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1.
We have compared the induction of apoptosis and cytokine release by UVB and gamma-radiation in primary (untransformed) and in two immortalized human epithelial/keratinocyte cell lines, HaCaT and KB (KB is now known to be a subline of the ubiquitous keratin-forming tumour cell line HeLa and we therefore designate it HeLa-KB). In both the primary and the immortalized cell lines apoptosis and release of the inflammatory cytokine interleukin-6 are induced rapidly following UVB irradiation. In contrast, only the immortalized cells undergo apoptosis and release interleukin-6 after gamma-irradiation and here the onset of apoptosis and cytokine release are delayed. The same distinction between primary and immortalized cells was observed when double-strand breaks were induced with the anticancer drug mitoxantrone, which stabilizes topoisomerase II-cleavable complexes. We suggest that immortalization may sensitize keratinocytes to the apoptogenic effect of ionizing radiation or mitoxantrone by deregulating normal cell cycle checkpoints. In both human keratinocytes and fibroblasts, cell killing, as assayed by loss of colony-forming ability, is not coupled to apoptosis. Immortalization increases resistance to gamma-radiation killing but sensitizes to apoptosis. In contrast, although immortalization also sensitizes to UVB-induced apoptosis, it does not affect UVB-induced cell killing. Apoptosis unambiguously indicates death at the single cell level but clonal cell survival integrates all the cellular and genetic processes which prevent or permit a scorable clone to develop.  相似文献   

2.
Alterations in the neoplastic activity of cyclophosphamide (CPA) by the extract of Alstonia scholaris(ASE) were studied in mice transplanted with Ehrlich ascites carcinoma (EAC). The tumor-bearing animals were injected with various doses of ASE and 25 mg/kg of CPA (1/10th of the LD50 dose). The combination of 120 mg/kg of ASE with 25 mg/kg of CPA was most effective, as it caused the highest tumor regression and enhanced the mean survival time (MST) and the average survival time (AST) up to 42 and 40.7, as against the 29 and 27.5 of CPA alone, respectively. Similarly, when 120 mg/kg of ASE was combined with different doses of CPA (3.125 to 50 mg/kg), a dose-dependent increase in the anticancer activity was observed up to 25 mg/kg of CPA. However, a further increase in the CPA dose up to 37.5 or 50 mg/kg resulted in toxic side effects and death. The best effect was observed when 120 mg/kg of ASE was combined with 25 mg/kg followed by 12.5 mg/kg of CPA, as evident by the greater tumor remission, when compared with the concurrent doses of either drug alone. The administration of 120 mg/kg of ASE 6 h before the administration of 25 mg/kg of CPA resulted in a drastic decline in the glutathione levels and increased the lipid peroxidation considerably when compared with either drug alone.  相似文献   

3.
The radioprotective effect of hydroalcoholic extract of ginger rhizome (Zingiber officinale; ZOE) was studied in mice administered 250 mg/kg ZOE orally using oral gavage once daily for 5 consecutive days before exposure to 6, 7, 8, 9, 10, or 11 Gy of gamma-radiation. The animals were monitored daily up to 30 days postirradiation for the development of symptoms of radiation sickness and mortality. Pretreatment of mice with ZOE reduced the severity of symptoms of radiation sickness and mortality at all the exposure doses and also increased the number of survivors in a ZOE + irradiation group compared to the concurrent double-distilled water + irradiation group. The ZOE treatment protected mice against gastrointestinal-related deaths as well as bone-marrow-related deaths. The dose-reduction factor was found to be 1.2. The administration of ZOE after exposure to irradiation was not effective, as no survivors lasted up to 30 days postirradiation. Reducing the administration schedule to 3 days or increasing the schedule to 7 days was not as effective compared to a 5 consecutive days' schedule. The irradiation of animals resulted in a dose-dependent elevation in the lipid peroxidation, while depletion in the glutathione (GSH) contents occurred on day 31 postirradiation. Treatment of mice with ZOE before irradiation caused a significant depletion in lipid peroxidation followed by a significant elevation in GSH concentration in the livers of mice at 31 days postirradiation. The mechanism of action of ZOE was determined by evaluating its free-radical scavenging capability. Ginger was found to scavenge *OH, O2*- and ABTS*+ radicals in a dose-dependent manner in vitro. The drug was nontoxic up to a dose of 1500 mg/kg body weight, the highest drug dose that could be tested for acute toxicity.  相似文献   

