in the mice fed with 20% plant, 10% plant, 10% animal and 20% animal protein diet (p-lt;0.0001). br After the injection of Rapamycin; Tumor weights -#102;-#114;-#111;-#109; the animals treated with Rapamycin alone or the 20% plant protein diet alone were significantly lower than 20% animal protein fed group. However, tumor br weights were significantly smaller in animals treated with Rapamycin fed the 20 % plant protein diet (p-lt; 0.001, 95% CI= 2.1 to 69.3) than in those treated with Rapamycin fed the 20% animal protein diet (p-lt; 0.005, 95% CI= 17.5 to 118.2). br After the injection of cisplatin, the tumor size in the mice fed with 20% plant protein diet showed a significant decrease in comparison to the mice fed with 20% animal protein diet (p-lt;0.0001). Furthermore, the body weight in the mice that were fed 20% animal protein diet without tumor injection was significantly decreased by cisplatin treatment in comparison to those that were fed 20% plant protein diet (p-lt;0.0001). br The proliferation index (Ki67 index) and expression of (p-4EBP1) activity were higher in the mice that were fed animal protein diet. The survival of the mice fed 20% animal protein diet was worse than the mice fed 20% plant protein diet (log-rank test, p=0.0007). br - Ovarian cancer is a multi-stage disease. DNA genetic material is modified and certain pathways up-regulated becomes capable of producing abnormal cells disrupting body functions and leading to poor prognosis, chemotherapy resistance, decrease survival and even death. br - Diet and other modifiable risk factors can affect any phase of the ovarian cancer process than thought pos¬sible a few years ago. br - Researchers studied large groups of dietary constituents to establish links between certain types of diet and increased rates of ovarian cancer, yet the results and inconsistent and conflicting. br - Our findings suggest that replacement of dietary animal protein with plant protein could be effective in inhibiting ovarian tumor growth, proliferation and metastasis. br - A healthy diet before Ovarian cancer diagnosis may indicate a stronger immune system and indicate the capacity to respond favorably to cancer therapy br - Plant protein diet might reinforce chemotherapeutic effect “greater cisplatin sensitivity “synergistically, and could result in a better prognosis in ovarian cancer. br - Our finding also suggest that high plant protein diet could modify the damaging effects of chemotherapy while simultaneously increasing the effectiveness of the chemotherapy. br - Furthermore, the prognosis of mice with ovarian cancer that were fed a diet that was high in plant protein was superior to that of mice with ovarian cancer that were fed a diet that was high in animal protein with increase progression free survival (PFS) after oncological therapy. br - The results -#102;-#114;-#111;-#109; our studies may have a rapid translation into the clinic. We envision that Women with healthier diets before an ovarian cancer diagnosis are less likely to die in the years following the cancer than women with poorer diets, also patients with recurrent OC could be offered diet modifications involving protein dietary content at different stages of their disease with appropriate monitoring.