视黄酸可调控的IFNα表达载体的构建及其对肿瘤细胞凋亡的影响
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摘要
视黄酸（retinoic acid，RA）是维生素A的活性代谢产物，具有多种生
物化学功能。RA的许多生物学效应是通过其核受体介导的，视黄酸受体
可分为RAR和RXR两个超家族，每个超家族都有α、β和γ三个成员。
RA与其受体的同源或异源二聚体（RXR/RXR、RAR/RXR）结合后，活
化的受体能与靶基因上的视黄酸反应元件（retinoic acid response
element，RARE）结合而调节基因表达。体内外及临床实验研究表明，RA
可抑制癌细胞增殖、诱导癌细胞分化和细胞凋亡，研究和应用较多的RA
是全反式视黄酸（ATRA）和13-顺式视黄酸（13-cRA）。目前ATRA和13-cRA
已用于白血病、肺癌、胃癌、肾癌、黑色素细胞瘤、鳞状上皮细胞癌、神
经胶质细胞瘤等多种癌症的临床治疗，并有较好的疗效。但是，单用RA
治疗有一定的缺陷：易复发或应用RA治疗一段时间后，患者出现对RA
的抵抗性或耐药性。因此，探索克服RA耐药的方法具有重要的临床意义。
癌症患者出现对RA的抵抗性或耐药性可能与机体加速RA的代谢有
关。α-干扰素（α-interferon，IFNα）不仅可抑制RA的代谢酶——细胞
色素P450的活性而减缓RA的代谢，还能与RA协同调节多种转录因子、
抑癌基因、癌基因的表达而发挥其协同抗肿瘤作用。临床研究表明，RA
和IFNα联合应用对某些白血病和实体瘤细胞的增殖抑制、诱导分化以及
凋亡都有协同效应。但是，临床上联合应用RA和IFNα治疗肿瘤时，RA
有较大的毒副作用，长期全身应用大剂量IFNα也会出现严重毒副效应。
如何才能发挥RA和IFNα的协同抗肿瘤作用，同时又能减轻它们的毒副
效应的研究就显得非常重要。
有研究表明，RA和IFNα单独应用均能提高肿瘤细胞对电离辐射诱
导细胞凋亡的敏感性，联合应用时作用更明显，而且 RA和 IFN a对辐
射引起的机体损伤还具有保护作用。因此，有学者认为，联合应用RA
和 IFN a并结合放疗治疗某些肿瘤是一种有效而可行的治疗策略。但其
分子机制仍不清楚，它们是否能协同上调caspase的表达和／或活性，有
待子深入研究。
针对以上问题，结合国内外研究进展，本研究首先验证了RA可调
控带有RARE的荧光素酶（LUC）报告基因的表达；接着，应用DNA重
组技术构建了带有 RARE的 IFN a表达载体中RARE4二FN a人并用 ELISA
和 RTICR分析证实了 IFN a在 pM朋4－IFN a转染细胞内的表达受 RA
诱导；最后，运用MTT实验、DNA梯形带检测、流式细胞仪分析、核酸
原位分子杂交、RTICR兔疫印迹、caspase活性分析以及caspase抑制
剂应用等技术手段，探讨了 RA及其诱导的 IFN a联合抗肿瘤作用及其可
能分子机制，以及 RA对 pRA朋4IFN a转染肿瘤细胞辐射敏感性的影响
及其可能分子机制。该研究的目的意义在于：（）视黄酸可诱导的干扰素
表达载体的成功构建，使干扰素在靶细胞的高效定位限时表达受控于
RA，体内应用时不仅有利于发挥它们的协同抗肿瘤作用，又能避兔全身
应用 IFN a的严重副效应，为 RA和 IFN a联合治疗肿瘤开辟了新的途径。
Q）探讨 RA和 IFN a协同抗肿瘤作用及其提高肿瘤细胞对电离辐射的
敏感性的可能分子机制，为它们在临床上的联合治疗策略提供理论依据。
主要研究结果和结论如下：
1．带有 RARE的 LUC报告基因表达载体转染 HL－60细胞后，2 X
10‘’mol／L RA处理一定时间，LUC活性升高数十倍。说明 RA可诱导带有
RARE的外源基因的表达，构建RA可调控的目的基因表达载体是可行的。
2．运用 DNA重组技术构建了带有 4个 RARE重复序列的 IFN a的
真核表达载体（pRARE4－IFN a），其转染 HL60、Beau37和 MCF7细
胞，G418筛选稳定表达后，ELISA分析 IFN a表达水平，IFN a分泌量分
别为21、16和24ng／ffil／10‘细胞，RA处理不同时间后，IFN a分泌量均显
著增高，最高时分别达到184、Zll、24lug／ffil八0‘细胞。而经RA处理24h
XI
③
的转染细胞，换无 RA的新鲜培养基继续培养 24h，IFN a分泌量又下降
到接近处理前的水平。表明 pRA旺4 IFN a转染细胞 IFN a表达受 RA诱
导，可限时高效表达，说明 RA可调控的 IFN a表达载体的构建是成功的。
3．pRARE4IFN a转染和未转染的 HL七0和 MCFJ细胞经 RA处理
后，生长减慢、细胞周期被阻滞在G；0。期、细胞凋亡率增加、DNA片
段化百分率升高、并可检测到DNA梯形带，其中，以pRARE4IFN。转
染细胞经 RA处理后变化更显著。说明 RA及其诱导的外源性 IFN a基因
产物也具有协同抗肿瘤作用。体内应用时，IFN a局部限时诱导表达有利
于发挥 IFN a与 RA的协同抗肿瘤作用，还可避免 IFN a的全身性副效应。
4．pRARE4－IFN a转染和未转染的 HL60和 MCF7细胞经 RA处理
后，IRFq和 STATI mRNA水平明显增高，IRF4和 STATI在IFN信号
转导通路中发挥中心作用，RA上调IRF－1和 STATI基因表达可能是RA
和 IFN a协同抗肿瘤的分子机制之一。RA处理后，H
Retinoids are derived from vitamin A, which play an essential role in
normal cell growth and differentiation. Retinoic acid (RA), particularly all-
trans retinoic acid (ATRA), has been regarded as one of the most suitable
agents for differentiative therapy because of its activity on acute promyelocytic
leukemia(APL) cells at relatively low concentrations,which can be reached in
vivo without major toxicities. Indeed, several clinical trials have reported
ATRA efficacy in inducing complete remission in APL patients. Retinoids
mediate their antiproliferative action, as well as their ability to induce
differentiation and apoptosis through their binding and activation of specific
nuclear receptors, ie, RARs or RXRs. These activated nuclear receptors, in turn,
bind to specific DNA sequences called as retinoic acid response element
(RARE) that are located in the regulatory portions of genes and thus modulate
gene activity. Considerable previous studies have demonstrated that retinoids
are promising as chemotherapeutic agents for the prevention and treatment of
several types of cancer. Nevertheless, the recurrence after RA therapy and/or
development of resistance to RA therapy have often been observed in patients.
