Knockdown of clusterin sensitizes pancreatic cancer cells to gemcitabine chemotherapy by ERK1/2 inactivation

ABSTRACT: ObjectivesTo study the hypothesis that gemcitabine treatment augments the chemoresistance to gemcitabine by clusterin(sCLU) upregulation. Clusterin inhibition could augment the chemosensitivity of human pancreatic cancer cells by inhibition of clusterin-dependent pERK1/2 activation. METHODS: Clusterin was silenced by serial concentration of OGX-011 transfection in pancreatic cancer MIAPaCa-2 and BxPC-3 cell lines, then treated with serial concentration of gemcitabine. After the cells were treated with OGX-011 for 8 h,the cells were then treated with 5 muM ERK inhibitor PD98059 for 18 h or transfected with a wt-pERK-expressing plasmid into these cells for 24 h, after which the cells were treated with 1.0 uM gemcitabine for 24--72 h. Cell proliferation was determined by MTT. Apoptosis was quantified by flow cytometry,.sCLU and pERK1/2 production was analyzed by western blot,and sCLU mRNA was analyzed by RT-PCR. Xenograft of established tumors was used to evaluate primary tumor growth and apoptosis after treatment with gemcitabine alone or in combination with OGX-011. Phosphorylated ERK1/2 and sCLU levels in tumor tissues were measured by TUNEL analysis. RESULTS: As detected by MTT and FACS assay, a combination of gemcitabine + OGX-011 reflected the chemotherapeutic sensitivity and increased the gemcitabine -induced apoptosis in MIAPaCa-2 and BxPC-3 cells. Western blotting and RT-PCR analysis revealed that the expression of clusterin was higher in gemcitabine -resistant MIAPaCa-2 cells, however, decreased significantly after pretreatment with OGX-011. Furthermore, the OGX-011 or combination of gemcitabine + OGX-011 decreased the gemcitabine -induced activation of pERK1/2. wt-pERK-re-expression decreased OGX-011+ gemcitabine -induced apoptosis. Finally, OGX-011 in combination with gemcitabine substantially decreased the in vivo tumor growth and promoted apoptosis. Taken together, clusterin confers gmcitabine resistance in pancreatic cancer cells. CONCLUSIONS: Knockdown of clusterin by OGX-011 transfection sensitizes pancreatic cancer cells to gemcitabine by inhibition of gemcitabine -induced clusterin-pERK1/2 activation.     

XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer

Survivin and XIAP are members of inhibitors of apoptosis (IAPs) family. They are upregulated in various malignancies. Inactivation of these molecules has resulted in chemosensitization. The purpose of this study was to determine whether inhibition of survivin, XIAP, or both enhances radiotherapy in a lung cancer model. Transient transfection of H460 cells with antisense oligonucleotides (ASOs) against either molecule has specifically reduced their expression, by Western analysis. Results from 3-(4,5-methylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and clonogenic assays suggest that inhibition of survivin or XIAP greatly decreased cell survival following irradiation. A significantly increased number of apoptotic cells were detected when H460 cells were treated with either antisurvivin, anti-XIAP or both ASOs (P=0.03, 0.0003 and 0.01, respectively) plus irradiation. H460 xenografts that were treated with ASOs plus radiotherapy demonstrated growth delay beyond 15 days. Growth delay in the groups of combined treatment was greater than that in other groups. However, treatment with ASOs alone did not affect tumor growth delay in mice, but decreased the survival of H460 cells in culture. Antisense treatment did not cause any mortality or weight loss during the 32 days of study. These data suggest that inhibition of survivin or XIAP radiosensitizes H460 lung cancer cells by upregulating apoptosis and downregulating cell survival. Combination of radiotherapy and inhibition of survivin and XIAP through the antisense approach results in improved tumor control by radiotherapy in a mouse model of lung cancer.     

