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1.
Li Zhao Zhen Chen Jun Wang Li Yang Qing Zhao Jia Wang Qi Qi Rong Mu Qi-Dong You Qing-Long Guo 《Cancer chemotherapy and pharmacology》2010,65(3):481-489
Aim
To investigate the synergistic inhibitory effects of the combination of 5-fluorouracil (5-FU) with the natural flavanoid oroxylin A on human hepatocellular carcinoma cells HepG2 in vitro and on transplanted murine hepatoma 22 (H22) tumors in vivo and the preliminary mechanisms.Methods
The inhibitory effects of 5-FU combined with the natural flavanoid oroxylin A in vitro were detected by MTT assay and the effects in vivo were investigated by transplanted H22 mice model. DAPI staining and Annexin V/propidium iodide (PI) double staining were used to detect the cell morphological changes and apoptosis. The mRNA levels of thymidine synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in HepG2 cells after oroxylin A and 5-FU combination treatment were observed by quantitative real-time PCR. Western blotting assay was used to reveal the expressions of apoptotic-inducing proteins P53, cleaved PARP, COX-2, Bcl-2, and pro-caspase3.Results
Oroxylin A in combination with 5-FU presented synergistic effect (CI < 1) on HepG2 cells in vitro when the inhibitory rate was higher than 7.5%. The inhibitory rate on H22 murine solid tumor in vivo in the combination group was higher than monotherapy. 5-FU combined with oroxylin A exerted stronger apoptotic induction in HepG2 cells than either single drug treatment. Quantitative real-time PCR discovered the downregulation of TS mRNA and DPD mRNA in HepG2 cells after combination treatment. Western blotting assay revealed oroxylin A enhanced 5-FU-induced apoptosis in HepG2 cells by elevating the expressions of apoptotic-inducing proteins P53 and cleaved PARP and decreasing the expression of apoptotic-inhibitory proteins COX-2, Bcl-2, and pro-caspase3.Conclusion
The anti-hepatocellular carcinoma effects in vitro and in vivo of 5-FU and oroxylin A combinations were synergistic and oroxylin A increased the sensitivity of HepG2 cells to 5-FU by modulating the metabolic enzymes of 5-FU and apoptotic-related proteins. 相似文献2.
Sunjoo Ahn Dong Jin Hwang Christina M. Barrett Jun Yang Charles B. Duke III Duane D. Miller James T. Dalton 《Cancer chemotherapy and pharmacology》2011,67(2):293-304
Purpose
Microtubules are one of the most useful subcellular targets in chemotherapy. We identified a novel indole, (3-(1H-indol-2-yl)phenyl)(1H-indol-2-yl)methanone (15), that inhibits tubulin action and exhibits potent antitumor activity in various preclinical models.Methods
In vitro cancer cell growth inhibition was measured by SRB or MTT assay in human cancer cell lines. Apoptosis induced by 15 was examined in LNCaP and PC-3 cells. Effects of 15 on cell cycle distribution and tubulin were investigated via in vitro models. In vivo toxicity and xenograft efficacy studies were conducted in mice.Results
Indole 15 inhibited the in vitro growth of a number of human cancer cell lines, including drug-resistant cell lines that over-express P-glycoprotein, multidrug resistance-associated proteins, and breast cancer resistance protein with IC50 values in the range of 34?C162?nM. Nanomolar concentrations of the compound caused down-regulation of bcl-2, induced PARP cleavage, and induced apoptosis in both LNCaP and PC-3 prostate cancer cells, as confirmed by anti-histone ELISA and DNA laddering. In vitro studies revealed that the compound inhibited polymerization of purified tubulin and induced a strong and concentration-dependent G2M arrest in PC-3 cells. In vivo studies in immunodeficient mice bearing PC-3 tumor xenografts showed that the compound effectively inhibited tumor growth.Conclusions
The potent in vitro and in vivo antitumor activities of this novel indole suggest that drugs with this novel chemical scaffold might be developed for treatment of drug-resistant prostate cancer. 相似文献3.