Therefore, it is necessary to take optimal strategies to overcome the clinical
resistance to RA.
One of the major molecular mechanisms of clinical resistance to RA is
up-regulation of metabolic enzyme of RA in cells stimulated with RA. In our
previous study, as well as in papers from other groups, evidence was reported
that the expression and activity of metabolic enzyme of RA could be inhibited
V
by interferons (IFNs). Numerous studies have demonstrated differentiation
and/or apoptosis induction and growth inhibition in human cancer cells by
treatment with retinoids and IFNs. The combination of both compounds, which
probably act through different molecular mechanisms, often results in a
synergistic amplification. They synergistically inhibited growth and induced
differentiation and apoptosis in several types of cancer, including
hematological malignancies and solid tumors. IFN a even could restore
responsiveness of a subline of HL-60, which was otherwise resistant to the
effects of RA. Although the combination of retinoids and lENs has shown
promising results in preclinical studies and clinical trials, the major toxicities
were not neglectable, and the median duration of response was less than 20
weeks. Thus, it is important and necessary to explore optimal strategies to
relieve the side effects and enhance the response.
In order to relieve the side effects of combination of RA and LEN a,
firstly,the possibility of the expression of exogenous lEN a gene mediated by
RA through RARE was investigated in this paper. An IFN a gene eukaryotic
expression vector containing four copies of RARE (pRARB4-IFN a ) was
constructed with recombinant DNA technique, identificated with restriction
endonuclease digest and PCR and DNA sequence analysis, then transfected
into the cells of HL-60,Bcap-37 and MCF-7 with liposome DOTAP, the
expression of LEN a gene was analyzed in transfected and nontransfected cells
stimulated with RA by RT-PCR and ELISA. Secondly, the synergistic effects
of RA and the transfection of pRARE4-IFN a on the proliferation and
apoptosis of tumor cells and its possible molecular mechanisms were study.
After tested that the expression of lEN a in pRARE4-IFN a transfected cells
was
物化学功能。RA的许多生物学效应是通过其核受体介导的，视黄酸受体
可分为RAR和RXR两个超家族，每个超家族都有α、β和γ三个成员。
RA与其受体的同源或异源二聚体（RXR/RXR、RAR/RXR）结合后，活
化的受体能与靶基因上的视黄酸反应元件（retinoic acid response
element，RARE）结合而调节基因表达。体内外及临床实验研究表明，RA
可抑制癌细胞增殖、诱导癌细胞分化和细胞凋亡，研究和应用较多的RA
是全反式视黄酸（ATRA）和13-顺式视黄酸（13-cRA）。目前ATRA和13-cRA
已用于白血病、肺癌、胃癌、肾癌、黑色素细胞瘤、鳞状上皮细胞癌、神
经胶质细胞瘤等多种癌症的临床治疗，并有较好的疗效。但是，单用RA
治疗有一定的缺陷：易复发或应用RA治疗一段时间后，患者出现对RA
的抵抗性或耐药性。因此，探索克服RA耐药的方法具有重要的临床意义。
癌症患者出现对RA的抵抗性或耐药性可能与机体加速RA的代谢有
关。α-干扰素（α-interferon，IFNα）不仅可抑制RA的代谢酶——细胞
色素P450的活性而减缓RA的代谢，还能与RA协同调节多种转录因子、
抑癌基因、癌基因的表达而发挥其协同抗肿瘤作用。临床研究表明，RA
和IFNα联合应用对某些白血病和实体瘤细胞的增殖抑制、诱导分化以及
凋亡都有协同效应。但是，临床上联合应用RA和IFNα治疗肿瘤时，RA
有较大的毒副作用，长期全身应用大剂量IFNα也会出现严重毒副效应。
如何才能发挥RA和IFNα的协同抗肿瘤作用，同时又能减轻它们的毒副
效应的研究就显得非常重要。
有研究表明，RA和IFNα单独应用均能提高肿瘤细胞对电离辐射诱
导细胞凋亡的敏感性，联合应用时作用更明显，而且 RA和 IFN a对辐
射引起的机体损伤还具有保护作用。因此，有学者认为，联合应用RA
和 IFN a并结合放疗治疗某些肿瘤是一种有效而可行的治疗策略。但其
分子机制仍不清楚，它们是否能协同上调caspase的表达和／或活性，有
待子深入研究。
针对以上问题，结合国内外研究进展，本研究首先验证了RA可调
控带有RARE的荧光素酶（LUC）报告基因的表达；接着，应用DNA重
组技术构建了带有 RARE的 IFN a表达载体中RARE4二FN a人并用 ELISA
和 RTICR分析证实了 IFN a在 pM朋4－IFN a转染细胞内的表达受 RA
诱导；最后，运用MTT实验、DNA梯形带检测、流式细胞仪分析、核酸
原位分子杂交、RTICR兔疫印迹、caspase活性分析以及caspase抑制
剂应用等技术手段，探讨了 RA及其诱导的 IFN a联合抗肿瘤作用及其可
能分子机制，以及 RA对 pRA朋4IFN a转染肿瘤细胞辐射敏感性的影响
及其可能分子机制。该研究的目的意义在于：（）视黄酸可诱导的干扰素
表达载体的成功构建，使干扰素在靶细胞的高效定位限时表达受控于
RA，体内应用时不仅有利于发挥它们的协同抗肿瘤作用，又能避兔全身