A phase I study of OGX-011, a 2'-methoxyethyl phosphorothioate antisense to clusterin, in combination with docetaxel in patients with advanced cancer.

PURPOSE: Clusterin is a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum treatment resistance. OGX-011 is a 2'-methoxyethyl-modified phosphorothioate antisense oligonucleotide that is complementary to clusterin mRNA, has a prolonged tissue half life, enhances drug efficacy in xenograft models, and reduces clusterin expression in humans with a biologically effective dose of 640 mg. The objective of this study was to determine a recommended phase II dose of OGX-011 in combination with docetaxel. EXPERIMENTAL DESIGN: Patients with cancers known from the literature to express clusterin were eligible. OGX-011 was given by 2-h i.v. infusion starting at 40 mg weekly after loading doses on days 1, 3, and 5. Docetaxel was given i.v. 30 mg/m(2) weekly for 5 of 6 weeks (schedule A) or 75 mg/m(2) every 3 weeks (schedule B). All patients had serial samples of peripheral blood mononuclear cells and serum assessed for clusterin expression. RESULTS: Forty patients were enrolled to eight cohorts. OGX-011 could be given at the full biologically effective single-agent dose of 640 mg with both docetaxel schedules. Toxic effects were primarily myelosuppression, fatigue, hair loss, gastrointestinal effects (expected docetaxel effects), as well as dose-related chills and fever (expected OGX-011 effects). OGX-011 AUC and C(max) increased proportionally with no apparent effect on docetaxel pharmacokinetics. At the end of cycle 1, serum clusterin showed mean decreases of 34% and 38% (range, 15-99%) at the 640-mg dose levels. CONCLUSIONS: OGX-011 can be given at a biologically effective dose with standard doses of docetaxel. Phase II trials of combined OGX-011 and chemotherapy are ongoing in patients with prostate, breast, and lung cancers.     

Clusterin inhibition using OGX-011 synergistically enhances antitumour activity of sorafenib in a human renal cell carcinoma model

Background:

The objective of this study was to investigate whether the therapeutic activity of sorafenib could be enhanced by combining with OGX-011, an antisense oligodeoxynucleotide (ODN) targeting clusterin, in renal cell carcinoma (RCC).

Methods:

We investigated the effects of combined treatment with OGX-011 and sorafenib on a human RCC ACHN model both in vitro and in vivo.

Results:

Although clusterin expression was increased by sorafenib, additional treatment of ACHN with OGX-011 significantly blocked the upregulation of clusterin induced by sorafenib. Despite the lack of a significant effect on the growth of ACHN, OGX-011 synergistically enhanced the sensitivity to sorafenib, reducing the IC₅₀ by >50%. Apoptotic changes were intensively detected in ACHN after combined treatment with OGX-011 and a sublethal dose of sorafenib, but not either agent alone. Furthermore, this combined treatment resulted in the marked downregulation of phosphorylated Akt and p44/42 mitogen-activated protein kinase in ACHN compared with treatment with either agent alone. In vivo systemic administration of OGX-011 plus sorafenib significantly decreased the ACHN tumour volume compared with control ODN plus sorafenib.

Conclusion:

Combined use with OGX-011 may be useful in enhancing the cytotoxic effect of sorafenib on RCC by inducing apoptosis and inactivating major signal transduction pathways.     