Andrea Réti Éva Pap Vilmos Adleff András Jeney Judit Kralovánszky Barna Budai 《Cancer chemotherapy and pharmacology》2010,66(2):219-227
Purpose
To prove that 5-FU cytotoxicity could be increased by combination with low-dose non-steroidal anti-inflammatory drugs (NSAIDs) (indomethacin or NS-398) in high cyclooxygenase-2- (COX-2) expressing cells and xenografts through the modulation of dihydropyrimidine dehydrogenase (DPD) mRNA expression and/or enzyme activity.Methods
HT-29 cells were grown on collagen IV coated plates (HT-29-C). The antiproliferative effect of 5-fluorouracil (5-FU) ± NSAIDs was examined on non-COX-2 expressing HT-29 and COX-2-expressing HT-29-C cells by sulphorhodamine B assay. The COX-2 and DPD expressions were visualized by immunofluorescent staining, and prostaglandin E2 levels were measured by ELISA kit. The HT-29 xenograft was established in SCID mice and treated with 5-FU ± NSAIDs for 5 days. The tumor volume, enzyme activity, and DPD mRNA expression were investigated by caliper, radioenzymatic method, and real-time RT-PCR, respectively. The drug interaction was calculated for both combinations (5-FU + indomethacin and 5-FU + NS-398).Results
Collagen IV up-regulated significantly the COX-2 and DPD mRNA, and protein expressions, and also their enzyme activities in HT-29 cells. NSAIDs enhanced in a synergistic manner the cytotoxic effect of 5-FU treatment both in vitro and in vivo. Downregulation of DPD was observed after 5-FU monotherapy, but the combined effect of NSAIDs and 5-FU on DPD mRNA expression, and enzyme activity was superior to the effect of 5-FU alone.Conclusions
Since 5-FU + NSAID treatment can alter the DPD enzyme activity resulting in an enhanced cytotoxic effect, further studies in clinical practice are warranted. 相似文献4.
Junichi Kurebayashi Mamoru Nukatsuka Hiroshi Sonoo Junji Uchida Mamoru Kiniwa 《Cancer chemotherapy and pharmacology》2010,65(2):219-225
Purpose
Our previous study indicated that concurrent administration of 4-OH-tamoxifen (TAM) and 5-fluorouracil (5-FU), but not doxorubicin (Dox), resulted in additive antitumor effects on endocrine-responsive breast cancer cells. We further clarified the effects of combined administration of endocrine therapy with chemotherapeutic agents in this study.Methods
Concurrent treatment with 4-OH-TAM and paclitaxel (Ptx) was investigated in estrogen receptor (ER)-positive breast cancer cells. Additionally, the combined effects of estrogen depletion from culture medium mimicking estrogen ablative therapy with 5-FU, Dox, and Ptx were investigated.Results
Concurrent treatment with 4-OH-TAM and Ptx yielded less than additive antitumor effects in ER-positive breast cancer cells, as observed with Dox in our previous study. More interestingly, estrogen depletion with 5-FU, but with neither Dox nor Ptx, yielded additive antitumor effects on these cells. We also performed preliminary experiments to elucidate the mechanisms of action responsible for the combined antitumor effects observed. Ptx up-regulated the level of expression of one of the molecules related to TAM resistance, Eph-A2, as observed with Dox in our previous study. Estrogen depletion down-regulated the level of expression of one of the molecules related to 5-FU resistance, thymidylate synthase, as observed with 4-OH-TAM in our previous study.Conclusions
These findings, together with those of our previous study, suggest that concurrent treatment with endocrine therapy, administration of TAM, or estrogen ablative therapy and 5-FU but neither Dox nor Ptx may yield additive antitumor effects on endocrine-responsive breast cancer. 相似文献5.
Xiaofan Zhang Julia Li Zhong Wei Liu Zuhua Gao Xia Xue Pan Yue Limei Wang Cuirong Zhao Wenfang Xu Xianjun Qu 《Cancer chemotherapy and pharmacology》2010,66(1):11-19
Purpose
N3-o-toluyl-fluorouracil (TFU), the prodrug of 5-fluorouracil (5-FU), is the metabolite of N1-acetyl-N3-o-toluyl-fluorouracil (atofluding). In the present study, we aimed to evaluate the efficacy of TFU on the inhibition of human hepatocellular carcinoma cells via sustained release of 5-FU. The metabolism of TFU underlying the inhibitory effect was also analyzed.Methods
In vitro assays, inhibition of cell growth by TFU was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide method. The levels of TFU and 5-FU in the cell culture supernatant fluid were measured by high-performance liquid chromatography (HPLC). In vivo assays, the efficacy of TFU was evaluated in a human hepatocellular carcinoma xenograft mice model after 3 weeks of oral administration. The distributions of TFU and 5-FU in plasma and homogenate tissues including liver, lung and tumor were determined by HPLC.Results
N3-o-toluyl-fluorouracil weakly inhibited the proliferation of SMMC-7721 and PLC/PRF/5 cells in the absence of liver microsomal enzymes. In contrast, the inhibition rates were significantly increased in the presence of these enzymes. HPLC results revealed that TFU was metabolized slowly by liver microsomal enzymes and therefore the concentration of 5-FU was gradually increased with a longer retention time in cell culture supernatant fluid. The efficacy of TFU was confirmed in SMMC-7721 xenografts in Balb/c athymic (nu+/nu+) mice model. TFU treatment induced inhibition of SMMC-7721 growth with few side effects. HPLC results showed that high levels of TFU were still in liver 48 h after the end of oral administration, implying that TFU preferentially accumulated in liver with slow conversion to 5-FU by enzymes. This led to a long-lasting concentration of 5-FU in plasma. Further, a high level of 5-FU was found in tumors with a relatively low level in lungs. These results suggest that the metabolite of TFU was preferentially converted or taken up by tumor cells. The distributions of 5-FU may contribute to its high anti-tumor activity and low adverse reactions in vivo.Conclusion
These results demonstrate that TFU is a promising prodrug of 5-FU for cancer treatment via sustained release of 5-FU in liver. 相似文献6.