4.
The radioprotective effect of a hydroalcoholic extracted material from the fruit of Aegle marmelos (AME) was studied in mice exposed to different doses of gamma radiation. The optimum dose for radioprotection was determined by administering 0, 5, 10, 20, 40, or 80 mg/kg body weight of AME intraperitoneally (ip) once daily, consecutively for 5 days before exposure to 10 Gy of gamma radiation. A total of 20 mg/kg of AME for 5 consecutive days before irradiation was found to afford maximum protection as evidenced by the highest number of survivors after 30 days postirradiation. Animals from all groups were monitored for 30 days postirradiation for development of symptoms of radiation sickness and mortality. Treatment of mice with AME before exposure to different doses of gamma radiation reduced the severity of symptoms of radiation sickness and mortality with all exposure doses. This was accompanied by an increase in number of survivors in the AME + irradiation group when compared with the concurrent sterile physiological saline (SPS) + irradiation group. AME pretreatment protected mice against the gastrointestinal as well as bone marrow deaths, as evidenced by the greater number of survivors on day 10 or 30, respectively. LD50/30 was found to be 8.2 Gy for the SPS + irradiation group, while it was 8.8 Gy for AME + irradiation. The dose-reduction factor (DRF) was found to be 1.1 for AME + irradiation group. The acute toxicity study of AME showed that it was nontoxic up to a dose of 6 g/kg body weight, the highest drug dose that could be administered. Irradiation of animals resulted in a dose-dependent elevation in lipid peroxidation in liver, kidney, stomach, and intestine of mice. Conversely, GSH concentration declined in a dose-dependent manner. Treatment of animals with AME before irradiation caused a significant decrease in the lipid peroxidation accompanied by a significant elevation in the GSH concentration in liver, kidney, stomach, and intestine of mice determined at 31 days postirradiation.  相似文献   

5.
The mutagenic effects of doxorubicin (Adriamycin, ADR) on mouse spermatogonial stem cells were examined by analysis of spermatocyte chromosomes and of dominant lethality transmitted through the spermatozoa. The effects of ADR on mutations, cytotoxicity, and sperm head abnormalities were compared with those of radiation. The cytotoxic effect of 6 Gy of gamma-radiation on stem spermatogonia was equivalent to about 4-5 mg ADR/kg. Chromosomal translocations were observed in 0.6% of the spermatocytes of mice treated with ADR (2-6 mg/kg). In contrast, 6 Gy of radiation induced translocations in 11.1% of spermatocytes. No increase in dominant lethality was observed after treatment with ADR at doses up to 6 mg/kg, while the frequency after 6 Gy of radiation was 3.6%. Based on these results, ADR would be expected to be only a weak inducer of balanced chromosomal rearrangements. Because ADR at 4.5 mg/kg was much weaker than 6 Gy of gamma-radiation at inducing chromosomal translocations, but just as effective at inducing sperm head abnormalities, the level of sperm head abnormalities is not indicative of balanced chromosomal rearrangements induced in stem spermatogonia by cytotoxic agents.  相似文献   