抗clusterin 反义核酸治疗提高肺癌H460细胞放射敏感性的实验研究

目的：研究抑制clusterin的表达对肺癌H460细胞放射敏感性的影响。方法：用脂质体转染的方法将抗clusterin反义核酸转染肺癌H460细胞，以^137Cs作为放射源对肺癌细胞进行放射干预。用流式细胞仪检测抗clusterin反义核酸治疗和放射干预对肺癌细胞凋亡的影响，用MTT法和克隆形成分析方法检测抗clusterin反义核酸治疗和放射干预对肺癌细胞增殖的影响。结果：抗clusterin反义核酸特异性抑制了分泌型clusterin的表达，而对核型clusterin的表达无明显作用。单纯放射干预或单纯反义核酸转染将凋亡细胞数提高了10％，反义核酸治疗联合放射干预使肺癌H460细胞的凋亡细胞数增加了25％，和单纯放疗或单纯反义核酸转染组比较有显著性差异（P〈0．01）。MTT和体外克隆计数分析显示抗clusterin反义核酸治疗联合放疗干预显著抑制了肺癌H460细胞的增殖（P〈0．01）。结论：体外实验提示抗clusterin反义核酸治疗可以提高肺癌细胞对放射的敏感性。     

Combined effects of the orally active cisplatin analog, JM216, and radiation in antitumor therapy

Purpose: We evaluated the orally administered platinum agent, JM216, in combination with ionizing radiation both in vivo and in vitro against human tumor cells. Methods: H460 human lung carcinoma cells were used as a subcutaneous xenograft in nude mice. JM216 (30 mg/kg) was administered orally, and radiation treatments (2 Gy) were given 1 h after JM216 delivery for five consecutive days. For in vitro analysis, attached H460 cells were treated with JM216 (15 μM) for 1 h and then irradiated. Cells were rinsed 20 min later, and survival was determined by clonogenic assay. Results: Tumor growth delay measurements showed that the combination of JM216 and radiation was additive in vivo, with an enhancement ratio of 1.24. In vitro clonogenic survival experiments demonstrated a dose enhancement ratio of 1.23. Isobologram analysis showed that this interaction was also additive. Conclusions: These data demonstrate that the combination of JM216 and fractionated radiotherapy is more effective against human lung cancer xenografts than either agent alone, and the in vivo results were supported by those observed using an in vitro system with the same tumor cell line. Received: 20 December 1999 / Accepted: 24 May 2000     

Effect of Targeting Clusterin Using OGX-011 on Antitumor Activity of Temsirolimus in a Human Renal Cell Carcinoma Model

Background

It has not been well documented that the modulation of stress response mediates the efficacy of the mammalian target of rapamycin (mTOR) inhibitor in renal cell carcinoma (RCC).

Objective

The objective of this study was to investigate whether the activity of the mTOR inhibitor temsirolimus against RCC could be enhanced by OGX-011, an antisense oligodeoxynucleotide (ODN) targeting the stress-activated chaperone clusterin.

Methods

We investigated the efficacy of combined treatment with temsirolimus plus OGX-011 in a human RCC Caki-1 model focusing on the effects on apoptotic and autophagic pathways.

Results

Although clusterin expression was increased by temsirolims, additional treatment of Caki-1 with OGX-011 significantly inhibited clusterin upregulation (p?<?0.05). Combined treatment of temsirolimus and OGX-011 synergistically enhanced the sensitivity of Caki-1 to temsirolimus (p?<?0.01), reducing the IC₅₀ by approximately 50 %. Apoptotic changes were marked in Caki-1 following combined treatment with a sublethal dose of temsirolimus and OGX-011, accompanying the significant downregulation of Mcl-1 (p?<?0.05), but not with either agent alone. Furthermore, this combined treatment markedly blocked the temsirolimus-induced activation of autophagy in Caki-1 (p?<?0.01). In-vivo systemic administration of temsirolimus plus OGX-011 significantly inhibited the growth of Caki-1 tumors compared with that of temsirolimus plus control ODN (p?<?0.05).

Conclusions

Silencing of clusterin using OGX-011 resulted in the further enhancement of proapoptotic activity as well as the marked attenuation of the autophagic pathway induced by temsirolimus in a human RCC model. Thus, the combined use of OGX-011 could be a promising strategy through the enhanced cytotoxic activity of temsirolimus against RCC.

