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Combination Effect (combination + effect)
Selected AbstractsCombination effect of AC-7700, a novel combretastatin A-4 derivative, and cisplatin against murine and human tumors in vivoCANCER SCIENCE, Issue 2 2003Yoshihiro Morinaga The in vivo combination effect of AC-7700, a novel combretastatin A-4 derivative, and cisplatin (CDDP) was examined. The combination of AC-7700 and CDDP increased antitumor activity against murine colon 26 tumor in mice and cured the mice. This combination effect was found over wide dosage ranges of AC-7700 (20,80 mg/kg) and CDDP (2.5,5 mg/kg). Moreover, this combination augmented antitumor activity against murine S180 and M109 tumors, and human LX-1 and LS180 tumor xenografts in mice. The effect was the strongest when AC-7700 and CDDP were administered simultaneously. To study this combination effect we measured the concentrations of CDDP in tumors, plasma and kidneys of the mice with colon 26 tumor. In the combination with AC-7700, the concentration of CDDP in the tumors increased from 0.5 to 96 h after administration, but did not change or decrease in plasma or kidneys. Against human LS180 xenografts in mice, the combination similarly increased the concentration of CDDP in the tumors. These results suggest that AC-7700 may specifically augment the accumulation of CDDP in tumors, and thus has the potential to be useful in combination chemotherapy with CDDP. (Cancer Sci 2003; 94: 200,204) [source] ERK inhibitor PD98059 enhances docetaxel-induced apoptosis of androgen-independent human prostate cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2003Stanislav Zelivianski Abstract Anticancer drugs docetaxel and vinorelbine suppress cell growth by altering microtubule assembly and activating the proapoptotic signal pathway. Vinorelbine and docetaxel have been approved for treating several advanced cancers. However, their efficacy in the management of advanced hormone-refractory prostate cancer remains to be clarified. Microtubule damage by some anticancer drugs can activate the ERK survival pathway, which conversely compromises chemotherapeutic efficacy. We analyzed the effect of ERK inhibitors PD98059 and U0126 on vinorelbine- and docetaxel-induced cell growth suppression of androgen-independent prostate cancer cells. In androgen-independent C-81 LNCaP cells, inhibition of ERK by PD98059, but not U0126, plus docetaxel resulted in enhanced growth suppression by an additional 20% compared to the sum of each agent alone (p < 0.02). The combination treatment of docetaxel plus PD98059 also increased cellular apoptosis, which was in part due to the inactivation of Bcl-2 by increasing phosphorylated Bcl-2 by more than 6-fold and Bax expression by 3-fold over each agent alone. At these dosages, docetaxel alone caused only marginal phosphorylation of Bcl-2 (10%). Docetaxel plus U0126 had only 20% added effect on Bcl-2 phosphorylation compared to docetaxel alone. Nevertheless, both U0126 and PD98059 exhibited an enhanced effect on docetaxel-induced growth suppression in PC-3 cells. No enhanced effect was observed for vinorelbine plus PD98059 or U0126. Thus, the combination therapy of docetaxel plus PD98059 may represent a new anticancer strategy, requiring lower drug dosages compared to docetaxel monotherapy. This may lower the cytotoxicity and enhance tumor suppression in vivo. This finding of a combination effect could be of potential clinical importance in treating hormone-refractory prostate cancer. © 2003 Wiley-Liss, Inc. [source] Induction of umbilical cord blood,derived ,2m,c-Met+ cells into hepatocyte-like cells by coculture with CFSC/HGF cellsLIVER TRANSPLANTATION, Issue 6 2005Yunfang Wang Several studies have indicated that adult stem cells derived from bone marrow (BM) and cord blood (CB) can differentiate into hepatocyte-like cells. This ability is important for the treatment of hepatic diseases with BM or CB as a potential approach. However, methods are still being developed for the efficient induction of stem cell differentiation and expansion to get enough cells to be useful. In the present study, we enriched a subset of umbilical cord blood ,2m,c-Met+ cells (UCBCCs) and investigated the combination effect of liver nonparenchymal cells (cirrhotic fat-storing cells [CFSCs]) and hepatocyte growth factor (HGF) on the induction of UCBCCs into hepatocyte-like cells. UCBCCs were cocultured with CFSC/HGF feeder layers either directly or separately using insert wells. Flow cytometric analysis showed that most UCBCCs were CD34+/,CD90+/,CD49f+CD29+Alb+AFP+. After cocultured with transgenic feeder layers for 7 days, UCBCCs displayed some morphologic characteristics of hepatocytes. Reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence cell staining proved that the induced UCBCCs expressed several hepatocyte specific genes including AFP, Alb, CYP1B1 and cytokeratins CK18 and CK19. Furthermore, the induced cells displayed liver specific functions of indocyanine green (ICG) uptake, ammonium metabolism and albumin secretion. Hence, our data have demonstrated that UCBCCs might represent a novel subpopulation of CB-derived