应用 IFN a的严重副效应，为 RA和 IFN a联合治疗肿瘤开辟了新的途径。
Q）探讨 RA和 IFN a协同抗肿瘤作用及其提高肿瘤细胞对电离辐射的
敏感性的可能分子机制，为它们在临床上的联合治疗策略提供理论依据。
主要研究结果和结论如下：
1．带有 RARE的 LUC报告基因表达载体转染 HL－60细胞后，2 X
10‘’mol／L RA处理一定时间，LUC活性升高数十倍。说明 RA可诱导带有
RARE的外源基因的表达，构建RA可调控的目的基因表达载体是可行的。
2．运用 DNA重组技术构建了带有 4个 RARE重复序列的 IFN a的
真核表达载体（pRARE4－IFN a），其转染 HL60、Beau37和 MCF7细
胞，G418筛选稳定表达后，ELISA分析 IFN a表达水平，IFN a分泌量分
别为21、16和24ng／ffil／10‘细胞，RA处理不同时间后，IFN a分泌量均显
著增高，最高时分别达到184、Zll、24lug／ffil八0‘细胞。而经RA处理24h
XI
③
的转染细胞，换无 RA的新鲜培养基继续培养 24h，IFN a分泌量又下降
到接近处理前的水平。表明 pRA旺4 IFN a转染细胞 IFN a表达受 RA诱
导，可限时高效表达，说明 RA可调控的 IFN a表达载体的构建是成功的。
3．pRARE4IFN a转染和未转染的 HL七0和 MCFJ细胞经 RA处理
后，生长减慢、细胞周期被阻滞在G；0。期、细胞凋亡率增加、DNA片
段化百分率升高、并可检测到DNA梯形带，其中，以pRARE4IFN。转
染细胞经 RA处理后变化更显著。说明 RA及其诱导的外源性 IFN a基因
产物也具有协同抗肿瘤作用。体内应用时，IFN a局部限时诱导表达有利
于发挥 IFN a与 RA的协同抗肿瘤作用，还可避免 IFN a的全身性副效应。
4．pRARE4－IFN a转染和未转染的 HL60和 MCF7细胞经 RA处理
后，IRFq和 STATI mRNA水平明显增高，IRF4和 STATI在IFN信号
转导通路中发挥中心作用，RA上调IRF－1和 STATI基因表达可能是RA
和 IFN a协同抗肿瘤的分子机制之一。RA处理后，H
Retinoids are derived from vitamin A, which play an essential role in
normal cell growth and differentiation. Retinoic acid (RA), particularly all-
trans retinoic acid (ATRA), has been regarded as one of the most suitable
agents for differentiative therapy because of its activity on acute promyelocytic
leukemia(APL) cells at relatively low concentrations,which can be reached in
vivo without major toxicities. Indeed, several clinical trials have reported
ATRA efficacy in inducing complete remission in APL patients. Retinoids
mediate their antiproliferative action, as well as their ability to induce
differentiation and apoptosis through their binding and activation of specific
nuclear receptors, ie, RARs or RXRs. These activated nuclear receptors, in turn,
bind to specific DNA sequences called as retinoic acid response element
(RARE) that are located in the regulatory portions of genes and thus modulate
gene activity. Considerable previous studies have demonstrated that retinoids
are promising as chemotherapeutic agents for the prevention and treatment of
several types of cancer. Nevertheless, the recurrence after RA therapy and/or
development of resistance to RA therapy have often been observed in patients.
Therefore, it is necessary to take optimal strategies to overcome the clinical
resistance to RA.
One of the major molecular mechanisms of clinical resistance to RA is
up-regulation of metabolic enzyme of RA in cells stimulated with RA. In our
previous study, as well as in papers from other groups, evidence was reported
that the expression and activity of metabolic enzyme of RA could be inhibited
V
by interferons (IFNs). Numerous studies have demonstrated differentiation
and/or apoptosis induction and growth inhibition in human cancer cells by
treatment with retinoids and IFNs. The combination of both compounds, which
probably act through different molecular mechanisms, often results in a
synergistic amplification. They synergistically inhibited growth and induced
differentiation and apoptosis in several types of cancer, including
hematological malignancies and solid tumors. IFN a even could restore
responsiveness of a subline of HL-60, which was otherwise resistant to the
effects of RA. Although the combination of retinoids and lENs has shown
promising results in preclinical studies and clinical trials, the major toxicities
were not neglectable, and the median duration of response was less than 20
weeks. Thus, it is important and necessary to explore optimal strategies to
relieve the side effects and enhance the response.