Masanori Terashima Hisataka Fujiwara Akinori Takagane Kaoru Abe Takashi Irinoda Tsutomu Nakaya Hitoshi Yonezawa Kenichi Oyama Kazuyoshi Saito Norio Kanzaki Satoshi Ohtani Tsuyoshi Nemoto Yutaka Hoshino Michihiko Kogure Mitsukazu Gotoh 《Gastric cancer》2003,6(1):71-81
Background
This study was designed to investigate the role of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) in tumor progression and sensitivity to 5-fluorouracil (5-FU).Methods
A total of 275 tumor samples from 275 patients with gastric cancer were utilized in this study. TS activity was determined in 130 samples by 5-fluorodeoxyuridine monophosphate binding assay. DPD activity was measured in 140 samples by radioenzymatic assay, and TP protein level was determined in 157 samples by an enzyme-linked immunosorbent assay (ELISA) system. These parameters were compared with several clinicopathologic factors and sensitivity to 5-FU determined by in-vitro ATP assay. The antitumor activities of 5-FU, uracil plus tegafur (UFT), and 1?M tegafur — 0.4?M 5-chloro-2,4-dihydroxypyridine — 1?M potassium oxonate (S-1 [TS-1®]) were also compared, using three human gastric cancer xenografts in nude mice.Results
There was no correlation between either TS or TP and sensitivity to 5-FU. However, a weak inverse correlation was found between DPD activity and sensitivity to 5-FU. High DPD activity in tumor resulted in poor prognosis, especially in patients who received 5-FU-based adjuvant chemotherapy. Although TP was significantly correlated with depth of tumor invasion and with lymphatic and venous invasions, TP alone had no impact on survival. On the other hand, TS, as well as peritoneal, hepatic, and lymph node metastases, was selected as an independent prognostic factor in gastric cancer. In the animal model, there was no significant difference in antitumor activities among the drugs in a tumor with low DPD activity. However, S-1 showed superior antitumor activity to 5-FU or UFT in tumors with high DPD activity.Conclusion
DPD is considered to be a most important predictive factor of 5-FU sensitivity. The use of DPD inhibitory fluoropyrimidines is strongly recommended for tumors with high DPD activity.7.
Sheng-hua Zhang Hao Zhang Hong-wei He Liang Li Xing-qi Li Yi-ping Zhang Rong-guang Shao 《Cancer chemotherapy and pharmacology》2013,72(4):777-788
Purpose
Capecitabine (CAP), a prodrug, needs to be converted to 5-fluorouracil by several key enzymes, including thymidine phosphorylase (TP). To improve the therapeutic index, potentiation of antitumor activity of CAP is required. In this study, we explored whether lidamycin (LDM), an enediyne anticancer antibiotic, can induce synergistic antitumor effects in combination with CAP in murine breast cancer in vitro and in vivo.Methods
Using MTT, cell migration and invasion, siRNA knockdown, and Western blot assays, the in vitro synergistic effects of LDM plus CAP on 4T1LUC cells were evaluated, and the mechanism of this synergy was explored. For in vivo model of orthotopic implantation model of 4T1LUC cells, optical molecular imaging system was utilized to evaluate the growth of primary tumor and metastasis. To further understand the mechanism of action of the LDM/CAP combination, immunohistochemistry analysis was carried out to detect thymidine phosphorylase induction and ERK signaling.Results
As determined by MTT and transwell assay, LDM enhanced the inhibitory effects of CAP on cancer cell proliferation, migration, and invasion. Western blot showed that this synergistic effect was attributed to the up-regulated expression of TP induced by LDM. Knocking down TP impaired the synergistic anti-proliferative effect of LDM and CAP. Furthermore, our data suggested that LDM-induced up-regulation of TP both in vitro and in vivo is associated with ERK activation, because the inhibition of ERK activity by ERK inhibitor U0126 abrogated LDM-induced TP up-regulation. In animal models, LDM plus CAP potently inhibited primary tumor growth as well as lung metastasis compared with control or single-agent-treated group.Conclusions
LDM can potentiate the antitumor effects of CAP on breast cancer line. The synergistic effects suggest that the combination of LDM and CAP is an innovative antitumor strategy for breast cancer therapy. 相似文献8.
