Antiangiogenic and antitumor effects of SRC inhibition in ovarian carcinoma

Src, a nonreceptor tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid tumors, including ovarian carcinoma. The purpose of this study was to determine the role of activated Src inhibition on tumor growth in an orthotopic murine model of ovarian carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor, AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of docetaxel in both chemosensitive and chemoresistant ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of AP23846, significantly decreased tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on tumor reduction was observed in combination therapy with docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively). Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with docetaxel (P = 0.007) significantly reduced tumor proliferation. In addition, Src inhibition alone and in combination with docetaxel significantly down-regulated tumoral production of vascular endothelial growth factor and interleukin 8, whereas combination therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces tumor burden in preclinical ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian carcinoma.     

低剂量环磷酰胺对肺癌肿瘤血管生成的影响

目的研究低剂量环磷酰胺(CTX)对肺癌肿瘤血管生成的影响,观察其抑瘤效果及对生存期影响.方法以荷Lewis肺癌的C57/BL6小鼠为模型,分别给予低剂量CTX、最大耐受剂量(MTD)CTX灌胃,免疫组化染色测定肿瘤微血管密度(MVD)、血管内皮生长因子(VEGF)和核增殖抗原表达基因(Ki-67),观察小鼠生存期.结果低剂量CTX治疗组小鼠肿瘤MVD值较对照组和MTDCTX治疗组均降低,同时低剂量CTX组VEGF及Ki-67表达也降低(P＜0.05);低剂量CTX治疗组小鼠生存期较MTD CTX治疗组延长(P＜0.05).结论持续低剂量CTX给药方式可抑制肺癌肿瘤微血管生成,具有良好抑瘤效果,动物生存期延长.     

低剂量化疗抑制肺癌血管生成的研究

背景与目的近期一些国外研究表明降低化疗药物的剂量可特异地杀伤新生肿瘤血管内皮细胞,利用化疗药物的这一新靶点,可能帮助解决常规化疗剂量引起的毒副作用和耐药性的难题。为此本研究观察持续低剂量环磷酰胺(CTX)对肺癌血管生成的影响,并观察其抑瘤效果和毒副作用。方法建立荷Lewis肺癌C57/BL6小鼠模型,分别给予持续低剂量(LDM)CTX、最大耐受剂量(MTD)CTX治疗,观察肿瘤体积、小鼠体重和外周血白细胞计数及小鼠生存期。实验终末时行免疫组化染色,测定肿瘤微血管密度(MVD)和血管内皮生长因子(VEGF)表达情况。结果与对照组和MTDCTX治疗组比较,LDMCTX治疗组小鼠肿瘤MVD值和VEGF表达均显著降低(P<0.05)。与MTDCTX治疗组比较,LDMCTX治疗组肿瘤生长比较缓慢,并且没有明显的体重减轻或白细胞数下降等毒性迹象,小鼠生存期显著延长(P<0.05)。结论CTX的持续低剂量给药方式靶向于肺癌血管生成,不易产生耐药,增加了抑瘤效果,毒副作用小,动物生存期明显延长。     

T-cell-dependent antitumor effects produced by CD40 ligand expressed on mouse lung carcinoma cells are linked with the maturation of dendritic cells and secretion of a variety of cytokines

CD40/CD40 ligand (CD40L) interaction plays an essential role in cell-mediated immune responses. We examined whether expression of CD40L in murine lung carcinoma (A11) cells could produce antitumor effects. The proliferation rate in vitro of A11 cells transfected with the murine CD40L gene (A11/CD40L) was not different from that of parent cells; however, half of the immunocompetent mice inoculated with A11/CD40L cells did not form tumors and the growth of A11/CD40L tumors developed in the rest of mice was significantly retarded compared with that of parent tumors. Protective immunity was also induced in the mice that had rejected A11/CD40L cells. In T-cell-defective nude mice, these antitumor effects were not observed. Bone-marrow-derived dendritic cells (DCs), when cultured with A11/CD40L cells, formed clusters with the tumors and showed upregulated CD86 expression. Expression of the interleukin-23 (IL-23) p19, IL-12p35, IL-18, interferon-gamma (IFN-gamma) and Mig (monokine induced by IFN-gamma) genes was induced in the DCs that were cultured with A11/CD40L but not with A11 cells, and P40, the subunit of both IL-12 and IL-23, was secreted from the cocultured DCs. These data directly showed that the expression of CD40L in tumors facilitated the interaction between DCs and the tumors, enhanced the maturation of DCs, induced secretion of cytokines, and consequently produced T-cell-dependent systemic immunity.     

Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human HT-29 colon carcinoma and human CaKi1 renal cell carcinoma xenografts

The compound 317615 x 2HCl, a selective protein kinase Cbeta inhibitor, was not very cytotoxic toward human CaKi1 renal cell carcinoma cells or human HT-29 colon carcinoma cells in monolayer culture. Isobologram analysis was used to determine additivity or synergy of the combination regimens. Exposure of CaKi1 cells to 317615 x 2HCl (10 or 100 mM) along with gemcitabine or 5-fluorouracil for 24 hours resulted in cytotoxicity that appeared to be less-than-additive to additive for the two agents. Exposure of HT-29 cells to gemcitabine along with 317615 x 2HCl (10 mM or 100 mM) resulted in a synergistic cytotoxicity while combinations with 5-fluorouracil resulted in additive to greater-than-additive cytotoxicity for the agents. After treatment of CaKi1 or HT-29 xenograft-bearing mice with 317615 x 2HCl, immunohistochemical staining for expression of endothelial specific markers, either CD31 or CD105, was used to quantify the number of intratumoral vessels in the samples. CaKi1 tumor angiogenesis was very responsive to treatment with 317615 x 2HCl such that the number of intratumoral vessels stained by CD31 or CD105 was decreased to 20% of the control. The HT-29 colon carcinoma angiogenesis was also responsive to 317615 x 2HCl, such that the number of intratumoral vessels stained by CD31 or CD105 was decreased to 40% to 50% of the controL 5-fluorouracil, cisplatin or fractionated radiation therapy was combined with treatment with 317615 x 2HCl in the simultaneous combination treatment regimen in animals bearing HT-29 colon carcinoma xenografts. The resulting tumor growth delays indicated that administration of 317615 x 2HCl increased the effects of the cytotoxic therapy. Both a simultaneous or an overlapping treatment regimen and a sequential treatment regimen were used to assess 317615 x 2HCl alone and along with fractionated radiation therapy or gemcitabine against the human CaKi1 renal cell carcinoma xenograft. The CaKi1 tumor was quite sensitive to fractionated radiation therapy and to gemcitabine and, although 317615 x 2HCl was an effective single agent in this tumor, the combination regimens did not reach additivity for the combination regimens in vivo. 317615 x 2HCl is in early clinical testing.     

Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors

We provide evidence that cyclooxygenase (COX)-2-derived prostaglandins contribute to tumor growth by inducing newly formed blood vessels (neoangiogenesis) that sustain tumor cell viability and growth. COX-2 is expressed within human tumor neovasculature as well as in neoplastic cells present in human colon, breast, prostate, and lung cancer biopsy tissue. COX-1 is broadly distributed in normal, as well as in neoplastic, tissues. The contribution of COX-2 to human tumor growth was indicated by the ability of celecoxib, an agent that inhibits the COX-2 enzyme, to suppress growth of lung and colon tumors implanted into recipient mice. Mechanistically, celecoxib demonstrated a potent antiangiogenic activity. In a rat model of angiogenesis, we observe that corneal blood vessel formation is suppressed by celecoxib, but not by a COX-1 inhibitor. These and other data indicate that COX-2 and COX-2-derived prostaglandins may play a major role in development of cancer through numerous biochemical mechanisms, including stimulation of tumor cell growth and neovascularization. The ability of celecoxib to block angiogenesis and suppress tumor growth suggests a novel application of this anti-inflammatory drug in the treatment of human cancer.     

