纖維肉瘤是軟組織肉瘤的一種，無論是以放射線治療或化學藥物治療，都發現癌細胞會對這些治療方式產生抗性，因此纖維肉瘤的癒後情況不良。放射線合併化學治療的方法是目前臨床上常見的惡性腫瘤治療模式，以提高癌症病人的存活率與病情控制。放射線治療可以誘使細胞產生不同的細胞反應，包括誘發DNA的傷害及G2/M期停滯。而化學治療藥物三氧化二砷(arsenic trioxide, As2O3)可以藉由促進細胞凋亡、誘使細胞分化或是抑制細胞增生與血管新生來達到治療癌症的功效。本篇研究最主要的目的在探討當合併放射線與三氧化二砷治療時，是否會增加對纖維肉瘤HT1080細胞的毒性並進一步探討其作用機制。在細胞實驗中，利用trypan blue來計算細胞存活率；使用流式細胞儀分析細胞週期、活性氧化物含量、粒線體膜電位的變化，及藉由annexin V-FITC分析早期細胞凋亡現象；DNA ladder則用來分析DNA的片段化；利用acridine orange染色觀察自體吞噬的酸性小泡(AVOs)產生；Western blotting則用來探討細胞凋亡與自體吞噬相關蛋白的表現；最後，並利用腫瘤異種移植之活體動物模式來探討放射線合併三氧化二砷的治療效果。結果指出，合併治療模式不論二者同時處理(co-treat)與先處理放射線後再加入三氧化二砷(post-treat)的方式，都比單獨處理放射線或三氧化二砷的效果好，包括降低細胞存活率及粒線體膜電位，增加細胞週期G2/M期的停滯、ROS的產生、以及早期細胞凋亡和自體吞噬百分比。在蛋白質表現量方面，合併治療可以增加p53、p21、p-cdc2、cyclin B1、p-cdc25c、LC3的表現，p-ERK、Bax、Hsp70及PARP的表現也有些微增加，cdc25c、bcl-2的表現量則是下降的趨勢，cyclin A、cdc2、Akt、p-Akt等蛋白沒有明顯改變。動物實驗中則發現，相較於單獨處理三氧化二砷與放射線的組別，合併處理可以有效抑制腫瘤的生長。此研究證明，三氧化二砷和放射線的合併治療能使具有抗性的HT1080細胞株死亡，達到癌症治療的效果，而其所誘發的死亡方式則包含了細胞凋亡及自體吞噬。

Fibrosarcoma is one of soft tissue sracoma which is resistance to radiotherapy and chemotherapy, and the prognosis is extremely poor. Currently, combined chemotherapy and radiotherapy has been shown in clinical to produced an improved survival and an improved disease control for cancer patients. Irradiation (IR) is thought to kill cells by causing DNA damage and inducing G2/M arrest. The anti-cancer effects of arsenic trioxide (ATO), a chemotherapeutic agent, has been attributed to the induction of apoptosis, inhibition of proliferation and angiogenesis, and promotion of differentiation. The major propose of this study is to investigate the cytotoxic mechanism of irradiation combined with arsenic trioxide in the treatment of fibrosarcoma HT1080 cells. In in vitro study, cell viability was detected by trypan blue. Cell cycle distribution, ROS, membrane potential and early apoptosis with annexin V-FITC apoptosis detection kit was analyzed by flow cytometry. DNA fragmentation was detected by agarose gel electrophoresis. In order to observe the expression of acidic vesicular organelle (AVOs) which is characteristic of autophagy; cells were stained with acridine orange. Western blotting was performed to analysis the expression of protein related to apoptosis and autophagy. In in vivo study, therapeutic efficacy of ATO and IR in HT1080 cells xenografts after treatment was assessed. Our results indicated the combination of IR and ATO was shown to be significantly more active than either treatment alone in two combination sequences comcomitant treatment, or sequential treatment with IR followed by ATO in HT1080 cells. Combined treatment decreased cell viability, caused membrane potential damage, and cell cycle G2/M arrest. They also increased the persentage of intracellular ROS, apoptosis and autophagy. The expression level of p53, p21, p-cdc2, cyclin B1, p-cdc25c and LC3 was increased significantly, however, p-ERK, Bax, Hsp70 and PARP were increased slightly. Decrement of cdc25c and bcl-2 expression was observed. Otherwise, no significantly change was found in the expression of cyclin A, cdc2, Akt and p-Akt. In in vivo study, combined treatment with IR and ATO inhibited tumor growth significantly than either treated alone. Taken together, this study demonstrated that IR combined with ATO may increase therapeuic efficacy of HT1080 cells. The cell death mechanisms induced by this combined treatment include apoptosis and autophagy.