stem/progenitor cells capable of successful differentiation into hepatocyte-like cells when incubated with CFSC/HGF cells. In conclusion, not only HGF but also CFSCs and/or the secreted extracellular matrix (ECM) have been shown to be able to serve as essential microenvironment for hepatocyte differentiation. (Liver Transpl 2005;11:635,643.) [source] Thermal evolution of a rotating strange star in the colour superconductivity phaseMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 4 2006Xiaoping Zheng ABSTRACT Under the combination effect of recommencement heating due to the spin-down of strange stars (SSs) and heat preservation due to the weak conduction heat of the crust, Cooper pair breaking and formation (PBF) in colour superconducting quark matter arises. We investigate the cooling of SSs with a crust in the colour superconductivity phase including both deconfinement heating (DH) and the PBF process. We find that DH can delay the thermal evolution of SSs and the PBF process suppresses the early temperature rise of the stars. The cooling SSs behave within the brightness constraint of young compact objects when the colour superconductivity gap is small enough. [source] New potential anti-cancer agents synergize with bortezomib and ABT-737 against prostate cancerTHE PROSTATE, Issue 8 2010Bulbul Pandit Abstract BACKGROUND We previously described the identification of a transcriptional inhibitor ARC and FoxM1 inhibitors, thiazole antibiotics, Siomycin A and thiostrepton that were able to induce potent p53-independent apoptosis in cancer cell lines of different origin. Here, we report the characterization of these drugs individually or in combination with ABT-737 and bortezomib on a panel of prostate cancer cell lines. METHODS DU 145, LNCaP and PC-3 prostate cancer cells were treated with ARC, Siomycin A and thiostrepton to evaluate their activity as single agents or in combination with ABT-737 and bortezomib to measure their synergistic potential in anti-proliferative and cell cycle assays. Chou-Talalay method was used to quantitate the synergistic interaction. Western blot method was used to determine Mcl-1 and FoxM1 expression and caspase-3 cleavage. RESULTS We show that ARC inhibited the viability of prostate cancer cells and induced apoptosis in low nanomolar concentration. It potently downregulated the expression of Mcl-1 and showed synergistic combination effect with Bcl-2 inhibitor ABT-737. Thiazole antibiotics, Siomycin A and thiostrepton inhibited growth, FoxM1 expression and induced cell death in prostate cancer cells in low micromolar concentrations. In addition, thiostrepton and ARC synergistically induced apoptosis in prostate cancer cells following combination treatment with proteasome inhibitor bortezomib. Furthermore, we found that all tested drug combinations were able to induce apoptosis selectively in transformed, but not normal cells of the same origin. CONCLUSIONS Based on their in vitro activity as single or combination agents, ARC, Siomycin A and thiostrepton represent potential candidates for drug development against prostate cancer. Prostate 70: 825,833, 2010. © 2010 Wiley-Liss, Inc. [source] Tumor blood flow interruption after radiotherapy strongly inhibits tumor regrowthCANCER SCIENCE, Issue 7 2008Katsuyoshi Hori To clarify the therapeutic significance of interrupting tumor blood flow after irradiation, we investigated X-irradiation-induced changes in hemodynamic parameters (blood flow, extravasation and washout of fluorescein isothiocyanate-dextran, and interstitial fluid pressure) in a variant of Yoshida sarcoma, LY80. Tumors in anesthetized male Donryu rats received local irradiation (10 Gy). At 48 h after irradiation, tumor blood flow increased significantly; at 72,96 h after irradiation, a 2,2.5-fold increase was observed. All parameters then consistently showed improved tumor microcirculation, which probably contributed to regrowth of cancer because certain cells survived irradiation. Rats received an intravenous dose (10 mg/kg) of a combretastatin derivative, AC7700 (AVE8062), which interrupts tumor blood flow and disrupts tumor vessels. At all times evaluated after irradiation, AC7700 completely stopped tumor blood flow. Radiotherapy efficacy was significantly enhanced when combined with AC7700: AC7700 given 48 h after irradiation, when tumor blood flow increased significantly, remarkably suppressed tumor regrowth compared with AC7700 given 48 h before irradiation. Also, postirradiation AC7700 completely inhibited not only primary tumor regrowth but also regional lymph node metastases in half of tumor-bearing rats and led to a significant improvement in survival. These results strongly suggest that the combination effect was enhanced via interruption of increased tumor blood flow after irradiation. This therapeutic combination and timing may have important benefits, even in tumors with low sensitivity to either treatment alone, because the effect was considerably greater than additive. Our data thus show that destruction of tumor microcirculation after irradiation is quite effective for preventing cancer recurrence. (Cancer Sci 2008; 99: 1485,1491) [source] | ||||||||||