| Gemcitabine is a nucleoside analog used as chemotherapy, in which the hydrogen atoms on the 2' carbon of deoxycytidine are replaced by fluorine atoms. The triphosphate analogue of gemcitabine replaces cytidine of the building blocks of nucleic acids during DNA replication, resulting in apoptosis. The diphosphate analogue of gemcitabine binds to ribonucleotide reductase (RNR) active site and inactivates the enzyme irreversibly. As a result, the cell cannot produce the deoxyribonucleotides required for DNA replication and repair, and cell apoptosis is induced.[1] The IC50 for gemcitabine in the four endometrial cancer cell lines MES-SA, RL95-2, HEC-1-A and HEC-1-B are 60 ng/mL, 9.5 µg/mL, 91.4 µg/mL and 110 ng/mL, respectively.[2] Gemcitabine inhibits the pancreatic cancer cell lines T3M4, Mia-PaCa-2, Capan-1 and AsPC-1 with IC50s of 42.2, 35.9, 11.5 and 14.6 nM, repectively. mRNA of bcl-xS, blk, bak and bax is significantly upregulated in Capan-1 cells (0.9- to 8.6-fold), slightly upregulated in T3M4 (2.0- to 5.0-fold) and Mia-PaCa-2 (1.1- to 1.8-fold) cells, and downregulated in AsPC-1 cells (0.3- to 0.6-fold) following 8 days of gemcitabine treatment with double IC50 concentration.[3] It is also reported that gemcitabine inhibits the human pancreatic cancer lines PANC1, MiaPaCa2, BxPC3, and Capan2 with IC50s of 50, 40, 18 and 12 nM, repectively. The IC50 of gemcitabine for PANC1GemRes (a gemcitabine-resistant cell line) is 10 µM.[4] In a nude mouse orthotopic xenograft model, the tumor growth inhibition rate is 25% in the 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) treatment group and 5% in the gemcitabine (100 mg/kg, three times a week) treatment group. PP2 and gemcitabine combination produces a tumor growth inhibition rate of 98%. Hepatic metastasis occurrs in 100% of control and gemcitabine-treated groups; 88% of the PP2-treated group develops liver metastases. There are no detectable metastases in the group treated with PP2 and gemcitabine in combination.[4] In a nude mouse xenograft model of pancreatic adenocarcinoma, tumor growth is markedly retarded, the ?nal mean tumor mass is reduced by 87%, and the mean tumor apoptotic fraction and caspase 3 activity are significantly increased in mice treated with RRM2 (M2 subunit of ribonucleotide reductase) siRNA in combination with gemcitabine, compared to those treated with gemcitabine alone or in combination with control siRNA. Hepatic metastasis occurs in 80% of PBS-treated mice and 40% of gemcitabine-treated mice. There are no metastases in mice treated with RRM2 siRNA and gemcitabine.[5] |