壹、序 論 1
貳、文獻回顧 2
第一節 軟組織肉瘤及治療策略 2
第二節 人類纖維肉瘤及其治療 2
第三節 放射線治療 4
第四節 化學治療法 5
第五節 三氧化二砷與其醫療用途 5
第六節 放射線合併化學治療 8
第七節 細胞週期與放射線敏感性 9
第八節 細胞凋亡(Apoptosis)與自體吞噬(Autophagy) 10
?、研究目的 13
肆、研究架構 14
伍、研究材料與方法 16
研究材料
(一) 細胞株 16
(二) 儀器 16
(三) 試劑 17
(四) 溶液 18
研究方法
(一) 細胞培養 19
(二) 細胞解凍 20
(三) 細胞繼代培養 20
(四) 細胞冷凍 20
(五) 細胞計數 21
(六) 細胞週期分析 21
(七) 活性氧物種(ROS)分析 22
(八) 粒線體膜電位分析 22
(九) 細胞凋亡分析 22
(十) 自體吞噬(細胞自噬)分析 23
(十一) DNA ladder Analysis 23
(十二) Acridine orange免疫螢光染色 24
(十三) Western blotting 24
(十四) BALB/c nu/nu mice腫瘤誘發實驗 27
(十五) 統計分析 28
陸、實驗結果 30
第一節 放射線和三氧化二砷對HT1080細胞的劑量及時間效應 30
第二節 放射線合併三氧化二砷對HT1080細胞的細胞週期變化 31
第三節 探討放射線與三氧化二砷對HT1080細胞凋亡現象 32
第四節 分析HT1080細胞Autophagy的表現 33
第五節 細胞訊息傳遞路徑之相關蛋白表現 34
第六節 腫瘤異種移植活體動物模式 35
柒、討 論 36
捌、結論與建議 40
玖、參考文獻 41
圖表 51

Amaravadi, R.K., Thompson, C.B., 2007. The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin Cancer Res 13, 7271-7279.
Auclair, P.L., Langloss, J.M., Weiss, S.W., Corio, R.L., 1986. Sarcomas and sarcomatoid neoplasms of the major salivary gland regions. A clinicopathologic and immunohistochemical study of 67 cases and review of the literature. Cancer 58, 1305-1315.
Baj, G., Arnulfo, A., Deaglio, S., Mallone, R., Vigone, A., De Cesaris, M.G., Surico, N., Malavasi, F., Ferrero, E., 2002. Arsenic trioxide and breast cancer: analysis of the apoptotic, differentiative and immunomodulatory effects. Breast Cancer Res Treat 73, 61-73.
Bode, A.M., Dong, Z., 2002. The paradox of arsenic: molecular mechanisms of cell transformation and chemotherapeutic effects. Crit Rev Oncol Hematol 42, 5-24.
Bursch, W., Ellinger, A., Gerner, C., Frohwein, U., Schulte-Hermann, R., 2000. Programmed cell death (PCD). Apoptosis, autophagic PCD, or others? Ann N Y Acad Sci 926, 1-12.
Cavigelli, M., Li, W.W., Lin, A., Su, B., Yoshioka, K., Karin, M., 1996. The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase. EMBO J 15, 6269-6279.
Charrier-Savournin, F.B., Chateau, M.T., Gire, V., Sedivy, J., Piette, J., Dulic, V., 2004. p21-Mediated nuclear retention of cyclin B1-Cdk1 in response to genotoxic stress. Mol Biol Cell 15, 3965-3976.
