Cyclo-oxygenase-2 (Cox-2) expression and resistance to platinum versus platinum/paclitaxel containing chemotherapy in advanced ovarian cancer

BACKGROUND: Cyclo-oxygenase-2 (COX-2), the key enzyme in the conversion of arachidonic acid to prostaglandins, is involved in critical steps of tumor onset and progression, and is a strong predictor of chemotherapy resistance and poor outcome in advanced ovarian cancer. To our knowledge, no data has been reported until now about the association between COX-2 status and response to different chemotherapy regimens. METHODS: A retrospective study was performed to investigate the association of COX-2 with outcome and response to platinum versus platinum/paclitaxel in 68 primary ovarian cancer. COX-2 immunoreaction was performed on paraffin-embedded sections by using rabbit polyclonal antiserum against COX-2. RESULTS: In the overall series, COX-2 positivity was found in a statistically significant higher percentage of not responding cases than in patients responding to chemotherapy (n = 15/21; 71.4% versus n = 17/47; 36.1%; p value = 0.0072). A higher percentage of COX-2 positivity was found in patients unresponsive (n = 11/13; 84.6%) versus patients responsive to platinum-based chemotherapy (n = 9/26; 34.6%). In cases administered platinum/paclitaxel, COX-2 positivity was found in 4 out of 8 (50%) of un responsive versus 8 out of 21 (38.1%) of responsive cases. Logistic regression analysis of parameters likely to affect response to treatment resulted in a p value = 0.17 for the interaction COX-2/type of treatment. CONCLUSION: Although these findings need to be confirmed in a larger series, our study suggests a possible indication that there is a difference in the influence of COX-2 on response depending on treatment regimen

Human parathyroid hormone-related protein and human parathyroid hormone receptor type 1 are expressed in human medulloblastomas and regulate cell proliferation and apoptosis in medulloblastoma-derived cell lines

Human parathyroid hormone-related protein (hPTHrP), identified in patients with paraneoplastic hypercalcemia and expressed by different cell types during development and adult life, plays important roles in many human neoplasms. Immunohistochemical and RT-PCR analyses of hPTHrP and human parathyroid hormone receptor type 1 (PTHR-1) in primary medulloblastoma confirmed their expression in both classic and desmoplastic variants at RNA and protein levels. To evaluate the functional role of hPTHrP, DAOY and D283 medulloblastoma and U87MG glioma cells, expressing high levels of hPTHrP and PTHR-1, were treated with anti-sense oligonucleotides for hPTHrP. Anti-sense treatment produced in all cell lines a decrease of cell proliferation and clonogenic activity and an increase of apoptosis, while addition of exogenous hPTHrP (1-37) prevented these effects. Anti-sense induced the increase of Caspase-3, Fas (CD95) mRNAs and Bax/Bcl-2 mRNA ratio after 12 h of cell treatment. Exogenous hPTHrP (1-37) increased intracellular Ca2+ concentration in DAOY cells as revealed by FURA. Anti-sense treated cells showed a significant decrease of steady-state levels of intracellular Ca2+, which was reverted by addition of exogenous hPTHrP (1-37). This study indicates that hPTHrP and PTHR-1 are expressed in medulloblastoma and could promote tumor growth, protecting cells from apoptosis

The combination of quercetin and cytosine arabinoside synergistically inhibits leukemic cell growth.

It has been demonstrated that quercetin (3,3',4',5,7-pentahydroxyflavone) inhibits the growth of several cancer cell lines and that the antiproliferative activity of this substance is probably mediated through a binding interaction with type II estrogen binding sites (type II EBS). The effect of quercetin and cytosine arabinoside (Ara-C) alone or in combination, was tested on HL-60 cell growth. Quercetin significantly synergized the inhibitory activity of Ara-C on HL-60 cell growth while rutin, the 3-rhamnosylglucoside of quercetin, neither competed with [3H]estradiol for type II EBS nor was effective alone or in combination with Ara-C. Based on these results, we studied by a clonogenic assay the effect of quercetin and Ara-C alone and in combination on colony formation by human leukemic cells (CFU-L). In all cases both drugs exhibited a dose-related inhibition of CFU-L in a range of concentrations between 10 nM and 10 microM and 0.01 nM and 10 microM for quercetin and Ara-C, respectively. The combination of the two drugs resulted in a synergistic inhibitory activity on CFU-L. Considering that plasma concentrations of quercetin effective in vitro were obtained in vivo without any apparent side effects, we conclude that this report represents further experimental evidence that quercetin could be used in the treatment of acute leukemias