6.
Purpose: The aim of this study was to evaluate the antitumor efficacy of combretastatin A-4 disodium phosphate (combretastatin prodrug) in the rodent KHT sarcoma model either alone or in combination with radiation therapy.Methods: KHT tumors were grown in C3H/HeJ mice. Combretastatin A-4 prodrug was injected intraperitoneally at doses ranging from 10 to 100 mg/kg. Tumors were irradiated in unanesthetized mice using a 137Cs source. Tumor response to combretastatin A-4 prodrug was assessed by histological evaluations as well as an in vivo to in vitro cell survival assay.Results: Histological evaluation showed morphological damage of tumor cells within a few hours after drug treatment, followed by extensive central necrosis. Administering increasing doses of combretastatin A-4 prodrug to tumor-bearing mice resulted in a dose-dependent increase in cell killing irrespective of whether the tumors were irradiated or not. When combined with radiation, a 100 mg/kg dose of combretastatin A-4 prodrug reduced tumor cell survival 10–500-fold lower than that seen with radiation alone. Further, the shape of the cell survival curve observed following the combination therapy suggested that including combretastatin in the treatment had a major effect on the radiation-resistant hypoxic cell subpopulation associated with this tumor.Conclusion: The present results demonstrated that in the KHT sarcoma, combretastatin A-4 prodrug caused rapid vascular shutdown, a concentration-dependent direct cell killing, and effective enhancement of the antitumor effects of radiation therapy.  相似文献   

7.
 目的 探讨γ射线对人宫颈癌细胞系HeLa端粒酶活性的影响。方法 不同剂量的γ射线照射HeLa细胞后 2 4h、72h、12 0h ,用TRAP ELISA法检测端粒酶的活性。结果 γ射线照射细胞后 2 4h ,较低剂量 (0 .5~ 1.5 )Gy时 ,端粒酶的活性呈剂量依赖式增加 ;(2~ 3)Gy时增加的幅度减低 ;而较高剂量 (4~ 12 )Gyγ射线照射时 ,又呈剂量依赖式增加。与照射后 2 4h相比 ,在较高剂量 (4~ 12 )Gy照射后 72h及 12 0h ,酶的活性呈剂量依赖式减少。结论 HeLa细胞在较高剂量γ射线照射后 2 4h出现的端粒酶活性上调反应 ,可能是其组分从DNA释放增加或者与端粒酶的核内位置调节有关 ;较低剂量照射后的上调反应 ,可能与DNA的修复 ,稳定断裂的染色体有关。  相似文献   

8.
Methanol extract of Indigofera linnaei (MEIL) was investigated for antitumor, cytotoxic and antioxidantactivities against transplantable tumors and human cancer cell lines. In vitro cytotoxicity was evaluated in HeLa,Hep-2, HepG-2, MCF-7, HT-29, Vero and NIH 3T3 cells by MTT assay and in vivo antitumor activity with Ehrlichascites carcinoma (EAC) and Dalton’s ascites lymphoma (DLA) tumor-bearing mice. Activity was measuredby monitoring the mean survival time, effect on hematological parameters, antioxidant enzyme levels and solidtumor volume. The extract exhibited strong in vitro cytotoxicity against all the tested cancer cell lines, but itwas found to be safe with normal cells. MEIL at the dose of 200 and 400 mg/kg, significantly increase the meansurvival time (P<0.001), exerted a protective effect on the hemopoietic system, demonstrated in vivo antioxidantactivity and significantly reduce solid tumor volume (P<0.01). These results show a significant antitumor andcytotoxic effect of MEIL against EAC, DLA and human cancer cell lines and support the ethnomedical use ofIndigofera linnaei.  相似文献   

9.

Objective

The aim was to study the assistant radiotherapeutic effect of Jiaqi Mixture (JQM) on Ehrlich’s ascites carcinoma (EAC) mice.

Methods

The EAC-cancer model was made up with Kunming mice. The tumor-bearing mice were treated with whole body exposure (8 Gy) and intragastric administration of JQM, and the changes of tumor weight, the total number of white blood cells (WBC) and immune system were observed.

Results

The average tumor weight, WBC, spleen coefficient, the stimulation index (SI) of Con A and LPS and the natural killing (NK) cell activity of mice decreased in some degree after radiotherapy, but the average tumor weight decreased more obviously in radiotherapy + medicine groups (compared with tumor control group, P < 0.05); and the other above indexes were much higher in radiotherapy + medicine groups than those in radiotherapy groups (P < 0.05?0.01).