Wei-Hua Hao Jong-Jing Wang Shu-Ping Hsueh Pei-Jing Hsu Li-Chien Chang Chang-Shan Hsu Kuang-Yang Hsu 《Cancer chemotherapy and pharmacology》2013,71(2):379-388
Purpose
The chemotherapy agent gemcitabine is currently administered intravenously because the drug has poor oral bioavailability. In order to assess the pharmacokinetics and antitumor activity of D07001-F4, a new self-microemulsifying oral drug delivery system preparation of gemcitabine, this study was performed to compare the effect of D07001-F4 with administered gemcitabine in vitro and in vivo.Methods
D07001-F4 pharmacokinetics was examined by evaluation of in vitro deamination of D07001-F4 and gemcitabine hydrochloride by recombinant human cytidine deaminase (rhCDA) and in vivo evaluation of D07001-F4 pharmacokinetics in mice. Antitumor activity was evaluated by comparing the effect of D07001-F4 and gemcitabine hydrochloride in inhibiting growth in nine cancer cell lines and by examining the effect of D07001-F4 and gemcitabine in two xenograft tumor models in mice.Results
In vitro deamination of D07001-F4 by rhCDA was 3.3-fold slower than deamination of gemcitabine hydrochloride. Growth inhibition by D07001-F4 of 7 of the 8 cancer cell lines was increased compared with that seen with gemcitabine hydrochloride, and D07001-F4 inhibited the growth of pancreatic and colon cancer xenografts. In vivo pharmacokinetics showed the oral bioavailability of D07001-F4 to be 34 %.Conclusions
D07001-F4 was effective against several cancer types, was metabolized more slowly than gemcitabine hydrochloride, and exhibited enhanced oral bioavailability. 相似文献9.
Pradip De Nandini Dey Breanne Terakedis P. Leif Bergsagel Zhi Hua Li Daruka Mahadevan Joseph R. Garlich Suzanne Trudel Milan T. Makale Donald L. Durden 《Cancer chemotherapy and pharmacology》2013,71(4):867-881
Purpose
Multiple reports point to an important role for the phosphoinositide-3 kinase (PI3K) and AKT signaling pathways in tumor survival and chemoresistance in multiple myeloma (MM). The goals of our study were: (1) to generate the preclinical results necessary to justify a Phase I clinical trial of SF1126 in hematopoietic malignancies including MM and (2) to begin combining pan-PI3K inhibitors with other agents to augment antitumor activity of this class of agent in preparation for combination therapy in Phase I/II trials.Methods
We determined the in vitro activity of SF1126 with 16 human MM cell lines. In vivo tumor growth suppression was determined with human myeloma (MM.1R) xenografts in athymic mice. In addition, we provide evidence that SF1126 has pharmacodynamic activity in the treatment of patients with MM.Results
SF1126 was cytotoxic to all tested MM lines, and potency was augmented by the addition of bortezomib. SF1126 affected MM.1R cell line signaling in vitro, inhibiting phospho-AKT, phospho-ERK, and the hypoxic stabilization of HIF1α. Tumor growth was 94 % inhibited, with a marked decrease in both cellular proliferation (PCNA immunostaining) and angiogenesis (tumor microvessel density via CD31 immunostaining). Our clinical results demonstrate pharmacodynamic knockdown of p-AKT in primary patient-derived MM tumor cells in vivo.Conclusions
Our results establish three important points: (1) SF1126, a pan-PI3K inhibitor has potent antitumor activity against MM in vitro and in vivo, (2) SF1126 displays augmented antimyeloma activity when combined with proteasome inhibitor, bortezomib/Velcade®, and (3) SF1126 blocks the IGF-1-induced activation of AKT in primary MM tumor cells isolated from SF1126-treated patients The results support the ongoing early Phase I clinical trial in MM and suggest a future Phase I trial in combination with bortezomib in hematopoietic malignancies. 相似文献10.
