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Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all malignancies. At time of diagnosis, 80% of patients with PDAC have unresectable tumors, and conventional therapies are nearly ineffective. The relative poor efficacy of chemo/radiotherapy against PDAC indicates that the development of new therapeutic strategies is a crucial step to improve the survival of patients with this disease. This includes the modification of established therapies, the testing of new targets and the improved delivery of drugs to their target. Riproximin (Rpx) is a new plant agent, which was isolated from the plant Ximenia Americana. Riproximin was classified as a ribosome inactivating protein (RIP) of type II and its anticancer activity has been recently demonstrated in vitro and in vivo Methods: In vivo experiments The rat pancreatic cancer cell line (ASML) was used for its property to mimic liver metastasis in nude rats, as shown before (Eyol et al). Tumor-bearing rats were treated intravenously with different concentrations of Rpx as single agent or in combination with gemcitabine (GEM) or dinaline (DIN). Ripx was administered twice weekly at doses ranging from 500µg/kg to 1500µg/kg. GEM and DIN were administered to animals for a period of 2 weeks either intravenously at a dose of 50mg/kg or perorally at a 5 times weekly dose of 10mg/kg. 98 representative apoptosis genes were analyzed by quantitative-RT/PCR in with Rpx treated cells in comparison to untreated cells. Results: The intravenous administration of Rpx (1500µg/kg and 500µg/kg) reduced the tumor growth significantly by 61% and 67%, respectively (p=0.00174 -p= 0.00024). The survival rate was also significantly increased (21.8 days for riproximin treated versus 17.6 days in untreated control rats; P=0.01349) after the intravenous administration of Rpx. Rats, which were treated with the high dose of Rpx showed no further reduction in tumor size, when compared with rats treated with the low dose. In comparison, no significant effect on tumor size or on survival was observed after treatment with gemcitabine or dinaline. The combination therapy with Rpx and GEM as well as Rpx and DIN produced a significant reduction in mean tumor size when compared with the corresponding untreated control group but it was not superior over the single therapy with Rpx. 17 apoptosis gens have been found to be modulated after exposure to Rpx. Conclusion: Taken together the results of our in vivo experiment suggest that riproximin has a clear potential for pancreatic cancer treatment. Further experiments are required for optimizing the combination therapy with other antineoplastic agents.

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/content/papers/10.5339/qfarf.2013.BIOP-0126
2013-11-20
2019-11-17
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