Conclusion

It was suggested that JQM can enhance the effect of radiation therapy and protect the normal immune system caused by radiation therapy.  相似文献   

10.
Wei LH  Lai KP  Chen CA  Cheng CH  Huang YJ  Chou CH  Kuo ML  Hsieh CY 《Oncogene》2005,24(3):390-398
Arsenic trioxide (ATO) has been implicated as a promising anticancer agent by inhibiting cell growth and inducing apoptosis in certain types of cancer cells. This study explored the antimetastasis property of arsenic, drew potential link between arsenic use and radiotherapy, and uncovered the specific mechanisms underlying these remarkable responses. Using gelatin invasion assay and intravasation assay, we report the novel finding that low-dose ATO (1 muM) reduced the intrinsic migration ability of HeLa cells and significantly inhibited radiation-promoted tumor invasive potential of CaSki cells without inducing apoptotic cell death. Using the murine Lewis lung carcinoma model, the control animals and ATO treatment animals (1 mg/kg i.p., twice weekly) displayed similar in vivo growth kinetics, whereas the radiation (30 Gy in one fraction) and concurrent treatment groups showed considerable growth inhibition. Importantly, although concurrent treatment did not enhance the effectiveness of radiation therapy to the primary tumor, further examination of the lungs revealed that all animals succumbed to radiation-accelerated lung metastases could be effectively treated by combination of ATO and radiation. Radiation-induced matrix metalloproteinase-9 (MMP-9) expression was significantly inhibited by ATO using sequential analysis of the expression of MMPs in xenografts. Supporting this observation, ATO directly downregulates radiation-induced MMP-9 mRNA expression by inhibiting nuclear factor kappaB activity in human cervical cancer cells. In sum, concurrent arsenic-radiation therapy not only achieves local tumor control but also inhibits distant metastasis. Experimental results of this study highlight a novel strategy in cancer treatment.  相似文献   

11.
Intestinal proliferative activity in BDF, mice bearing the Lewis lung tumor (LLca/BDF1) was markedly depressed with increasing tumor burden. When compared with non-tumor-bearing mice (BDF1), integrated cell production over 7 days was reduced to 56% in animals with small (400 mm3) tumors and to 30% in animals with large (2500 mm3) tumors. Gastrointestinal radiosensitivity was measured by proliferative compensatory response kinetics to a radiation dose of 600 rad. The presence of tumor (mean tumor volume = 859 ± 209 mm3) delayed the jejunal response to radiation by 24 hr and reduced the integrated cell production from 136% in BDF1 mice to 119% in the LLca/BDF1 mice. While the presence of tumor did not alter the temporal response of the colonic epithelium to radiation, the compensatory peak was reduced from 248% (BDF1) to 200% (LLca/BDF1). Adriamycin (Adr; 10 mg/kg) given 60 days prior to radiation failed to enhance the jejunal radiosensitivity in BDF1 mice. However, when tumor-bearing LLca/BDF1 mice were treated under an identical dose and time configuration, the jejunal response to 600 rad was significantly impaired: proliferative peaks were reduced from 182 to 115% ; integrated cell production was reduced from 119 to 72%. In the colon of tumor-bearing mice, pretreatment with AdR reduced the proliferative compensatory peak from the subsequent radiation dose to 120% of pretreatment levels.  相似文献   

12.
PURPOSE: Radiosurgery refers to the delivery of high, single focused beams of ionizing radiation to defined intracranial lesions. 1,3 Bis[2-chloroethyl]-1-nitrosourea (BCNU) and cis-diammine-1, 1-cyclobutane-dicarboxylate platinum (II) (carboplatin) are commonly used cytotoxic agents for the treatment of malignant gliomas of the brain. Drug therapies have exhibited a modest enhanced cell killing when combined with radiation in experimental animal tumor systems. The purpose of the present study was to investigate the role of cytotoxic drugs, such as BCNU and carboplatin, in combination with a single high dose of radiosurgery on the tumor control rates of 9L tumors in the rat brain. METHODS AND MATERIALS: Combined radiosurgery (25 Gy single dose) and/or chemotherapy (a single dose of BCNU, 7 mg/kg, i.p. 1.5 or 16 h prior to or 16 h after irradiation or a single dose of carboplatin, 30 mg/kg, administered either 1 h or 4 h prior to irradiation) was delivered 12 days after stereotactic tumor implantation. For dose escalation study, 4-10 mg/kg of BCNU was used. RESULTS: The radiation alone group showed a dose-dependent survival. A single dose of 25 Gy to the control group resulted in an increase of the median survival time from 20 days to 42 days, but all animals died of the tumor in 50 days. A significant prolongation of the median survival time of animals was more than 100 days, resulting in animal cures of 50% or more when combined with radiosurgery (25 Gy) and BCNU (7 mg/kg). BCNU alone did not prolong the median survival time of the animal with the 9L brain tumor. In contrast, there was no survival improvement when the animals were treated with combined radiosurgery and carboplatin. None of the long-term surviving animals showed any significant brain tissue damage as evaluated by histopathology and clinical observations. CONCLUSION: The data clearly suggest that the combined modalities of radiosurgery and concomitant BCNU represent an effective therapeutic regimen in the treatment of radioresistant human malignant gliomas of the brain. This study represents the first experimental report of the effectiveness of combined chemotherapy and radiosurgery.  相似文献   