Particle-mediated cytokine gene therapy leads to antitumor and antimetastatic effects in mouse carcinoma models

BACKGROUND: We investigated the effects of continuous cancer gene therapy including (antigen-presenting cell) (APC) engineering and local stimulation of the immune system. MATERIALS AND METHODS: Lewis lung carcinomas and B16 melanomas, intradermally established on C57/Bl6 mice, were shot using a gene gun every 4th day with a combination of plasmids. The first therapy group received plasmids coding the genes for interleukin (IL)-12 and IL-2. The second therapy group was treated with plasmids coding for B7.1 interferon-gamma (IFN-gamma)/IL-12 alternated by a plasmid coding IL-2. Control were mice without any therapy or treatment with the empty plasmid. RESULTS: Gene therapy led to reduced tumor sizes in the therapy groups of both models (significant for the Lewis lung carcinoma). We found an enhanced survival and reduced tumor growth rate in the therapy groups; however, the effects were not significant. IL- 12/IL-2 therapy was more effective, compared to B7.1/IFN-gamma/IL-12 and IL-2. Cytokine gene transfer let to a significantly lower metastasis rate in Lewis lung carcinoma. CONCLUSIONS: Continuous particle-mediated gene transfer is easy to handle and shows good results. Gene therapy combining the genes coding for IL-12 and IL-2 was superior to additional IFN-gamma/B7.1. APC engineering does not appear to be sufficient in these poorly antigenic tumors.     

Glycosphingolipids in lectin-resistant variants of mouse Lewis lung carcinoma cells

Neutral glycolipids and gangliosides from murine Lewis lung carcinoma cell line LL2 and its lectin-resistant variants, differing in metastatic properties, were studied by fast-atom-bombardment mass spectrometry (FAB-MS), exoglycosidase treatment and an immunostaining procedure. The neutral glycolipids identified in all cell lines studied included CMH, CDH, CTH, asialo GM2, globoside and a glycolipid with a preliminary structure of Hex-Hexl-4HexNAc-Hex-Hex-Cer. The major gangliosides were GM3, GM2, GM1 and GD1a. No qualitative differences in glycosphingolipid expression were found between the metastatic cell lines (LL2 and LL2AAA) and the weakly metastatic variants (LL25, LL28, LL230 and LL2RCA II). Some quantitative differences were observed between the cell lines, e.g., in the level of ganglioside-bound sialic acid, which was not apparently correlated with the metastatic capacities.     

Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist

Tumor-associated angiogenesis is critical for tumor growth and metastasis and is controlled by various pro- and antiangiogenic factors. The Eph family of receptor tyrosine kinases has emerged as one of the pivotal regulators of angiogenesis. Here we report that interfering with EphA signaling resulted in a pronounced inhibition of angiogenesis in ex vivo and in vivo model systems. Administration of EphA2/Fc soluble receptors inhibited, in a dose-dependent manner, microvessel formation in rat aortic ring assay, with inhibition reaching 76% at the highest dose of 5000 ng/ml. These results were further confirmed in vivo in a porcine aortic endothelial cell-vascular endothelial growth factor (VEGF)/basic fibroblast growth factor Matrigel plug assay, in which administration of EphA2/Fc soluble receptors resulted in 81% inhibition of neovascularization. The additive effects of simultaneous inhibition of VEGF receptor 2 and EphA signaling pathways in aortic ring assay and antiangiogenic efficacy of EphA2/Fc soluble receptors against VEGF/basic fibroblast growth factor-mediated neovascularization in vivo indicated a critical and nonredundant role for EphA signaling in angiogenesis. Furthermore, in two independent experiments, we demonstrated that EphA2/Fc soluble receptors strongly (by approximately 50% versus controls) suppressed growth of ASPC-1 human pancreatic tumor s.c. xenografts. Inhibition of tumor growth was due to decreased proliferation of tumor cells. In an orthotopic pancreatic ductal adenocarcinoma model in mice, suppression of EphA signaling by i.p. administration of EphA2/Fc (30 micro g/dose, three times a week for 56 days) profoundly inhibited the growth of primary tumors and the development of peritoneal, lymphatic, and hepatic metastases. These data demonstrate a critical role of EphA signaling in tumor growth and metastasis and provide a strong rationale for targeting EphA2 receptors for anticancer therapies.     

Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors.

PURPOSE: The antiangiogenic and proapoptotic mechanisms of dietary caloric restriction (DR) are unknown. In this study, we evaluated the effects of moderate (40%) DR on the orthotopic growth of mouse and human brain tumors that differ in cell origin, angiogenicity, host environment, and biochemical composition. EXPERIMENTAL DESIGN: A malignant mouse astrocytoma (CT-2A) and a human glioma (U87-MG) were highly angiogenic and fast growing, whereas a mouse ependymoblastoma was less vascularized and slower growing. The tumors were evaluated for growth, cell proliferation, microvessel density, and apoptosis under DR and ad libitum feeding. Serum vascular endothelial growth factor and insulin-like growth factor I levels were examined as angiogenic biomarkers. RESULTS: DR significantly decreased vascularity (factor VIII) and increased apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling) in all tumors. These effects were associated with enhanced caspase-3 and poly(ADP-ribose) polymerase cleavage in the CT-2A and ependymoblastoma tumors, but not in the U87-MG tumor. DR also caused reductions of serum insulin-like growth factor I and glucose levels. CONCLUSIONS: DR had significant antiangiogenic and proapoptotic effects in the three distinct brain tumor models. DR, however, had differential effects on cell proliferation, biomarkers of angiogenesis, and apoptosis, suggesting multiple mechanisms of action. Because extensive angiogenesis and resistance to apoptosis are hallmarks of gliomas, this study provides new insight into the molecular basis of the DR-induced inhibition of brain tumor growth.     

Novel synergistic antitumor effects of rapamycin with bortezomib on hepatocellular carcinoma cells and orthotopic tumor model

ABSTRACT: BACKGROUND: Despite recent advances in the treatment of hepatocellular carcinoma (HCC), the chemotherapy efficacy against HCC is still unsatisfactory. The mammalian target of rapamycin (mTOR) has been emerged as an important cancer therapeutic target. However, HCC cells often resistant to rapamycin because of the paradoxical activation of Akt by rapamycin. In this study, we investigated whether bortezomib could enhance the antitumor effects of rapamycin. METHODS: The effects of rapamycin and bortezomib on HCC proliferation, apoptosis, migration, and invasiveness in vitro were assessed by CCK-8 analysis, flow cytometry, hoechst 33342 staining and transwell assays, respectively. Total and phosphorylated protein levels of Akt were detected by Western blotting. The effects of rapamycin and/or bortezomib on the mRNA expression levels of p53, p27, p21 and Bcl-2 family in HCCLM3 cells were evaluated by RT-PCR. The roles of rapamycin and bortezomib on HCC growth and metastasis in xenograft models were evaluated by tumor volumes and fluorescent signals. The effects of rapamycin and bortezomib on cell proliferation and apoptosis in vivo were test by PCNA and TUNEL staining. RESULTS: Bortezomib synergized with rapamycin to reduce cell growth, induce apoptosis, and inhibit cell mobility in vitro. Further mechanistic studies showed that bortezomib inhibited rapamycin-induced phosphorylated Akt, which in turn enhanced apoptosis of HCC cell lines. The alteration of the mRNA expression of cell cycle inhibitors p53, p27, p21 and apoptosis associated genes Bcl-2, Bax were also involved in the synergistic antitumor effects of rapamycin and bortezomib. P53 inhibitor PFT-alpha significantly attenuate the effect of rapamycin and bortezomib on cell apoptosis, which indicated that the pro-apoptotic effect of rapamycin and bortezomib may be p53-dependent. Treatment of HCCLM3-R bearing nude mice with rapamycin and bortezomib significantly enhanced tumor growth inhibition (72.4 %), comparing with either rapamycin- (54.7 %) or bortezomib-treated mice (22.4 %). In addition, the lung metastasis was significantly suppressed in mice received the combination treatment (16.6 %). The combination treatment of rapamycin and bortezomib significantly inhibited tumor cell proliferation and tumor angiogenesis in vivo. CONCLUSION: The combination of rapamycin with bortezomib could be a novel and promising therapeutic approach to the treatment of HCC.     