In order to relieve the side effects of combination of RA and LEN a,
firstly,the possibility of the expression of exogenous lEN a gene mediated by
RA through RARE was investigated in this paper. An IFN a gene eukaryotic
expression vector containing four copies of RARE (pRARB4-IFN a ) was
constructed with recombinant DNA technique, identificated with restriction
endonuclease digest and PCR and DNA sequence analysis, then transfected
into the cells of HL-60,Bcap-37 and MCF-7 with liposome DOTAP, the
expression of LEN a gene was analyzed in transfected and nontransfected cells
stimulated with RA by RT-PCR and ELISA. Secondly, the synergistic effects
of RA and the transfection of pRARE4-IFN a on the proliferation and
apoptosis of tumor cells and its possible molecular mechanisms were study.
After tested that the expression of lEN a in pRARE4-IFN a transfected cells
was
引文
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25． Nanus DM, Geng Y, Shen R, et al. Interaction of retinoic acid and interferon in renal cancer cell lines. J Interferon Cytokine Res. 2000;20 (9) :787-94
26． Cassinat B, Chomienne C. Future perspectives for acute promyelocytic leukemia therapy. Semin Hematol. 2001;38(1) :86-91
27． Warrell RP Jr, de The H, Wang ZY,ET AL.Acute promyelocytic leukemia.N Engl J Med. 1993 ;329(3) :177-89
28． Yamamoto Y, Zolfaghari R, Ross AC. Regulation of CYP26 (cytochrome P450RAI) mRNA expression and retinoic acid metabolism by retinoids and dietary vitamin A in liver of mice and rats.FASEB J. 2000; 14(13) : 2119-27
29． Lippman SM, Lotan R, Schleuniger U. Retinoid-interferon therapy of solid tumors. Int J Cancer. 1997;70(4) :481-483
30． Nason-Burchenal K, Gandini D, Botto M, et al. Interferon augments PML and PML/RAR alpha expression in normal myeloid and acute promyelocytic cells and cooperates with all-trans retinoic acid to induce maturation of a retinoid-resistant promyelocytic cell line. Blood. 1996;
88(10) :3926-36
31． Kolla V,Linder DJ,Weihua X, et al. Modulation of interferon (IFN)-inducible gene expression by retinoic acid. Up-regulation of Stat1 protein in IFN-unresponsive cells. J Biol Chem. 1996;271(18) :10508-10514
32． Leid M, Kastner P, Chambon P. Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci. 1992;17(10) :427-33
33． Costa-Giomi MP, Gaub MP, Chambon P, et al. Characterization of a retinoic acid responsive element isolated by whole genome PCR. Nucleic Acids Res. 1992;20(12) :3223-32
34． Brembeck FH, Kaiser A, Detjen K, et al. Retinoic acid receptor alpha mediates growth inhibition by retinoids in rat pancreatic carcinoma DSL-6A/C1 cells. Br J Cancer. 1998;78(10) :1288-95
35． Baust C, Redpath L, Schwarz E. Different ligand responsiveness of human retinoic-acid-receptor beta-gene transcription in tumorigenic and non-tumorigenic cervical-carcinoma-derived cell lines is mediated through a large retinoic-acid-response domain. Int J Cancer. 1996;67(3) :409-16
36． Gianni M, Zanotta S, Terao M, et al. Interferons induce normal and aberrant retinoic-acid receptors type alpha in acute promyelocytic leukemia cells: potentiation of the induction of retinoid-dependent differentiation markers. Int J Cancer.l996;68(1) :75-83
37． Berg WJ, Nanus DM, Leung A, et al, Up-regulation of retinoic acid receptor beta expression in renal cancers in vivo correlates with response to 13-cis-retinoic acid and interferon-alpha-2a. Clin Cancer Res. 1999; 5(7) :1671-5
38． Chen WT, He RG, Liu XK, et al. Effects of all-trans retinoic acid and interferon-gamma on expression of RAR beta gene in Tca8113 cells. Chin J Dent Res. 1999;2(3-4) :25-30
39． Gastman BR,Atarshi Y,Reichert TE,et al.Fas ligand is expressed on human squamous cell carcinomas of the head and neck,and it promotes apoptosis of T lymphocytes. Cancer Res. 1999;59(20) :5356-64
40． Zhang R, Straus FH, DeGroot LJ. Effective genetic therapy of established medullary thyroid carcinomas with murine interleukin-2: dissemination and cytotoxicity studies in a rat tumor model. Endocrinology. 1999;140(5) : 2152-8
41． Lindner DJ, Borden EC, Kalvakolanu DV. Synergistic antitumor effects of a combination of interferons and retinoic acid on human tumor cells in vitro and in vivo. Clin Cancer Res. 1997;3(6) :931-7
42． Weiss GR, Liu PY, Alberts DS, et al. 13-cis-retinoic acid or all-trans-retinoic acid plus interferon-alpha in recurrent cervical cancer: a Southwest Oncology Group phase II randomized trial. Gynecol Oncol. 1998; 71(3) : 386-90
43． Pelicano L, Brumpt C, Pitha PM, et al. Retinoic acid resistance in NB4 APL cells is associated with lack of interferon-α synthesis, Statl and p48 expression. Oncogene.1999;18(27) :3944-3953
44． Hobeika A,Subramaniam PS,Johnson H. IFN alpha induces the expression of the cyclin-dependent kinase inhibitor p21 in human prostate cancer cells.0ncogene.1997;14(10) :1165-1170