13.
The effect of in vivo administration of recombinant human interleukin 1 (IL-1) on T cell functions in tumor-bearing mice was studied using an in vitro assay system. The in vitro induction of trinitrophenyl (TNP)-specific cytotoxic T cell and proliferative T cells responses from spleen cells was impaired in X5563 plasmacytoma-bearing C3H/He mice. However, the administration of IL-1 alpha or IL-1 beta to tumor-bearing mice restored T cell functions in a dose-dependent manner. Antigen-presenting activities of spleen cells in tumor-bearing mice for T cell activation were not restored by the administration of IL-1. The activities of cytotoxic T cells and cytostatic T cells specific for X5563 cells were also enhanced by the administration of IL-1. Furthermore, in IL-1-treated mice, NK cell activity of spleen cells detected in terms of the killing of Yac-1 cells was also restored. In accordance with these results, the growth of X5563 cells was significantly inhibited and the lymphocytes from IL-1-treated mice specifically inhibited the growth of tumor cells. These results suggest that the in vivo administration of IL-1 restored the impaired T cell and NK cell functions in tumor-bearing mice and activated protective immunity against tumor cells. Thus, recombinant IL-1 can be applied for tumor immunotherapy.  相似文献   

14.
A protein preparation obtained from the Ehrlich ascites carcinoma (EAC) by acetone precipitation, water extraction and subsequent two-step alcohol fractionation reduced significantly EAC cell proliferation in vivo and in vitro. The preparation was found to contain a low molecular-weight growth-inhibitory activity, suppressing both DNA synthesis in cultured EAC cells and EAC cell division in tumor-bearing mice. The approximate molecular weight of this inhibitory component(s) is about 300-500 Da, corresponding to oligopeptide molecule(s).  相似文献   

15.
目的 探讨用异体淋巴细胞(Heterogeneic lymphocyte, HL)和自体淋巴细胞(Autogeneic lymphocyte, AL)序贯注射的抗肿瘤作用。方法 用CC3HF1小鼠作供鼠, 制备异体淋巴细胞(HL);用CB6F1小鼠作受鼠, 在受鼠腹股沟皮下组织内接种Hepa1-6细胞。用冻融法从小鼠血浆提取冷沉淀, 制成纤维蛋白胶(Fibrin glue, FG);用FG与HL或AL组合为FG-HL或FG-AL。实验治疗分两个阶段。前阶段(共15 d):用FG-HL注射到受鼠荷瘤组织表面(实验组);用FG-磷酸盐缓冲液(FG-PBS)同法注射受鼠作对照组。而后检测两组受鼠的脾淋巴细胞杀瘤细胞率和脾淋巴细胞、CD8+T、NK细胞数量等免疫学指标。后阶段(共10 d):从实验组、对照组中随机选出部分受鼠, 取淋巴细胞(AL)组成FG-AL分别注射到本组其余受鼠的荷瘤组织表面;治疗后剥出受鼠体内肿瘤, 比较两组的瘤体积和抑瘤率。结果 前阶段治疗后, 实验组受鼠AL的杀瘤细胞率(26.70±7.22)%明显高于对照组AL的相应值(5.70±2.68)(P<0.01);实验组受鼠脾淋巴细胞、CD8+T细胞和NK细胞数量均明显高于对照组的相应值(P<0.05)。两阶段治疗结束后, 实验组受鼠的瘤平均体积(1.20±0.33)cm3明显小于对照组的瘤平均体积(2.05±0.37)cm3(P<0.01);实验组的抑瘤率为41.5%。结论 肿瘤局部注射FG-HL, 再注射FG-AL可明显抑制小鼠移植瘤生长, 有望成为一种抗肿瘤生物疗法。  相似文献   