CPC/CMC-CD55sp 纳米微球对宫颈癌Caski 细胞的靶向杀伤作用

目的:制备一种新型C-藻蓝蛋白（C-phycocyanin,CPC）/羧甲基壳聚糖-CD55 配体肽（carboxymethyl chitosan-CD55-specific ligand peptide, CMC-CD55sp）(CPC/CMC-CD55sp)纳米微球,并探究其对宫颈癌Caski 细胞的靶向治疗作用。方法：采用离子交联法制备新型CPC/CMC-CD55sp 纳米微球,通过透射电镜（DLS）和红外光谱仪（FTIR）观察纳米微球的表征,Western blotting和流式细胞术检测CD55 在Caski 细胞和成纤维（L-929）细胞表面的表达情况,CCK-8 法检测纳米微球对Caski 细胞增殖的影响,流式细胞术和荧光显微镜检测纳米微球被细胞摄取情况,Western blotting 和流式细胞术检测纳米微球对Caski 细胞凋亡相关信号蛋白和凋亡率的影响,溶血试验测定药物的生物安全性。结果：成功制备新型CPC/CMC-CD55sp 纳米微球,其形态良好、直径分布均匀,CD55 在宫颈癌细胞Caski 表面高表达而在小鼠L-929 细胞表面低表达（P<0.01）。纳米微球能靶向、高效地到达Caski细胞并被摄入细胞;其在人外周血中溶血作用微弱,且在安全范围;其对Caski 细胞的增殖具有明显的抑制作用并且能够诱导Caski 细胞凋亡（P<0.05 或P<0.01）。结论：新型CPC/CMC-CD55sp 纳米微球能够靶向抑制宫颈癌Caski 细胞的增殖并诱导其凋亡,具有较好的安全性,为海洋抗肿瘤药物的研发提供了新思路。     

Expression of the TNF-alpha gene on mouse lung carcinoma cells suppresses spontaneous lung metastasis without affecting tumorigenicity

Forced expression of TNF-alpha in tumor cells has been shown to inhibit their tumor growth in vivo through a number of mechanism such as activation of an immune system and induction of an apoptotic process. We re-examined the anti-tumor effects caused by the TNF-alpha gene transfer using high-metastatic, murine lung carcinoma A11 cells. Expressed TNF-alpha molecules remained on cell surface and were not secreted into culture supernatants in vitro. Syngeneic immunocompetent mice developed tumors of TNF-alpha-expressed A11 cells and the growth of their subcutaneous tumors was not different from that of parent tumors. Spleen of the mice that developed TNF-alpha-expressed A11 tumors was significantly larger than that of the mice bearing parent tumors, but relative ratios of each cell population were not different. In contrast to subcutaneous tumors, the number of spontaneous lung foci metastasized from the subcutaneous TNF-alpha-expressed A11 tumors was markedly reduced compared with that from parent tumors. Expressed TNF-alpha on tumors is released by matrix metalloproteinases from surrounding tissues and anti-tumor effects by TNF-alpha can be influenced by local environmental conditions.     

Inhibitory effects of B cells on antitumor immunity

B-cell functions in antitumor immunity are not well understood. In this study, we evaluated the role of B cells in the development of antitumor immunity using Friend murine leukemia virus gag-expressing mouse EL-4 (EL-4 gag), D5 mouse melanoma, or MCA304 mouse sarcoma cells. To screen tumors for susceptibility to B-cell-deficient immune environments, spleen cells from naive C57BL/6 [wild-type (WT)] and B-cell knockout (BKO) mice were cultured with irradiated tumor cells in vitro. When cells were stimulated with EL-4 gag or D5 (but not MCA304 tumors), IFN-gamma production from CD8 T cells and natural killer cells was markedly decreased in WT compared with BKO cultures. IFN-gamma production was correlated with CD40 ligand expression on the tumor and inversely with interleukin-10 (IL-10) production by B cells. Sorted WT B cells produced more IL-10 than CD40 knockout (CD40KO) B cells when cocultured with EL-4 gag or D5 (but not MCA304). IFN-gamma production by BKO cells was reduced by the addition of sorted naive WT B cells (partially by CD40KO B cells) or recombinant mouse IL-10. In vivo tumor progression mirrored in vitro studies in that WT mice were unable to control tumor growth whereas EL-4 gag and D5 tumors (but not MCA304) were eliminated in BKO mice. Robust in vivo antitumor CTLs developed only in BKO tumor-challenged mice. Our studies provide the first mechanistic basis for the concept that B-cell depletion could therapeutically enhance antitumor immune responses to certain tumors by decreasing IL-10 production from B cells.     