Chen, G.Q., Shi, X.G., Tang, W., Xiong, S.M., Zhu, J., Cai, X., Han, Z.G., Ni, J.H., Shi, G.Y., Jia, P.M., Liu, M.M., He, K.L., Niu, C., Ma, J., Zhang, P., Zhang, T.D., Paul, P., Naoe, T., Kitamura, K., Miller, W., Waxman, S., Wang, Z.Y., de The, H., Chen, S.J., Chen, Z., 1997. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 89, 3345-3353.
Chen, Y., Pandya, K., Keng, P.P., Feins, R., Raubertas, R., Smudzin, T., Rosenblatt, J., Okunieff, P., 2001. Schedule-dependent pulsed paclitaxel radiosensitization for thoracic malignancy. Am J Clin Oncol 24, 432-437.
Cho, N.H., Cordon-Cardo, C., Li, G.C., Kim, S.H., 2002. Allotype imbalance or microsatellite mutation in low-grade soft tissue sarcomas of the extremities in adults. J Pathol 198, 21-29.
Chun, Y.J., Park, I.C., Park, M.J., Woo, S.H., Hong, S.I., Chung, H.Y., Kim, T.H., Lee, Y.S., Rhee, C.H., Lee, S.J., 2002. Enhancement of radiation response in human cervical cancer cells in vitro and in vivo by arsenic trioxide (As2O3). FEBS Lett 519, 195-200.
Clarke, P.G., 1990. Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol (Berl) 181, 195-213.
Couldwell, W.T., Weiss, M.H., DeGiorgio, C.M., Weiner, L.P., Hinton, D.R., Ehresmann, G.R., Conti, P.S., Apuzzo, M.L., 1993. Clinical and radiographic response in a minority of patients with recurrent malignant gliomas treated with high-dose tamoxifen. Neurosurgery 32, 485-489; discussion 489-490.
Dai, J., Weinberg, R.S., Waxman, S., Jing, Y., 1999. Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. Blood 93, 268-277.
Davison, K., Mann, K.K., Waxman, S., Miller, W.H., Jr., 2004. JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells. Blood 103, 3496-3502.
De Duve, C., Wattiaux, R., 1966. Functions of lysosomes. Annu Rev Physiol 28, 435-492.
Debnath, J., Baehrecke, E.H., Kroemer, G., 2005. Does autophagy contribute to cell death? Autophagy 1, 66-74.
Douer, D., 2002. Advances in the treatment of relapsed acute promyelocytic leukemia. Acta Haematol 107, 1-17.
Edinger, A.L., Thompson, C.B., 2004. Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol 16, 663-669.
El Bougrini, J., Pampin, M., Chelbi-Alix, M.K., 2006. Arsenic enhances the apoptosis induced by interferon gamma: key role of IRF-1. Cell Mol Biol (Noisy-le-grand) 52, 9-15.
Ellington, A.A., Berhow, M.A., Singletary, K.W., 2006. Inhibition of Akt signaling and enhanced ERK1/2 activity are involved in induction of macroautophagy by triterpenoid B-group soyasaponins in colon cancer cells. Carcinogenesis 27, 298-306.
Eymin, B., Leduc, C., Coll, J.L., Brambilla, E., Gazzeri, S., 2003. p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice. Oncogene 22, 1822-1835.
Fuchs, J., Huflejt, M.E., Rothfuss, L.M., Wilson, D.S., Carcamo, G., Packer, L., 1989. Impairment of enzymic and nonenzymic antioxidants in skin by UVB irradiation. J Invest Dermatol 93, 769-773.
Glantz, M.J., Burger, P.C., Friedman, A.H., Radtke, R.A., Massey, E.W., Schold, S.C., Jr., 1994. Treatment of radiation-induced nervous system injury with heparin and warfarin. Neurology 44, 2020-2027.
Gonzalez-Polo, R.A., Boya, P., Pauleau, A.L., Jalil, A., Larochette, N., Souquere, S., Eskelinen, E.L., Pierron, G., Saftig, P., Kroemer, G., 2005. The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death. J Cell Sci 118, 3091-3102.
Griffin, R.J., Williams, B.W., Park, H.J., Song, C.W., 2005. Preferential action of arsenic trioxide in solid-tumor microenvironment enhances radiation therapy. Int J Radiat Oncol Biol Phys 61, 1516-1522.
