No abstract

No abstract

ProTide and cyclic phosphate ester are two successful prodrug technologies to overcome the limitations of nucleoside drugs, among which the cyclic phosphate ester strategy has not been widely used in the optimization of gemcitabine. Herein, we designed a series of novel ProTide and cyclic phosphate ester prodrugs of gemcitabine. Cyclic phosphate ester derivative 18c exhibits much higher anti-proliferative activity than positive control NUC-1031 with IC50s of 3.6–19.2 nM on multiple cancer cells. The metabolic pathway of 18c demonstrates that 18c’s bioactive metabolites prolong its anti-tumor activity. More importantly, we separated the two P chiral diastereomers of gemcitabine cyclic phosphate ester prodrugs for the first time, revealing their similar cytotoxic potency and metabolic profile. 18c displays significant in vivo anti-tumor activity in both 22Rv1 and BxPC-3 xenograft tumor models. These results suggest that compound 18c is a promising anti-tumor candidate for treating human castration-resistant prostate and pancreatic cancer.

Objective: The objective of this research was to search the new ways to reconstruct the immune function. Methods: 200 Kunming mice, 5 to 6 weeks old, divided into 8 Groups: control group bearing tumors (Group B, n=9);observation group for combined transplantation of fetal liver, spleen and thymus cells(Group CI, n=15); observation group(Group CII, n=15; carry on combined transplantation to this group once a week for successive 5 weeks and then execute the mice);treatment group with transplantation of fetal liver cells (Group F);treatment group with transplantation of fetal spleen cells (Group G); treatment group with transplantation of fetal thymus cells (Group H); treatment group with combined transplantation of fetal liver and spleen cells (Group I);treatment group with combined transplantation of fetal liver and thymus cells (Group K), nF=nG=nH=nI=nJ=nK= 12. First, prepare mice of ascitic type after the anabiosis of the root of Ehrlich ascites tumor; when the ascites are formed, draw out the ascites of the cancer cells and collect them to inoculate the experimental mice under the skin of the right hollow viscera to make the subcutaneous solid tumor model bearing Ehrlich Ascites tumor. When the model is prepared, carry out correspondent cell transplantation once a week for each group. After prepared of the suspension of fetal liver, spleen and thymus, they were transplanted into above animal models to record the tumor growth, disappear, survival time, the immune function and the tissue pathology change and compared each experimental group number. Results: The results showed that in three experimental groups the rate which the tumors were completely disappeared is 40% in the early stages and the rate which the tumors were completely disappeared in the later stage is 46.67%. After the tumors completely disappeared, the animals can survive for a long time. The partial disappeared rate is 26.67% in the early group and is 13.33% in the long-term group. In the partial group the average survival time is above one month which the immune function increase and immune organ enlarge. The immune organ histology slides showed that the organ cells proliferation increased. Conclusion: Reconstitution of immune system organ completely and partially can help the host to fight the tumor and to improve the treatment effects. Citation Format: Jie Xu, Ze Xu, Sitthipol Tovanich, Bin Wu. The novel ways to inhibit atrophy of thymus and reconstructing the immune function in preventing the advance of tumor. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A33.