Introduction
It has been reported that a local injection of 5-fluorouracil (5-FU) administered endoscopically can have a favorable result in patients with early gastric cancer.Methods
We report the application of a local injection of 5-FU administered endoscopically in three patients with advanced gastric cancer (AGC) who refused or were not suitable for surgery or systemic chemotherapy. The benefits of locally applied endoscopic chemotherapy (EC) with 5-FU as an alternative therapy were evaluated.Results
Good tolerance with an important reduction of the tumor size and no adverse reactions was observed in all three patients.Conclusion
EC with 5-FU is a feasible technique that can be applied in a certain group of patients with AGC. Further studies will be required to corroborate these results. 相似文献11.
Allison Pledgie-Tracy Madhavi Billam Amy Hacker Michele D. Sobolewski Patrick M. Woster Zhe Zhang Robert A. Casero Nancy E. Davidson 《Cancer chemotherapy and pharmacology》2010,65(6):1067-1081
Introduction
Polyamine analogues have demonstrated significant activity against human breast cancer cell lines as single agents as well as in combination with other cytotoxic drugs. This study evaluates the ability of a polyamine analogue N 1,N 11-bis(ethyl)norspermine (BENSpm) to synergize with six standard chemotherapeutic agents, 5-fluorouracil (FU), fluorodeoxyuridine, cis-diaminechloroplatinum(II) (C-DDP), paclitaxel, docetaxel, and vinorelbine.Materials and methods
Four human breast cancer cell lines (MDA-MB-231, MCF-7, Hs578t, and T47D) and one immortalized, non-tumorigenic mammary epithelial cell line (MCF-10A) were used for in vitro combination studies with BENSpm and cytotoxic drugs. Xenograft mice models generated with MDA-MB-231 cells were used for in vivo studies with BENSpm and paclitaxel.Results and conclusion
BENSpm exhibited synergistic inhibitory effect on cell proliferation in combination with 5-FU or paclitaxel in human breast cancer cell lines (MDA-MB-231 and MCF-7) and was either antagonistic or less effective in the non-tumorigenic MCF-10A cell line. Synergism was highest with 120 h concomitant treatment or pre-treatment with BENSpm for 24 h followed by concomitant treatment for 96 additional hours. Since the cytotoxic effects of many polyamine analogues and cytotoxic agents are believed to act, in part, through induction of the polyamine catabolic enzymes SSAT and SMO, the role of these enzymes on synergistic response was evaluated in MDA-MB-231 and MCF-7 treated with BENSpm and 5-FU or paclitaxel. Combination treatments of BENSpm with 5-FU or paclitaxel resulted in induction of SSAT mRNA and activity in both cell lines compared to either drug alone, while SMO mRNA and activity were increased only in MDA-MB-231 cells. Induction was greater with BENSpm/paclitaxel combination than BENSpm/5-FU. Further, RNAi studies demonstrated that both SSAT and SMO play a significant role in the response of MDA-MB-231 cells to treatment with BENSpm and 5-FU or paclitaxel. In MCF-7 cells, only SSAT appears to be involved in the response to these treatments. In an effort to translate combination studies from in vitro to in vivo, and to form a basis for clinical setting, the in vivo therapeutic efficacy of BENSpm alone and in combination with paclitaxel on tumor regression was evaluated in xenograft mice models generated with MDA-MB-231 cells. Intraperitoneal exposure to BENSpm or taxol singly and in combination for 4 weeks resulted in significant inhibition in tumor growth. These findings help elucidate the mechanisms involved in synergistic drug response and support combinations of polyamine analogues with chemotherapeutic agents which could potentially be used in the treatment of breast cancer. 相似文献12.
Ghada M. Suddek 《Cancer chemotherapy and pharmacology》2011,67(5):1035-1044
Purpose
Therapeutic inhibition of angiogenesis has a benefit in the treatment of neoplastic diseases. Cisplatin is a widely used anti-cancer agent; however, it has serious side effects on non-tumor cells and causes nephrotoxicity due to its reactive oxygen species?Cmediated effect. Thus, a combination between cisplatin and angiogenesis inhibitors may be useful in cancer treatment. In the present study, the effect of sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, on the antitumor activity as well as the nephrotoxic side effect of cisplatin was examined.Methods
The antitumor activity was evaluated both in vitro using cultured Ehrlich ascites carcinoma (EAC) cells and in vivo using a mouse model of solid tumor. In addition, the effect of cisplatin and/or sunitinib on the angiogenic marker, VEGF, was examined. Nephrotoxicity was induced in rats by single i.p. injection of cisplatin (6?mg/kg).Results
Sunitinib significantly potentiated the cytotoxic effect of cisplatin in vitro and in vivo. The nephrotoxicity of cisplatin was evidenced by decrease in the body weight, increase in kidney/body weight ratio and decrease in the percent survival of rats. The toxicity was also confirmed biochemically by measuring some kidney function parameters and oxidative stress markers. Sunitinib significantly decreased cisplatin-induced changes in serum creatinine, blood urea nitrogen, creatinine clearance and micro total protein in urine, renal malondialdehyde levels and reduced glutathione contents. In addition, sunitinib effectively blunted cisplatin-induced proximal and distal tubules necrosis.Conclusion
The potential for sunitinib to ameliorate the cisplatin-evoked toxicity as well as to improve the chemotherapeutic effect could have beneficial implications for patients undergoing chemotherapy with cisplatin. 相似文献13.