45． Hofmann ER, Boyanapalli M, Lindner DJ, et al. Thioredoxin reductase mediates cell death effects of the combination of beta interferon and retinoic acid. Mol Cell Biol. 1998;18(11) :6493-504
46． Angell JE, Lindner DJ, Shapiro PS, et al. Identification of GRIM-19, a novel cell death-regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach. J Biol Chem. 2000; 275(43) :33416-26
47． 熊世勤,朱锡华,黄云辉。一种快速分离细胞调亡片段化DNA的简
单方法--NP-40法。免疫学杂志, 2000; 16 (3) : 228-31
48． Lenardo MJ. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature. 1991;353(6347) :858-61
49． Sun WH,Pabon C,Alsayed Y, et al. Interferon-a resistance in a cutaneous T-cell lymphoma cell line is associated with lack of Statl expression. Blood. 1998;91(2) :570-576
50． Percario ZA, Giandomenico V, Fiorucci G, et al. Retinoic acid is able to induce interferon regulatory factor 1 in squamous carcinoma cells via a STAT-1 independent signalling pathway.Cell Growth Differ. 1999; 10(4) : 263-70
51． Jarry A, Vallette G, Cassagnau E, et al. Interleukin 1 and interleukin 1 beta converting enzyme (caspase 1) expression in the human colonic epithelial barrier. Caspase 1 downregulation in colon cancer. Gut. 1999;45(2) :246-51
52． Donoghue S, Baden HS, Lauder I, et al. Immunohistochemical localization of caspase-3 correlates with clinical outcome in B-cell diffuse large-cell lymphoma. Cancer Res. 1999;59(20) :5386-91
53． Warrell RP Jr, Frankel SR, Miller WH Jr, et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid).N Engl JMed. 1991;324(20) :1385-93
54． Castleberry RP, Emanuel PD, Zuckerman KS, et al. A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia.N Engl JMed. 1994;331(25) :1680-4
55． Cheng AL, Su IJ, Chen CC, et al. Use of retinoic acids in the treatment of peripheral T-cell lymphoma: a pilot study. J Clin Oncol. 1994;12(6) :1185-92
56． Buer J, Probst M, Duensing S, et al. Clinical and in vitro response to 13-cis-retinoic acid in interferon-alpha resistant renal cell carcinoma. Cancer Biother Radiopharm. 1997; 12(3) : 143-7
57.Pfeffer LM,Dinarello CA,Herberman RB,et al.Biological properties of recombinant alpha-interferons:40~(th) anniverary of the discovery of interferons.Cancer Res.1998;58:2489-99
58.Gongora C, Degols G, Espert L, et al. A unique ISRE, in the TATA-Iess human Isg20 promoter, confers IRF-1-mediated responsiveness to both interferon typeⅠand type Ⅱ. Nucleic Acids Res. 2000;28(12): 2333-41
59.Williams BR. Transcriptional regulation of interferon-stimulated genes. Eur J Biochem. 1991;200(1):1-11
60．张乾勇，糜漫天，郎海滨等。视黄酸诱导HL-60细胞分化中对细胞周期素依赖性激酶的影响。中华血液学杂志，1999；20(2)：85
61.Tanaka N, Ishihara M, Lamphier MS, et al. Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damage. Nature. 1996;382(6594):816-8
62.Yuan J, Shaham S, Ledoux S,et al. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. 1993;75(4):641-52
63.Varfolomeev EE, Schuchmann M, Luria V,et al. Targeted disruption of the mouse caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apol, and DR3 and is lethal prenatally. Immunity. 1998;9(2):267-76
64.Stennicke HR, Jürgensmeier JM, Shin H, et al. Pro-caspase-3 is a major physiologic target of caspase-8. J Biol Chem. 1998; 273(42): 27084-27090
65.Zheng TS, Hunot S, Kuida K,et al. Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation. Nat Med. 2000;6(11):1241-7
66.Gianni M, Ponzanelli I, Mologni L,et al. Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases. Cell Death Differ. 2000;7(5):447-60
67.Mologni L, Ponzanelli I, Bresciani F, et al. The novel synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxy-lic acid (CD437) causes apoptosis in acute promyelocytic leukemia cells through rapid activation of caspases. Blood. 1999;93(3):1045-61
68．陈永乐。Fas-FasL凋亡途径和白血病。国外医学·生理、病理科学与临床分册。2000；20(2)：143-145
69.Eberstadt M, Huang B, Chen Z,et al. NMR structure and mutagenesis of the FADD (Mortl) death-effector domain. Nature.1998;392(6679):941-5
70.Muzio M, Chinnaiyan AM, Kischkel FC,et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell. 1996; 85(6):817-27
71.Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science.1998;281:1305-8
72.Liu J, Guo L, Jun-Wei L,et al. All-trans retinoic acid modulates fas expression and enhances chemosensitivity of human medulloblastoma cells. Int J Mol Med. 2000;5(2):145-9
73.Muschen M, Warskulat U, Schmidt B, et al. Regulation of CD95 (Apo-1/Fas) ligand and receptor expression in human embryonal carcinoma cells by interferon gamma and all-trans retinoic acid. Biol Chem. 1998;379(8-9):1083-91
74.Hoffmann W, Schiebe M, Hirnle P, et al. 13-cis retinoic acid and interferon-alpha irradiation in the treatment of squamous-cell carcinomas. Int J Cancer. 1997;70(4):475-7
75.Mason KA, Tofilon PJ. Unexpected radiation protection with 13-cis-retinoic acid plus interferon alpha-2a. Cancer Chemother Pharmacol. 1994;33(5):435-7
76.Ivanov AA, Kuznetsov VP, Ulanova AM, et al. Therapeutic antiradiation properties of leukinferon. Radiats Biol Radioecol. 1998; 38(1):62-70.