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Vascular endothelial growth factor tyrosine kinase inhibitor AZD2171 and fractionated radiotherapy in mouse models of lung cancer

The vascular endothelial growth factor receptor (VEGFR) tyrosine kinases are being explored as targets for antiangiogenic cancer therapy. Radiotherapy also inhibits tumor growth and affects vasculature. We investigated the combination of the potent VEGFR tyrosine kinase inhibitor AZD2171 and ionizing radiation in cell culture and mouse models of lung cancer. We show that ionizing radiation induces expression of phosphorylated VEGFR-2 (Flk-1) in endothelial cells and that this phosphorylation is inhibited by AZD2171. Human umbilical vascular endothelial cells become more sensitive to radiation after treatment with AZD2171 as determined by clonogenic assay. Matrigel assay showed a decrease in in vitro endothelial tubule formation with AZD2171/radiation combination treatment. When similar combination was applied to the H460 lung cancer xenograft model in nude mice, loss of radiation-induced phosphorylated Flk-1 was observed in the combination treatment group, which also showed a large decrease in tumor vascular density by staining of the von Willebrand factor. H460 tumor growth delay was enhanced in the combination treatment group compared with the groups treated with AZD2171 or radiation alone. Additionally, after therapy, Ki67 index showed >4-fold reduction of tumor proliferation in the combination therapy group, which also showed increased intratumoral apoptotic index by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. In conclusion, AZD2171 sensitizes lung tumor xenografts to radiation and inhibits angiogenesis both in vitro and in vivo. When used as a radiation enhancer, AZD2171 has the potential to improve tumor growth delay by inhibiting tumor proliferation and promoting apoptosis. Clinical trials are needed to determine the potential of this combination therapy in patients with locally advanced lung cancer.     

S-1, an oral fluoropyrimidine, enhances radiation response of DLD-1/FU human colon cancer xenografts resistant to 5-FU

S-1, a novel oral fluoropyrimidine, is increasingly used for the treatment of human cancer including gastrointestinal carcinomas. Using the 5-FU resistant DLD-1/FU human colon cancer cell xenografts, the present study investigated whether S-1 enhances the therapeutic efficacy of radiation and if so what are the underlying mechanisms. Nude mice bearing tumor xenografts were treated with radiation, S-1, or both. Tumor growth delay was the treatments' endpoint. To determine whether S-1 enhances intrinsic cell radiosensitivity, we performed clonogenic cell survival assay. Also we assessed the expression of thymidylate synthase (TS) using immunohistochemistry assay. While S-1 or 5 Gy were only slightly effective as single agents in delaying tumor growth, the combined treatment was highly effective. Clonogenic cell survival showed that S-1 strongly enhanced cell radiosensitivity. Immunohistochemistry showed that the expression of TS was down-regulated in tumors treated by S-1 plus radiation. Combined S-1 plus radiation treatment resulted in a synergistic effect in the therapy of 5-FU resistant human colon carcinoma xenografts (EF = 2.06). The effect could be attributed to the ability of S-1 to increase cell radiosensitivity (EF = 1.9) and to the down-regulation of TS involved in cellular processes leading to radio- and (or) chemo-resistance.     

Potentiation of platinum antitumor effects in human lung tumor xenografts by the angiogenesis inhibitor squalamine: effects on tumor neovascularization.

Squalamine is a novel anti-angiogenic aminosterol that is postulated to inhibit neovascularization by selectively inhibiting the sodium-hydrogen antiporter exchanger. To determine how to most effectively use this agent in patients with cancer, we examined the antitumor effects of squalamine with or without cytotoxic agents in human lung cancer xenografts and correlated these observations with the degree of tumor neovascularization. No direct cytotoxic effects of squalamine against tumor cells were observed in vitro with or without cisplatin. Squalamine was effective in inhibiting the establishment of H460 human tumors in BALBc nude mice but was ineffective in inhibiting the growth of H460, CALU-6, or NL20T-A human tumor xenografts when administered i.p. to mice bearing established tumors. However, when combined with cisplatin or carboplatin, squalamine increased tumor growth delay by > or =1.5-fold in the three human lung carcinoma cell lines compared with cisplatin or carboplatin alone. No enhancement of antitumor activity was observed when squalamine was combined with paclitaxel, vinorelbine, gemcitabine, or docetaxel. Repeated cycles of squalamine plus cisplatin administration delayed H460 tumor growth >8.6-fold. Squalamine plus cisplatin reduced CD31 vessel formation by 25% compared with controls, squalamine alone, or cisplatin alone; however, no inhibition in CD31 vessel formation was observed when squalamine was combined with vinorelbine. These data demonstrate that the combination of squalamine and a platinum analog has significant preclinical antitumor activity against human lung cancer that is related to the anti-angiogenic effects of squalamine.     