Gross, A., McDonnell, J.M., Korsmeyer, S.J., 1999. BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13, 1899-1911.
Hallahan, D.E., Virudachalam, S., Schwartz, J.L., Panje, N., Mustafi, R., Weichselbaum, R.R., 1992. Inhibition of protein kinases sensitizes human tumor cells to ionizing radiation. Radiat Res 129, 345-350.
Haykal, J., Fernainy, P., Itani, W., Haddadin, M., Geara, F., Smith, C., Gali-Muhtasib, H., 2008. Radiosensitization of EMT6 mammary carcinoma cells by 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide. Radiother Oncol 86, 412-418.
Ho, S.Y., Huang, P.C., Guo, H.R., Chang, W.H., Chen, R.J., Wei, B.L., Wu, W.J., Tai, C., Wang, Y.J., 2006. Mechanisms of apoptosis induction and cell cycle regulation in irradiated leukemia U937 cells and enhancement by arsenic trioxide. Radiat Res 165, 390-399.
Itani, W., Geara, F., Haykal, J., Haddadin, M., Gali-Muhtasib, H., 2007. Radiosensitization by 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide under oxia and hypoxia in human colon cancer cells. Radiat Oncol 2, 1.
Ito, S., Koshikawa, N., Mochizuki, S., Takenaga, K., 2007. 3-Methyladenine suppresses cell migration and invasion of HT1080 fibrosarcoma cells through inhibiting phosphoinositide 3-kinases independently of autophagy inhibition. Int J Oncol 31, 261-268.
Iwama, K., Nakajo, S., Aiuchi, T., Nakaya, K., 2001. Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+-dependent production of superoxide. Int J Cancer 92, 518-526.
Jeong, S.J., Jin, Y.H., Moon, C.W., Bae, H.R., Yoo, Y.H., Lee, H.S., Lee, S.H., Lim, Y.J., Lee, J.D., Jeong, M.H., 2001. Protein tyrosine kinase inhibitors modulate radiosensitivity and radiation-induced apoptosis in K562 cells. Radiat Res 156, 751-760.
Jiang, T.T., Brown, S.L., Kim, J.H., 2004. Combined effect of arsenic trioxide and sulindac sulfide in A549 human lung cancer cells in vitro. J Exp Clin Cancer Res 23, 259-262.
Jing, Y., Dai, J., Chalmers-Redman, R.M., Tatton, W.G., Waxman, S., 1999. Arsenic trioxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide-dependent pathway. Blood 94, 2102-2111.
Johnson, G.L., Lapadat, R., 2002. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911-1912.
Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y., Yoshimori, T., 2000. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19, 5720-5728.
Kajiguchi, T., Yamamoto, K., Hossain, K., Akhand, A.A., Nakashima, I., Naoe, T., Saito, H., Emi, N., 2003. Sustained activation of c-jun-terminal kinase (JNK) is closely related to arsenic trioxide-induced apoptosis in an acute myeloid leukemia (M2)-derived cell line, NKM-1. Leukemia 17, 2189-2195.
Kang, S.H., Song, J.H., Kang, H.K., Kang, J.H., Kim, S.J., Kang, H.W., Lee, Y.K., Park, D.B., 2003. Arsenic trioxide-induced apoptosis is independent of stress-responsive signaling pathways but sensitive to inhibition of inducible nitric oxide synthase in HepG2 cells. Exp Mol Med 35, 83-90.
Kang, Y.H., Yi, M.J., Kim, M.J., Park, M.T., Bae, S., Kang, C.M., Cho, C.K., Park, I.C., Park, M.J., Rhee, C.H., Hong, S.I., Chung, H.Y., Lee, Y.S., Lee, S.J., 2004. Caspase-independent cell death by arsenic trioxide in human cervical cancer cells: reactive oxygen species-mediated poly(ADP-ribose) polymerase-1 activation signals apoptosis-inducing factor release from mitochondria. Cancer Res 64, 8960-8967.
Kanzawa, T., Kondo, Y., Ito, H., Kondo, S., Germano, I., 2003. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res 63, 2103-2108.
Krutchkoff, D.J., Cutler, L., Laskowski, S., 1978. Oral lichen planus: the evidence regarding potential malignant transformation. J Oral Pathol 7, 1-7.