77.Ortaldo JR, McCoy JL. Protective effects of interferon in mice previously galatosytransferase after the acrosome reaction. J Cell Biol,1987,105:1663-1670.
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78． Broaddus WC, Liu Y, Steele LL, et al.Enhanced radio sensitivity of malignant giioma cells after adenoviral p53 transduction. J Neurosurg. 1999;91(6) :997-1004
79． Zhao QL, Kondo T, Noda A, et al. Mitochondrial and intracellular free-calcium regulation of radiation-induced apoptosis in human leukemic cells. Int J Radiat Biol. 1999;75(4) :493-504
80． Belka C, Marini P, Budach W, et al.Radiation-induced apoptosis in human lymphocytes and lymphoma cells critically relies on the up-regulation of CD95/Fas/APO-l ligand. Radiat Res. 1998;149(6) :588-95
81． Slee EA, Keogh SA, Martin SJ. Cleavage of BID during cytotoxic drug and UV radiation-induced apoptosis occurs downstream of the point of Bcl-2 action and is catalysed by caspase-3: a potential feedback loop for amplification of apoptosis-associated mitochondrial cytochrome c release. Cell Death Differ. 2000; 7(6) :556-65
82． Chan WH, Yu JS. Inhibition of UV irradiation-induced oxidative stress and apoptotic biochemical changes in human epidermal carcinoma A431 cells by genistein. J Cell Biochem. 2000;78(1) :73-84
83． Voehringer DW, Hirschberg DL, Xiao J, et al. Gene microarray identification of redox and mitochondrial elements that control resistance or sensitivity to apoptosis. Proc Nat1 Acad Sci USA. 2000;97(6) :2680-5
84． von Ahsen O, Renken C, Perkins G, et al. Preservation of mitochondrial structure and function after Bid-or Bax-mediated cytochrome c release. J Cell Biol. 2000; 150(5) : 1027-36
85． Kulms D, Poppelmann B, Yarosh D, et al.Nuclear and cell membrane effects contribute independently to the induction of apoptosis in human cells exposed to UVB radiation. Proc Natl Acad Sci USA. 1999; 96(14) : 7974-9
86． Park HS, Huh SH, Kim Y, et al.Selenite negatively regulates caspase-3 through a redox mechanism. J Biol Chem. 2000;275(12) : 8487-91
87． Coelho D, Holl V, Weltin D, et al. Caspase-3-like activity determines the type of cell death following ionizing radiation in MOLT-4 human leukaemia cells. Br J Cancer. 2000;83(5) :642-9
2． Lotan R. Retinoids in cancer chemoprevention. FASEB J. 1996;10:1031-1039
3． Liu M,Lavarone A,Freedman LP. Transcriptional activation of the p21(WAF/CIP1) gene by retinoic acid receptor: Correlation with retinoid induction of U937 cell differentiation. J Biol Chem. 1996;271(49) :31723-31728
4． De Luca LM. Retinoids and their receptors in differentiation, embryogenesis, and neoplasia. FASEB J. 1991;5(14) :2924-33
5． Evans TR, Kaye SB. Retinoids: present role and future potential. Br J Cancer. 1999;80(1-2) :1-8
6． Chomienne C, Fenaux P, Degos L. Retinoid differentiation therapy in promyelocytic leukemia. FASEB J. 1996;10(9) :1025-30
7． Cornic M, Agadir A, Degos L, et al. Retinoids and differentiation treatment: a strategy for treatment in cancer. Anticancer Res. 1994; 14(6A):2339-46
8． Kizaki M, Ueno H, Matsushita H, et al. Retinoid resistance in leukemic cells. Leuk Lymphoma. 1997;25(5-6) :427-34
9． Lin CP, Huang MJ, Chang IY,et al.Successful treatment of all-trans retinoic acid resistant and chemotherapy naive acute promyelocytic patients with arsenic trioxide-two case reports. Leuk Lymphoma. 2000;38(1-2) : 191-4
10． Lazzarino M, Regazzi MB, Corso A. Clinical relevance of all-trans retinoic acid pharmacokinetics and its modulation in acute promyelocytic leukemia. Leuk Lymphoma. 1996;23(5-6) :539-43
11． Lazzarino M, Corso A, Regazzi MB, et al. Modulation of all-trans retinoid acid pharmacokinetics in acute promyelocytic leukaemia by prolonged interferon-alpha therapy. Br JHaematol. 1995;90(4) :928-30
12． 糜漫天,张乾勇,朱俊东。视黄酸诱导细胞分化的分子机制研究进展,国外医学分子生物学分册, 1998;20(1) :17-19
13． Pelicano L,Li F,Schindler C, et al. Retinoic acid enhances the expression of interferon-induced proteins: evidence for multiple mechanisms of action. Oncogene,1997,15(19) :2349-2359
14． Weihua X,Kolla V,Kalvakolanu DV. Modulation of interferon action by retinoids. Induction of murine Statl gene expression by retinoic acid. J Biol Chem. 1997;272(15) :9742-9748
15． Motzer RJ, Murphy BA, Bacik J, et al. Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol. 2000;18(16) :2972-80
16． Cohen GM. Caspases: the executioners of apoptosis. Biochem J. 1997 ;326 (Pt 1) :1-16
17． Nicholson DW, Thornberry NA. Caspases: killer proteases. Trends Biochem Sci. 1997;22(8) :299-306
18． Wolf BB, Green DR. Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem. 1999;274(29) :20049-52
19． Malone C,Schiltz PM,Nayak SK, et al. Combination interferon-alpha2a and 13-cis-retinoic acid enhances radiosensitization of human malignant glioma cells in vitro. Clin Cancer Res. 1999;5(2) :417-423