16.
In this study the sensitizing effect of ornidazole is investigated in vivo. The selected test system is the acute killing effect of radiation within 4–6 days after abdominal irradiation ranging from 9 to 24 Gy, in groups of C57 black mice. Ornidazole is given intraperitoneally in 500 mg/kg, 100 mg/kg, 20 mg/kg doses prior to irradiation of animals breathing air, oxygen or nitrogen. A decrease of LD50 dose is observed from 24.39 ± 5.66 to 16.38 ± 1.86 and 18.04 2.48 Gy, respectively, in nitrogen breathing animals. No sensitizing effect was observed in doses of 20 mg/kg. Enhancement Ratio (ER) was found to be 1.48 ± 0.25 and 1.35 0.27, relative sensitizing efficiency (RSE) was 40 and 29% respectively. No sensitizing effect was observed in animals irradiated in oxic conditions. These results showed that ornidazole (Ro-7-0207) has a sensitizing effect on hypoxic cells in vivo. It is worthwhile to try this drug in a clinical study.  相似文献   

17.
Background: To study the radioprotective effects of flavonoids from Rosa roxburghii Tratt (FRT). Materialsand Methods: The radioprotective effects of FRT were investigated by examining cell viability, 30-day survivalof mice and the number of colony-forming units in spleen (CFU-S) after total-body 60Co irradiation. Results:The survival rates of irradiated cells gradually increased with increasing concentrations of FRT. The survivalrate was the highest at 87% with a concentration of 30 μg/mL. Pretreatment with FRT was needed to realize itsradioprotective activity in mice at the dose of 60 mg/kg. With the increasing doses of 30 mg/kg, 60 mg/kg and120 mg/kg, the numbers of CFU-S increased, and were significantly different compared with the control group.Conclusions: Pretreatment with FRT prior to irradiation resulted in significantly higher cell survival at 24 hafter 5 Gy radiation, increased 30-day survival in mice after exposure to a potentially lethal dose of 8 Gy, andresulted in a higher number of CFU-S in mice after exposure to a dose of 6 Gy. These results collectively indicatethat FRT is an effective radioprotective agent.  相似文献   

18.
KS Kim  KJ Choi  S Bae 《Cancer biology & therapy》2012,13(11):1018-1025
Interferon-gamma (IFNγ) is a cytokine with roles in immune responses as well as in tumor control. Interferon is often used in cancer treatment together with other therapies. Here we report a novel approach to enhancement of cancer cell killing by combined treatment of IFNγ with ionizing radiation. We found that IFNγ treatment alone in HeLa cells induced phosphorylation of Chk1 in a time- and dose-dependent manner, and resulted in cell arrest. Moreover IFNγ treatment was correlated with attenuation of Chk1 as the treatment shortened protein half-life of Chk1. As Chk1 is an essential cell cycle regulator for viability after DNA damage, attenuation of Chk1 by IFNγ pre-treatment in HeLa cells resulted in increased cell death following ionizing radiation about 2-folds than ionizing radiation treatment alone whereas IFNγ treatment alone had little effect on cell death. X-linked inhibitor of apoptosis-associated factor 1 (XAF1), an IFN-induced gene, seems to partly regulate IFNγ-induced Chk1 destabilization and radiation sensitivity because transient depletion of XAF1 by siRNA prevented IFNγ-induced Chk1 attenuation and partly protected cells from IFNγ-enhanced radiation cell killing. Therefore the results provide a novel rationale to combine IFNγ pretreatment and DNA-damaging anti-cancer drugs such as ionizing radiation to enhance cancer cell killing.  相似文献   