Combination of human plasminogen kringle 5 with ionizing radiation significantly enhances the efficacy of antitumor effect

Antiangiogenic therapy could destroy tumor vasculature and inhibit tumor growth. It might inhibit tumor growth significantly when used as a single treatment modality and its therapeutic benefit may even be greater when used in combination with established treatment modalities such as radiation therapy (RT). In the present report, we investigated the effect of recombinant human plasminogen kringle 5 domain (rhK5) in combination with ionizing radiation on angiogenesis, tumor growth and survival in a murine Lewis lung carcinoma (LLC) tumor model. Combined treatment using rhK5 and radiotherapy displayed obvious suppressive effect on LLC tumor growth as compared with single treatment with either modality (p < 0.05), and resulted in a more additive effect on tumor growth delay in this model. In addition, combined treatment significantly enhanced the survival of mice and no toxic effect, such as weight loss, was observed. The significant antitumor effect of rhK5 plus radiation was associated with a direct suppression effect on early neoangiogenesis and tumor cell apoptosis. Furthermore, the expression of VEGF and HIF-1alpha in tumor tissue correlated well with decreased vessel density. The results suggest that rhK5 significantly enhances the antitumor activity of RT and could be a potent adjuvant therapeutic approach to improve the efficacy of radiotherapy for lung cancer.     

Enhancement of radiation effects by combined docetaxel and flavopiridol treatment in lung cancer cells.

BACKGROUND AND PURPOSE: To evaluate the potential role and mechanism of docetaxel plus flavopiridol in modulating radiosensitivity in vitro and in vivo. PATIENTS AND METHODS: In vitro. H460 human lung carcinoma cells were treated with docetaxel (10 nM for 1 h, at t = 0 h) --> radiation (0-5 Gy, at t = 6 h) --> flavopiridol (120 nM for 24 h, at t = 8 h). Colony forming ability was measured to assess the modulation of sensitivity. Cell cycle redistribution was measured by flow cytometric analysis using propidium iodide. Percent apoptosis was also measured by flow cytometric analysis using 7-amino-actinomycin D staining. In vivo. H460 cell xenografts were used in nude mice. Tumors were grown subcutaneously on the flank, then treated with docetaxel (2.5 mg/kg, at t = 0 h) --> radiation (2 Gy, at t = 6 h) --> flavopiridol (1.25 mg/kg, at t = 8 h) for 5 consecutive days. Tumor growth delay was then measured and compared with the control group. RESULTS: Docetaxel plus flavopiridol enhanced the effect of radiation. The maximum radiopotentiation and apoptosis were observed when the cells were treated with the sequence of docetaxel-->radiation-->flavopiridol both in vitro and in vivo. Flavopiridol and docetaxel induced G1 and G2/M arrest, respectively. CONCLUSIONS: This study shows that docetaxel plus flavopiridol enhances the effects of radiation in vitro and in vivo. Our data suggest that the mechanism of radiopotentiation by combining flavopiridol and docetaxel involves an enhancement of apoptosis and changes of cell cycle by docetaxel and flavopiridol.     

Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa).