20． Syljuasen RG, Belldegrun A, Tso CL, et al. Sensitization of renal carcinoma to radiation using alpha interferon (IFNA) gene transfection. Radiat Res. 1997;148(5) :443-8
21． Sanceau J, Hiscott J, Delattre O, et al.IFN-beta induces serine phosphory-lation of Stat-1 in Ewing's sarcoma cells and mediates apoptosis via
induction of IRF-1 and activation of caspase-7． Oncogene. 2000; 19(30) : 3372-83
22． Kumar A, Commane M, Flickinger TW, et al. Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science. 1997;278(5343) : 1630-2
23． Chelbi-Alix MK.Pelicano L. Retinoic acid and interferon signaling cross talk in normal and RA-resistant APL cells. Leukemia. 1999;13(8) :1167-1174
24． Brodowicz T, Wiltschke C, Kandioler-Eckersberger D, et al. Inhibition of proliferation and induction of apoptosis in soft tissue sarcoma cells by interferon-alpha and retinoids. Br J Cancer. 1999;80(9) :1350-8
25． Nanus DM, Geng Y, Shen R, et al. Interaction of retinoic acid and interferon in renal cancer cell lines. J Interferon Cytokine Res. 2000;20 (9) :787-94
26． Cassinat B, Chomienne C. Future perspectives for acute promyelocytic leukemia therapy. Semin Hematol. 2001;38(1) :86-91
27． Warrell RP Jr, de The H, Wang ZY,ET AL.Acute promyelocytic leukemia.N Engl J Med. 1993 ;329(3) :177-89
28． Yamamoto Y, Zolfaghari R, Ross AC. Regulation of CYP26 (cytochrome P450RAI) mRNA expression and retinoic acid metabolism by retinoids and dietary vitamin A in liver of mice and rats.FASEB J. 2000; 14(13) : 2119-27
29． Lippman SM, Lotan R, Schleuniger U. Retinoid-interferon therapy of solid tumors. Int J Cancer. 1997;70(4) :481-483
30． Nason-Burchenal K, Gandini D, Botto M, et al. Interferon augments PML and PML/RAR alpha expression in normal myeloid and acute promyelocytic cells and cooperates with all-trans retinoic acid to induce maturation of a retinoid-resistant promyelocytic cell line. Blood. 1996;
88(10) :3926-36
31． Kolla V,Linder DJ,Weihua X, et al. Modulation of interferon (IFN)-inducible gene expression by retinoic acid. Up-regulation of Stat1 protein in IFN-unresponsive cells. J Biol Chem. 1996;271(18) :10508-10514
32． Leid M, Kastner P, Chambon P. Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci. 1992;17(10) :427-33
33． Costa-Giomi MP, Gaub MP, Chambon P, et al. Characterization of a retinoic acid responsive element isolated by whole genome PCR. Nucleic Acids Res. 1992;20(12) :3223-32
34． Brembeck FH, Kaiser A, Detjen K, et al. Retinoic acid receptor alpha mediates growth inhibition by retinoids in rat pancreatic carcinoma DSL-6A/C1 cells. Br J Cancer. 1998;78(10) :1288-95
35． Baust C, Redpath L, Schwarz E. Different ligand responsiveness of human retinoic-acid-receptor beta-gene transcription in tumorigenic and non-tumorigenic cervical-carcinoma-derived cell lines is mediated through a large retinoic-acid-response domain. Int J Cancer. 1996;67(3) :409-16
36． Gianni M, Zanotta S, Terao M, et al. Interferons induce normal and aberrant retinoic-acid receptors type alpha in acute promyelocytic leukemia cells: potentiation of the induction of retinoid-dependent differentiation markers. Int J Cancer.l996;68(1) :75-83
37． Berg WJ, Nanus DM, Leung A, et al, Up-regulation of retinoic acid receptor beta expression in renal cancers in vivo correlates with response to 13-cis-retinoic acid and interferon-alpha-2a. Clin Cancer Res. 1999; 5(7) :1671-5
38． Chen WT, He RG, Liu XK, et al. Effects of all-trans retinoic acid and interferon-gamma on expression of RAR beta gene in Tca8113 cells. Chin J Dent Res. 1999;2(3-4) :25-30
39． Gastman BR,Atarshi Y,Reichert TE,et al.Fas ligand is expressed on human squamous cell carcinomas of the head and neck,and it promotes apoptosis of T lymphocytes. Cancer Res. 1999;59(20) :5356-64
40． Zhang R, Straus FH, DeGroot LJ. Effective genetic therapy of established medullary thyroid carcinomas with murine interleukin-2: dissemination and cytotoxicity studies in a rat tumor model. Endocrinology. 1999;140(5) : 2152-8
41． Lindner DJ, Borden EC, Kalvakolanu DV. Synergistic antitumor effects of a combination of interferons and retinoic acid on human tumor cells in vitro and in vivo. Clin Cancer Res. 1997;3(6) :931-7
42． Weiss GR, Liu PY, Alberts DS, et al. 13-cis-retinoic acid or all-trans-retinoic acid plus interferon-alpha in recurrent cervical cancer: a Southwest Oncology Group phase II randomized trial. Gynecol Oncol. 1998; 71(3) : 386-90
43． Pelicano L, Brumpt C, Pitha PM, et al. Retinoic acid resistance in NB4 APL cells is associated with lack of interferon-α synthesis, Statl and p48 expression. Oncogene.1999;18(27) :3944-3953
