LT uptake despite high cell proliferation rate. Therefore it is possible that treatment of tumors relying 6 FDG and FLT PET Imaging of CaP Treatment doi: 10.1371/journal.pone.0085126.g004 primarily on de novo synthesis not necessarily will result in decreases in FLT uptake despite treatment with SB 1317 chemical information effective chemotherapy that reduces cell proliferation. Previously, we have reported that effective anti-cancer treatment reduced FLT uptake in the A2780 human ovarian cancer xenograft mouse model indicating that the salvage pathway contributes to the thymidine requirement in this tumor model. No decrease in the cell proliferation associated genes Ki67 and TK1 were observed on day 8 despite effective treatment. Thus, it seems likely that the combined treatment with carboplatin and paclitaxel does not change the cell proliferation late in the treatment course even though the therapy reduces the tumor growth. Carboplatin and paclitaxel were administered by injection on day 0 and 5. PET imaging was performed on day 4 and 8 and thus tracer uptake was measured on day 4 after the 1st and on day 3 after the 2nd administration of chemotherapy. This may suggest that the treatment does decrease cell proliferation for less than 3 days and this is the reason why no difference in cell proliferation was observed on day 4 and 8 because the tumor cells has started to re-proliferate. Further investigations are needed to determine for how long the proliferation is affected after a single injection of carboplatin and paclitaxel. Both carboplatin and paclitaxel cause cell cycle arrest in the G2/M phase. Phosphorylation of FLT by TK1 is assumed to be the limiting factor for FLT uptake and activity of TK1 is correlated with FLT uptake. TK1 is mainly expressed in the S-phase of cell cycle, therefore cell 1659286 cycle arrest later in the cell cycle might not influence uptake of FLT. The differences between cell proliferation and glucose uptake after initiation of carboplatin and paclitaxel therapy illustrates the importance of combining imaging of several physiological processes in order to analyze the biological effect of cancer treatment. Carboplatin and paclitaxel treatment induced significant decreases in FDG uptake after day 4 and onwards but was less effective in reducing tumor cell proliferation as measured by FLT. However FLT was an earlier marker than FDG, although transient. Also this underscores the importance of optimal timing between treatment and FLT or FDG imaging since treatment response may otherwise be overlooked. Thus, in 23584186 order to find an imaging biomarker that potentially could be predictive for treatment outcome in future clinical studies different imaging biomarkers, giving information of different physiological processes, need to be evaluated. One of the main limitations of the present study was that a limited number of animals were included in each group. This could be the reason that several of the measurements did not reach statistical significance due to type II error. Furthermore does the present study describe treatment response monitoring in human xenograft tumors in nude mice. Although the tumors are of human origin, the non-human host environment may cause that results acquired in this pre-clinical model not necessarily can be translated into clinical studies. Another limitation of the study was 
that the molecular markers were measured on the gene expression level and it is therefore unknown whether or not the gene expression levels are a refle