Hyperthermia‐treated mesenchymal stem cells exert antitumor effects on human carcinoma cell line

BACKGROUND:

Mesenchymal stem cells (MSCs) possess the potential for differentiation into multilineages. MSCs have been reported to play a role as precursors for tumor stroma in providing a favorable environment for tumor progression. Hyperthermia destroys cancer cells by raising the temperature of tumor‐loaded tissue to 40°C to 43°C and causes indirect sensitizing effects when combined with chemo‐ and/or radiotherapy. However, how hyperthermia affects the tumor‐supportive stroma is unknown. Here, the authors investigated the effects of hyperthermia‐treated MSCs, from different sources, on the human ovarian cancer cell line SK‐OV‐3.

METHODS:

MSCs from adipose tissue and amniotic fluid were untreated or heat‐treated (HS‐MSCs). The culture supernatant of each treatment group was collected and transferred to the SK‐OV‐3 cells.

RESULTS:

The morphological analysis and cell proliferation assay showed a reduced viability of the tumor cells in the conditioned medium with the HS‐MSCs. Further investigations revealed that the conditioned medium of the HS‐MSCs induced a higher nuclear condensation and a greater number of sub‐G1 cells among the tumor cells. Analysis of the mRNA expression demonstrated that the conditioned medium of the HS‐MSCs induced up‐regulation or down‐regulation of several tumor‐associated molecules. Finally, the cytokine array of each conditioned medium showed that angiogenin, insulin‐like growth factor binding protein 4, neurotrophin 3, and chemokine (C‐C motif) ligand 18 are involved as main factors.

CONCLUSIONS:

This study showed that the conditioned medium of the HS‐MSCs exerted a suppressive effect on tumor progression and malignancy, suggesting that hyperthermia enables tumor stromal cells to provide a sensitizing environment for tumor cells to undergo cell death. Cancer 2009. © 2009 American Cancer Society.     

小剂量化疗联合人参皂甙Rg3抑制小鼠Lewis肺癌血管生成作用实验研究

背景与目的目前发现一些细胞毒性化疗药物小剂量、短间隙、持续给药可表现出明显的抗肿瘤血管生成作用，从而抑制肿瘤生长和转移，被称作“抗肿瘤血管生成化疗（anti-angiogenic chemotherapy）”。近来从中药人参中提制的人参皂甙Rg3也被证实具有抑制肿瘤血管生成的作用。本研究的目的是观察小剂量吉西他滨和人参皂甙Rg3联合治疗对小鼠Lewis肺癌血管生成的抑制作用，以及对小鼠生存质量的影响。方法建立小鼠Lewis肺癌模型，分别给予小剂量吉西他滨、人参皂甙Rg3以及二者的联合治疗。利用彩色多谱勒超声、免疫组化技术等观察和比较各治疗组的肿瘤血管生成和肿瘤生长情况。结果人参皂甙Rg3和吉西他滨联合治疗组小鼠有较好的生存质量。彩色超声多谱勒以及免疫组化结果发现联合治疗组比单药治疗组具有更高的肿瘤坏死率和更强的抗肿瘤血管生成作用。结论小剂量吉西他滨与人参皂甙Rg3联合治疗可能具有协同抑制肿瘤血管生成的作用，从而取得协同抗肿瘤效应，同时可维持较好的生存质量。