44． Hobeika A,Subramaniam PS,Johnson H. IFN alpha induces the expression of the cyclin-dependent kinase inhibitor p21 in human prostate cancer cells.0ncogene.1997;14(10) :1165-1170
45． Hofmann ER, Boyanapalli M, Lindner DJ, et al. Thioredoxin reductase mediates cell death effects of the combination of beta interferon and retinoic acid. Mol Cell Biol. 1998;18(11) :6493-504
46． Angell JE, Lindner DJ, Shapiro PS, et al. Identification of GRIM-19, a novel cell death-regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach. J Biol Chem. 2000; 275(43) :33416-26
47． 熊世勤,朱锡华,黄云辉。一种快速分离细胞调亡片段化DNA的简
单方法--NP-40法。免疫学杂志, 2000; 16 (3) : 228-31
48． Lenardo MJ. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature. 1991;353(6347) :858-61
49． Sun WH,Pabon C,Alsayed Y, et al. Interferon-a resistance in a cutaneous T-cell lymphoma cell line is associated with lack of Statl expression. Blood. 1998;91(2) :570-576
50． Percario ZA, Giandomenico V, Fiorucci G, et al. Retinoic acid is able to induce interferon regulatory factor 1 in squamous carcinoma cells via a STAT-1 independent signalling pathway.Cell Growth Differ. 1999; 10(4) : 263-70
51． Jarry A, Vallette G, Cassagnau E, et al. Interleukin 1 and interleukin 1 beta converting enzyme (caspase 1) expression in the human colonic epithelial barrier. Caspase 1 downregulation in colon cancer. Gut. 1999;45(2) :246-51
52． Donoghue S, Baden HS, Lauder I, et al. Immunohistochemical localization of caspase-3 correlates with clinical outcome in B-cell diffuse large-cell lymphoma. Cancer Res. 1999;59(20) :5386-91
53． Warrell RP Jr, Frankel SR, Miller WH Jr, et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid).N Engl JMed. 1991;324(20) :1385-93
54． Castleberry RP, Emanuel PD, Zuckerman KS, et al. A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia.N Engl JMed. 1994;331(25) :1680-4
55． Cheng AL, Su IJ, Chen CC, et al. Use of retinoic acids in the treatment of peripheral T-cell lymphoma: a pilot study. J Clin Oncol. 1994;12(6) :1185-92
56． Buer J, Probst M, Duensing S, et al. Clinical and in vitro response to 13-cis-retinoic acid in interferon-alpha resistant renal cell carcinoma. Cancer Biother Radiopharm. 1997; 12(3) : 143-7
57.Pfeffer LM,Dinarello CA,Herberman RB,et al.Biological properties of recombinant alpha-interferons:40~(th) anniverary of the discovery of interferons.Cancer Res.1998;58:2489-99
58.Gongora C, Degols G, Espert L, et al. A unique ISRE, in the TATA-Iess human Isg20 promoter, confers IRF-1-mediated responsiveness to both interferon typeⅠand type Ⅱ. Nucleic Acids Res. 2000;28(12): 2333-41
59.Williams BR. Transcriptional regulation of interferon-stimulated genes. Eur J Biochem. 1991;200(1):1-11
60．张乾勇，糜漫天，郎海滨等。视黄酸诱导HL-60细胞分化中对细胞周期素依赖性激酶的影响。中华血液学杂志，1999；20(2)：85
61.Tanaka N, Ishihara M, Lamphier MS, et al. Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damage. Nature. 1996;382(6594):816-8
62.Yuan J, Shaham S, Ledoux S,et al. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. 1993;75(4):641-52
63.Varfolomeev EE, Schuchmann M, Luria V,et al. Targeted disruption of the mouse caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apol, and DR3 and is lethal prenatally. Immunity. 1998;9(2):267-76
64.Stennicke HR, Jürgensmeier JM, Shin H, et al. Pro-caspase-3 is a major physiologic target of caspase-8. J Biol Chem. 1998; 273(42): 27084-27090
65.Zheng TS, Hunot S, Kuida K,et al. Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation. Nat Med. 2000;6(11):1241-7
66.Gianni M, Ponzanelli I, Mologni L,et al. Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases. Cell Death Differ. 2000;7(5):447-60
67.Mologni L, Ponzanelli I, Bresciani F, et al. The novel synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxy-lic acid (CD437) causes apoptosis in acute promyelocytic leukemia cells through rapid activation of caspases. Blood. 1999;93(3):1045-61
68．陈永乐。Fas-FasL凋亡途径和白血病。国外医学·生理、病理科学与临床分册。2000；20(2)：143-145
69.Eberstadt M, Huang B, Chen Z,et al. NMR structure and mutagenesis of the FADD (Mortl) death-effector domain. Nature.1998;392(6679):941-5
70.Muzio M, Chinnaiyan AM, Kischkel FC,et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell. 1996; 85(6):817-27
71.Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science.1998;281:1305-8
72.Liu J, Guo L, Jun-Wei L,et al. All-trans retinoic acid modulates fas expression and enhances chemosensitivity of human medulloblastoma cells. Int J Mol Med. 2000;5(2):145-9
73.Muschen M, Warskulat U, Schmidt B, et al. Regulation of CD95 (Apo-1/Fas) ligand and receptor expression in human embryonal carcinoma cells by interferon gamma and all-trans retinoic acid. Biol Chem. 1998;379(8-9):1083-91
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