Zhen-Qian Wu Xiao-Dong Han Yu Wang Ke-Li Yuan Zhi-Ming Jin Jian-Zhong Di Jun Yan Ye Pan Pin Zhang Xin-Yu Huang Zhi-Gang Wang Qi Zheng 《Cancer chemotherapy and pharmacology》2011,68(1):87-96
Purpose
The aim of this study was to investigate the relationship between changes in IL-1?? expression and intestinal apoptosis after chemotherapy. And we further determine whether interleukin-1 receptor antagonist (IL-1Ra) reduces apoptosis in vivo after 5-fluorouracil (5-FU) chemotherapy in the small intestine.Methods
Intestinal mucositis was induced in mice by intraperitoneal injection of a single dose of 5-FU (200?mg/kg). IL-1Ra (1?mg/kg) was injected subcutaneously twice daily after 5-FU injection. 5-FU-induced intestinal apoptosis was detected by TUNEL assay. The expression of IL-1?? induced by 5-FU in local intestinal tissue was examined by RT-PCR and immunohistochemistry. Assessment of 5-FU-induced mucositis (histology, diarrhea scores, bowel weight) was performed. The apoptosis-related proteins were investigated by western blotting analysis. The proliferation of intestine was examined by immunohistological staining of PCNA. Viability of IEC-6 cells was determined using the CCK-8 assay. The apoptosis of IEC-6 cells was examined by Hoechst 33342 staining.Results
The variation of IL-1?? expression induced by 5-FU was in accordance with the changes in intestinal apoptosis. Administration of IL-1Ra could block the destructive effect of IL-1?? and reduce apoptosis in the small intestinal crypt after chemotherapy. The protection against apoptosis was in accordance with the reduction of the up-regulation of Bax and caspase 3 and the elimination of the down-regulation of Bcl-2 and Bcl-xL. Moreover, IL-1Ra attenuated the severity of intestinal mucositis induced by 5-FU and enhanced intestinal crypt proliferation. In vitro experiments showed that IL-1Ra suppressed apoptosis and increased cell viability in enterocyte IEC-6 cells treated with 5-FU. Additionally, IL-1Ra did not affect the chemotherapeutic effect of 5-FU in tumor CT-26 xenograft mice.Conclusions
Our studies elucidate that IL-1?? is quite possibly involved in and mediated the course of intestinal apoptosis after 5-FU chemotherapy. Administered with IL-1Ra protects mice against intestinal apoptosis induced by 5-FU, relieves mucosal impairment of the small intestine, and facilitates the recovery of the intestinal mucosa. IL-1Ra treatment offers a novel promising strategy for the prevention and cure of chemotherapy-induced intestinal mucositis in clinical practice. 相似文献14.
Christina Cherian Sita Kugel Desmoulin Lei Wang Lisa Polin Kathryn White Juiwanna Kushner Mark Stout Zhanjun Hou Aleem Gangjee Larry H. Matherly 《Cancer chemotherapy and pharmacology》2013,71(4):999-1011
Purpose
We examined whether the novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate, compound 2, might be an effective treatment for malignant pleural mesothelioma (MPM), reflecting its selective membrane transport by the proton-coupled folate transport (PCFT) over the reduced folate carrier (RFC).Methods
HeLa sublines expressing exclusively PCFT (R1-11-PCFT4) or RFC (R1-11-RFC6) and H2452 MPM cells were assayed for transport with [3H]compound 2. [3H]Polyglutamate metabolites of compound 2 were measured in R1-11-PCFT4 and H2452 cells. In vitro cell proliferation assays and colony formation assays were performed. Inhibition of glycinamide ribonucleotide formyltransferase (GARFTase) was assayed by nucleoside protection assays and in situ GARFTase assays with [14C]glycine. In vivo efficacy was established with early- and advanced-stage H2452 xenografts in severe-combined immunodeficient (SCID) mice administered intravenous compound 2.Results
[3H]Compound 2 was selectively transported by PCFT and was metabolized to polyglutamates. Compound 2 selectively inhibited proliferation of R1-11-PCFT4 cells over R1-11-RFC6 cells. H2452 human MPM cells were sensitive to the antiproliferative effects of compound 2. By colony-forming assays with H2452 cells, compound 2 was cytotoxic. Compound 2 inhibited GARFTase in de novo purine biosynthesis. In vivo efficacy was confirmed toward early- and advanced-stage H2452 xenografts in SCID mice administered compound 2.Conclusions
Our results demonstrate potent antitumor efficacy of compound 2 toward H2452 MPM cells in vitro and in vivo, reflecting its efficient membrane transport by PCFT, synthesis of polyglutamates, and inhibition of GARFTase. Selectivity for non-RFC cellular uptake processes by tumor-targeted antifolates such as compound 2 presents an exciting new opportunity for treating solid tumors. 相似文献15.
