Once tumor volume reached approximately a mean of mm, treatment was initiated.Ritonavir again significantly enhanced the ability of to decrease tumor size. We measured apoptosis of DU tumor cells using terminal deoxynucleotidyl transferasemediated nick end labeling assay.Conversely, docetaxel induced of DU cells to become TUNEL positive.At the end of this experiment, we sacrificed the mice, removed their tumors, extracted RNA, and measured levels of CYPA by realtime PCR.At hours before sacrifice, either docetaxel or ritonavir alone or in combination was administered to the mice.We also extracted nuclear protein from tumors and explored the effect of ritonavir on NFB DNA binding activity. Control tumors possessed measurable NFB DNA binding activity, and ritonavir inhibited this activity by. These results were consistent with those obtained from the in vitro studies. DU cells were injected bilaterally subcutaneously into BNX mice, forming two tumorsmouse.C, effect of ritonavir on docetaxelinduced expression of CYPA transcripts in vivo.After hours of drug administration, tumors were removed, RNA was extracted, and cDNA was synthesized.After hours of drug administration, tumors were removed, and nuclear protein was extracted and subjected to ELISA to measure NFB DNA binding activity.Thus, ritonavir probably protected docetaxel from inactivation in DU cells, resulting in increased intracellular levels and enhanced antitumor effects.Xenobiotics, including anticancer drugs such as docetaxel, bind to steroid and xenobiotic receptor.Ligandactivated steroid and xenobiotic receptor forms heterodimer with retinoid X receptor and binds to the promoter region of the CYPA gene and activates its transcription. Recent studies showed that coregulators, including silencing mediator for retinoid and thyroid receptor and steroid receptor coactivator, mediated basal and xenobioticinduced transcriptional activity of CYPA. The investigators found that the antifungal agent ketoconazole inhibited corticosteroneinduced CYPA transcriptional activity by interacting with these coregulators. Ritonavir may block docetaxelinduced expression of CYPA by also affecting these coregulators.Further studies clearly will be needed to elucidate molecular mechanism by which ritonavir inhibits docetaxelinduced expression of CYPA.Pgp is an integral plasma membrane protein encoded by the multidrugresistant. It is an energydependent efflux pump for a wide variety of compounds, including anticancer drugs such as docetaxel. Our preliminary studies showed that ritonavir enhanced the ability of docetaxel to decrease the growth of these cells. This was associated with growth arrest and apoptosis of these cells.Cancer cells including prostate cancer often have hyperactivity of the NFB pathway, which can make these malignant cells relatively resistant to chemotherapy. In this study, we have found that DU cells possessed strong NFB DNA binding activity, and ritonavir decreased this activity in vitro. This also may contribute to the increased cytotoxicity of the combination of ritonavir and docetaxel.Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from cancerres.aacrjournals.org on April. American Association for Cancer Research. Activation of PKCB has now also been implicated in tumor cell proliferation, apoptosis, and tumor invasiveness.Enzastaurin treatment also suppresses GSKB phosphorylation to a similar extent in peripheral blood mononuclear cells from these DPPC treated mice.PKC activation also contributes to tumor cell survival and proliferation and has been repeatedly implicated in the malignant progression of human cancers, notably B cell lymphomas.