PURPOSE: The epidermal growth factor receptor (EGFR) is expressed in the majority of human epithelial cancers and has been implicated in the development of cancer cell resistance to cyotoxic drugs and to ionizing radiation. Experimental Design: We used ZD1839, a selective small molecule EGFR tyrosine kinase inhibitor currently in clinical development. We tested the antiproliferative and the proapoptotic activity of ZD1839 in combination with ionizing radiation in human colon (GEO), ovarian (OVCAR-3), non-small cell lung (A549 and Calu-6), and breast (MCF-7 ADR) cancer cell lines. The antitumor activity of this combination was also tested in nude mice bearing established GEO colon cancer xenografts. RESULTS: With ionizing radiation or ZD1839, a dose-dependent growth inhibition was observed in all of the cancer cell lines growing in soft agar. A cooperative antiproliferative and proapoptotic effect was obtained when cancer cells were treated with ionizing radiation followed by ZD1839. This effect was accompanied by inhibition in the expression of the antiapoptotic proteins bcl-xL and bcl-2, and by a suppression of the activated (phosphorylated) form of akt protein. Treatment of mice bearing established human GEO colon cancer xenografts with radiotherapy (RT) resulted in a dose-dependent tumor growth inhibition that was reversible upon treatment cessation. Long term GEO tumor growth regressions were obtained after RT in combination with ZD1839. This resulted in a significant improvement in survival of these mice as compared with the control group (P < 0.001), the RT-treated group (P < 0.001), or the ZD1839-treated group (P < 0.001). The only mice alive 10 weeks after tumor cell injection were in the RT-plus-ZD1839 group. Furthermore, 10% of mice in this group were alive and tumor-free after 26 weeks. Similar results were obtained in mice bearing established human A549 lung adenocarcinoma xenografts. Finally, the combined treatment with RT plus ZD1839 was accompanied by a significant potentiation in the inhibition of transforming growth factor alpha, vascular epidermal growth factor, and basic fibroblast growth factor expression in cancer cells, which resulted in significant antiangiogenic effects as determined by immunohistochemical count of neovessels within the GEO tumors. CONCLUSION: This study provides a rationale for evaluating in cancer patients the combination of ionizing radiation and selective EGFR tyrosine kinase inhibitors such as ZD1839.     

Clusterin is a potential molecular predictor for ovarian cancer patient's survival: targeting Clusterin improves response to paclitaxel

Background

Clusterin is a cytoprotective chaperone protein involved in numerous physiological processes, carcinogenesis, tumor growth and tissue remodelling. The purpose of this study was to investigate whether clusterin (CLU), an antiapoptotic molecule, could be a potential predictor molecule for ovarian cancer and whether or not targeting this molecule can improve survival of ovarian cancer patients.

Methods

Clusterin expression was compared between ten primary and their recurrent tumors from same patients immunohistochemically. We analyzed prognostic significance of CLU expression in another 47 ovarian cancer tissue samples by immunohistochemistry. We used small interference RNA to knock down CLU in the chemo-resistant ovarian cancer cell lines. KF-TX and SKOV-3-TX, paclitaxel-resistant ovarian cancer cells, were established from parental KF and SKOV-3 chemo-sensitive cell lines, respectively. Either siRNA or second generation antisense oligodeoxynucleotide against CLU (OGX-011), which is currently evaluated in clinical phase II trials in other cancer s, was used to modulate sensitivity to paclitaxel (TX) in ovarian cancer cells in vitro. Cellular viability assay, FACS analysis and annexin V staining were used to evaluate the comparative effect of CLU knocking down in ovarian cancer cells.