Osamu Nakahara Hiroshi Takamori Hiroshi Tanaka Yasuo Sakamoto Yoshiaki Ikuta Satoshi Furuhashi Masayuki Watanabe Toru Beppu Masahiko Hirota Keiichiro Kanemitsu Hideo Baba 《International journal of clinical oncology / Japan Society of Clinical Oncology》2010,15(1):39-45
Background
Little is known about the clinical significance of TS and DPD in pancreatic cancer. We aimed to evaluate TS and DPD expression levels in not only pancreatic cancer but also surrounding normal pancreatic tissues to assess the clinical implications of the expression of TS and DPD in this study.Patients and methods
Pancreatic cancer and normal pancreatic tissues were obtained from 18 patients with pancreatic cancer who underwent pancreatic resection to measure TS and DPD activities. The TS and DPD activities were determined by enzyme-linked immunosorbent assay using non-fixed fresh-frozen specimens.Results
Pancreatic cancer tissues had significantly higher DPD and TS enzyme activities than surrounding normal tissue. Anaplastic ductal carcinoma had higher DPD and TS activities than the other histological types. Patients with high DPD in this study demonstrated poorer prognosis than those with low DPD. On the other hand, there was no statistically significant difference in survival between the high and the low TS groups.Conclusions
The efficacy of 5-FU may be lower in pancreatic cancer tissue than in normal tissue because DPD activity is upregulated in pancreatic cancer tissue compared to normal pancreatic tissue. It is necessary to develop an effective 5-FU delivery system and/or 5-FU combined with an inhibitor for DPD that can be used when 5-FU must be administered to patients with pancreatic cancer. High DPD activity may be a prognostic factor in patients with pancreatic cancer. 相似文献16.
Addition of 5-fluorouracil to doxorubicin-paclitaxel sequence increases caspase-dependent apoptosis in breast cancer cell lines 总被引:2,自引:0,他引:2 下载免费PDF全文
Zoli W Ulivi P Tesei A Fabbri F Rosetti M Maltoni R Giunchi DC Ricotti L Brigliadori G Vannini I Amadori D 《Breast cancer research : BCR》2005,7(5):R681-R689
Introduction
The aim of the study was to evaluate the activity of a combination of doxorubicin (Dox), paclitaxel (Pacl) and 5-fluorouracil (5-FU), to define the most effective schedule, and to investigate the mechanisms of action in human breast cancer cells.Methods
The study was performed on MCF-7 and BRC-230 cell lines. The cytotoxic activity was evaluated by sulphorhodamine B assay and the type of drug interaction was assessed by the median effect principle. Cell cycle perturbation and apoptosis were evaluated by flow cytometry, and apoptosis-related marker (p53, bcl-2, bax, p21), caspase and thymidylate synthase (TS) expression were assessed by western blot.Results
5-FU, used as a single agent, exerted a low cytotoxic activity in both cell lines. The Dox→Pacl sequence produced a synergistic cytocidal effect and enhanced the efficacy of subsequent exposure to 5-FU in both cell lines. Specifically, the Dox→Pacl sequence blocked cells in the G2-M phase, and the addition of 5-FU forced the cells to progress through the cell cycle or killed them. Furthermore, Dox→Pacl pretreatment produced a significant reduction in basal TS expression in both cell lines, probably favoring the increase in 5-FU activity. The sequence Dox→Pacl→48-h washout→5-FU produced a synergistic and highly schedule-dependent interaction (combination index < 1), resulting in an induction of apoptosis in both experimental models regardless of hormonal, p53, bcl-2 or bax status. Apoptosis in MCF-7 cells was induced through caspase-9 activation and anti-apoptosis-inducing factor hyperexpression. In the BRC-230 cell line, the apoptotic process was triggered only by a caspase-dependent mechanism. In particular, at the end of the three-drug treatment, caspase-8 activation triggered downstream executioner caspase-3 and, to a lesser degree, caspase-7.Conclusion
In our experimental models, characterized by different biomolecular profiles representing the different biology of human breast cancers, the schedule Dox→Pacl→48-h washout→5-FU was highly active and schedule-dependent and has recently been used to plan a phase I/II clinical protocol. 相似文献17.