19.
The effect of 3'-deoxyadenosine N1-oxide (3'-dANO) on Ehrlich ascites tumor and a human squamous lung cell carcinoma was investigated. The 3'-dANO concentration that inhibited the cell growth 50% (IC50) in Ehrlich ascites tumor cells in vitro was 0.15 mM, and the killing efficiency concentration (concentration of the drug that kills all cells) was 1 mM. By simultaneous administration of 3'-dANO and the adenosine deaminase inhibitor erythro-9-(2-hydroxyl-3-nonyl) adenine (EHNA), the IC50 of 3'-dANO was unchanged, but the killing efficiency concentration of 3'-dANO was reduced to 0.3 mM. When mice bearing Ehrlich ascites tumor were treated i.p. with 3'-dANO doses of 200 mg/kg daily for 4 days, the mean increased life span (ILS) was 200%. 3'-dANO in combination with EHNA did not further increase the life span of the tumor-bearing mice. The specific growth delay (SGD) of the Ehrlich tumor and of a human squamous lung cell carcinoma growing subcutaneously in 3'-dANO-treated mice were calculatedfrom Gomperts tumor growth curves. The Ehrlich tumor-bearing mice received 3'-dANO i.p. at doses of 250 mg/kg daily for 4 days, and the nude mice bearing human carcinoma received 3'-dANO i.p. at doses of 225 mg/kg daily for 5 days. The SGD for the investigated tumors were calculated to be 1.0 and 1.1, respectively.  相似文献   

20.
PURPOSE: Patients with glioblastoma multiforme (GBM) do extremely poorly despite aggressive therapy with surgery, radiotherapy (RT), and chemotherapy. In an effort to increase the efficacy of therapy for GBM, we studied the efficacy of arsenic trioxide (ATO) combined with high-dose RT in GBM cells in vitro and GBM xenograft tumors in nude mice. METHODS AND MATERIALS: Human glioblastoma cell line SNB75 cells were irradiated in vitro with doses of 0-15 Gy with or without ATO. Clonogenic assays were used to generate radiation survival curves. Intracellular reactive oxygen species and apoptosis induced by ATO and RT were measured. The therapeutic efficacy of ATO alone, local tumor RT alone, and the combined therapy was tested in nude mice bearing established s.c. SNB75 tumors. A single RT dose of 20 Gy was administered locally to tumors. ATO at 10 mg/kg was injected i.p. 10 min after RT for the in vivo experiments. RESULTS: Radiation survival curves of GBM SNB75 cells demonstrated that a dose of 0.2 microM ATO increased radiation-induced cell killing by 2 logs at 10 Gy. ATO at 1 microM decreased survival from 4 x 10(-2) after 7 Gy of RT alone to 4 x 10(-5). A time-course experiment demonstrated that the greatest level of cell killing occurred when ATO was administered immediately before or within 2 hours after RT. To test the therapeutic efficacy of this combined treatment regimen in vivo, nude mice with established SNB75 GBM tumors were treated with a single local tumor dose of 20 Gy of RT with or without ATO (10 mg/kg x two doses) administered weekly. Appropriate control groups were included as well. ATO alone did not inhibit tumor growth. RT at 20 Gy alone inhibited tumor growth by 45 days, with regrowth of tumors thereafter. The combination of RT and ATO resulted in complete regression of the tumors in 4 of 5 mice without tumor regrowth for up to 4 months. The fifth mouse in the combined treatment group had a 90% reduction in tumor size without progression during the 4-month follow-up period. Furthermore, ATO alone and in combination with RT did not produce any obvious signs of toxicity. CONCLUSION: These results have demonstrated that ATO increases intracellular levels of reactive oxygen species, induces apoptosis, and enhances the radiation cell killing of GBM cells. RT combined with ATO was an effective treatment for GBM tumors in this preclinical model. These preclinical results are encouraging and provide a rationale for further study of ATO combined with RT for the treatment of GBM and other histologic types of brain cancer using a variety of RT schemes.  相似文献   

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