Results

Immunohistochemical analysis of CLU expression in primary ovarian cancer tissue specimens and their recurrent counterparts from same patients demonstrated higher expression of CLU in the recurrent resistant tumors compared with their primary tumors. High expression of CLU by immunohistochemistry among 47 surgical tissue specimens of early-stage (stage I/II) ovarian cancer, who underwent complete cytoreduction as a primary surgery, significantly related to poor survival, while none of other clinicopathological factors analyzed were related to survival in this patient cohort. Secretory CLU (s-CLU; 60 KDa) expression was upregulated in TX-resistant ovarian cancer cells compared to parental cells. Transfection of siRNA or OGX-011 clearly reduced CLU expression. Cell viability assay, FACS analysis and annexin V staining demonstrated that targeting CLU expression by siRNA or OGX-011 sensitized ovarian cancer cells to TX.

Conclusion

We conclude that CLU could be a potential molecular target to predict survival while targeting this s-CLU may improve survival of patients with ovarian cancer.     

Preclinical evaluation of the orally active camptothecin analog, RFS-2000 (9-nitro-20(S)-camptothecin) as a radiation enhancer

PURPOSE: To test for enhancement of radiation effects in vitro and in vivo by the orally administered camptothecin derivative, 9-nitrocamptothecin (RFS-2000); to study whether the mechanism of this enhancement involves inhibition of sublethal damage recovery. METHODS AND MATERIALS: In vitro: H460 human lung carcinoma cells were incubated with RFS-2000 for various times at 37 degrees C, irradiated, immediately rinsed, and assessed for colony-forming ability. Sublethal damage recovery (SLDR) was also assessed using two split doses of radiation. In vivo: H460 cell xenografts were used in nude mice. Tumors were grown subcutaneously on the flank, then treated with RFS-2000 (1 mg/kg) and/or radiation (2 Gy) for 5 consecutive days. Tumor growth delay was then measured for each treatment group. RESULTS: Radiation enhancement was observed in vitro for incubation times between 4 and 24 hr with 10 nM RFS-2000. Using a 24-hr treatment, the radiation dose enhancement ratio values (DER) for 5, 10, and 15 nM were 1.22, 1.54, and 2.0, respectively. Incubation with 10 nM RFS-2000 inhibited SLDR by a factor of 2. The results of three independent in vivo experiments showed that RFS-2000 can enhance the effects of fractionated radiotherapy, with an enhancement factor (EF) of 1.64. CONCLUSION: Our results show that RFS-2000 can enhance the effects of radiation in human lung cancer cells both in vitro and in vivo, and that the mechanism of this effect may involve the inhibition of SLDR.     

每周低剂量长春瑞滨、顺铂同步后程适形放射治疗局部晚期非小细胞肺癌的Ⅱ期临床研究

目的：探讨每周低剂量长春瑞滨（NVB）、顺铂（PDD）同步后程适形放射治疗局部晚期非小细胞肺癌（NSCLC）的可行性及观察其近期疗效和毒副反应。方法：首程经病理确诊的21例局部晚期NSCLC（根据UICC1997分期标准ⅢA期8例，ⅢB期13例）患者，符合KPS≥70分，年龄≤70岁，近3月体重下降≤5％，器官功能正常。全部患者均行每周1次低剂量NP方案（NVB12．5mg／m^2，PDD20mg／m^2）化疗，共7～9次。每周化疗结束后立即行放疗，先期同步常规放疗38Gy／19F，继之适形放疗推量至60～64Gy／6～7周；锁骨上区照射者推量至60Gy。结果：21例全部完成治疗计划，可行疗效评估，肺原发灶完全缓解（CR）14、3％（3／21），部分缓解（PR）61、9％（13／21），无变化和进展（NC＋PD）22．8％（5／21），总有效率（CR＋PR）为76．2％（16／21）。1年和2年生存率分别为76．2％、40、8％。3～4级白细胞减少发生率为33．3％（7／21）；3级血小板减少发生率为4．8％（1／21）；3级放射性食管炎9．6％（2／21）；无3级及以上放射性肺炎的发生。加用糖皮质激素后症状及影像学表现均好转，无治疗相关性死亡。结论：同期化疗加适形放疗治疗局部晚期NSCLC能为绝大多数患者耐受，有较好的近期疗效，值得临床进一步研究。