Zhu Yuan Fei Yan Yong-sheng Wang Huan-yi Liu Lan-tu Gou Xin-yu Zhao Song-tao Lai Hong-xin Deng Jiong Li Zhen-yu Ding Shao-qun Xiong Bing Kan Yong-qiu Mao Li-juan Chen Yu-quan Wei Xia Zhao 《Cancer chemotherapy and pharmacology》2009,65(1):13-25
Purpose
PNAS-4, a novel pro-apoptotic gene activated during the early response to DNA damage, can inhibit proliferation via apoptosis when overexpressed in some tumor cells. The objectives of this study were to determine whether PNAS-4 could enhance apoptosis induced by cisplatin besides its induction of apoptosis, and to evaluate the usefulness of combined treatment with mouse PNAS-4 (mPNAS-4) gene therapy and low-dose cisplatin chemotherapy in the inhibition of tumor growth in colon carcinoma (CT26) and Lewis lung carcinoma (LL/2) murine models.Methods
In this study, the in vitro growth-inhibitory and pro-apoptotic effects of PNAS-4 and/or cisplatin on CT26, LL/2, and SKOV3 cancer cells were assessed by MTT assay, flow cytometric analysis, DNA fragmentation, and morphological analysis, respectively. The in vivo antitumor activity of combined treatment with mPNAS-4 gene therapy and low-dose cisplatin were evaluated in the inhibition of tumor growth in colon carcinoma (CT26) and Lewis lung carcinoma (LL/2) murine models. Tumor volume and survival time were observed. Induction of apoptosis was also assessed in tumor tissues.Results
In vitro, PNAS-4 inhibited proliferation of colon carcinoma (CT26), Lewis lung carcinoma (LL/2) and human ovarian cancer (SKOV3) cell lines via apoptosis, and significantly enhanced the apoptosis of CT26, LL/2, and SKOV3 cells induced by cisplatin. In vivo systemic administration of expression plasmid encoding mPNAS-4 (pcDNA3.1-mPS) and cisplatin, significantly decreased tumor growth through increased tumor cell apoptosis compared to treatment with mPNAS-4 or cisplatin alone.Conclusions
Our data suggests that the combined treatment with mPNAS-4 plus cisplatin may augment the induction of apoptosis in tumor cells in vitro and in vivo, and that the augmented antitumor activity in vivo may result from the increased induction of apoptosis. The present study may provide a novel way to augment the antitumor efficacy of cytotoxic chemotherapy. 相似文献18.
19.
Li Wei Fan DongMei Yang Ming Shi RuiZan Yan Yan Jiang Linlin Yan Cihui Li Shuangjing Wang Min Wang Jianxiang Xiong DongSheng 《Cellular oncology (Dordrecht)》2012,35(6):423-434
Background
A diabody is a bispecific antibody that is capable of recruiting a polyclonal T cell to antibody target-expressing tumor cells. However, the two chains of diabodies tend to dissociate because they are integrated non-covalently. Therefore, it is necessary to remodel the diabody to increase its stability in order to enhance the antitumor activity.Methods
We constructed an antiCD3×antiCD19 diabody with one binding site for the T cell antigen receptor (TCRCD3) and the other for the B cell-specific antigen (CD19) by recombinant gene engineering technology. Cysteine residues were introduced into the V domains of the anti-CD3 segment. The stability and cytotoxicity of the two diabodies were compared in vitro and vivo.Results
The disulfide-stabilized (ds) diabodies produced by Escherichia coli were secreted with high yields in a fully active form without a decrease in affinity. Compared with the parental diabody, the disulfide-stabilized (ds) diabody proved more stable in vitro and in vivo without reducing binding affinity. Both were able to effectively eliminate human lymphoma Raji cells by redirecting T lymphocytes in vitro and in vivo, but the ds diabody was more effective in inhibiting the growth of xenografts transplanted in BALB/C nude mice.Conclusion
The antiCD3×antiCD19 ds diabody is more suitable for a controlled polyclonal T cell therapy of human CD19-positive B cell malignancies than its parental diabody. 相似文献20.
Fávaro WJ Nunes OS Seiva FR Nunes IS Woolhiser LK Durán N Lenaerts AJ 《Infectious agents and cancer》2012,7(1):14-15