Kurki, S., Latonen, L., Laiho, M., 2003. Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization. J Cell Sci 116, 3917-3925.
Leist, M., Jaattela, M., 2001. Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2, 589-598.
Li, Y.M., Broome, J.D., 1999. Arsenic targets tubulins to induce apoptosis in myeloid leukemia cells. Cancer Res 59, 776-780.
Lindberg, R.D., Martin, R.G., Romsdahl, M.M., 1975. Surgery and postoperative radiotherapy in the treatment of soft tissue sarcomas in adults. Am J Roentgenol Radium Ther Nucl Med 123, 123-129.
Liu, P., Han, Z.C., 2003. Treatment of acute promyelocytic leukemia and other hematologic malignancies with arsenic trioxide: review of clinical and basic studies. Int J Hematol 78, 32-39.
Lockshin, R.A., Zakeri, Z., 2001. Programmed cell death and apoptosis: origins of the theory. Nat Rev Mol Cell Biol 2, 545-550.
Lockshin, R.A., Zakeri, Z., 2004. Apoptosis, autophagy, and more. Int J Biochem Cell Biol 36, 2405-2419.
Maeda, H., Hori, S., Nishitoh, H., Ichijo, H., Ogawa, O., Kakehi, Y., Kakizuka, A., 2001. Tumor growth inhibition by arsenic trioxide (As2O3) in the orthotopic metastasis model of androgen-independent prostate cancer. Cancer Res 61, 5432-5440.
Mark, R.J., Sercarz, J.A., Tran, L., Selch, M., Calcaterra, T.C., 1991. Fibrosarcoma of the head and neck. The UCLA experience. Arch Otolaryngol Head Neck Surg 117, 396-401.
Meijer, A.J., Codogno, P., 2004. Regulation and role of autophagy in mammalian cells. Int J Biochem Cell Biol 36, 2445-2462.
Miller, W.H., Jr., Schipper, H.M., Lee, J.S., Singer, J., Waxman, S., 2002. Mechanisms of action of arsenic trioxide. Cancer Res 62, 3893-3903.
Mizushima, N., Yamamoto, A., Hatano, M., Kobayashi, Y., Kabeya, Y., Suzuki, K., Tokuhisa, T., Ohsumi, Y., Yoshimori, T., 2001. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 152, 657-668.
Ning, S., Knox, S.J., 2006. Optimization of combination therapy of arsenic trioxide and fractionated radiotherapy for malignant glioma. Int J Radiat Oncol Biol Phys 65, 493-498.
Olive, P.L., 1998. The role of DNA single- and double-strand breaks in cell killing by ionizing radiation. Radiat Res 150, S42-51.
Paglin, S., Hollister, T., Delohery, T., Hackett, N., McMahill, M., Sphicas, E., Domingo, D., Yahalom, J., 2001. A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 61, 439-444.
Pang, L.P., Huang, W., Sun, Q., Guo, W., Li, R.T., Cui, J.R., 2008. SLXM-2, a derivative of cyclophosphamide: mechanism of growth inhibition on hepatocarcinoma 22 cells. Anticancer Drugs 19, 167-174.
Park, M.J., Lee, J.Y., Kwak, H.J., Park, C.M., Lee, H.C., Woo, S.H., Jin, H.O., Han, C.J., An, S., Lee, S.H., Chung, H.Y., Park, I.C., Hong, S.I., Rhee, C.H., 2005. Arsenic trioxide (As2O3) inhibits invasion of HT1080 human fibrosarcoma cells: role of nuclear factor-kappaB and reactive oxygen species. J Cell Biochem 95, 955-969.
Pelicano, H., Feng, L., Zhou, Y., Carew, J.S., Hileman, E.O., Plunkett, W., Keating, M.J., Huang, P., 2003. Inhibition of mitochondrial respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J Biol Chem 278, 37832-37839.
Pradier, O., Rave-Frank, M., Lehmann, J., Lucke, E., Boghun, O., Hess, C.F., Schmidberger, H., 2001. Effects of docetaxel in combination with radiation on human head and neck cancer cells (ZMK-1) and cervical squamous cell carcinoma cells (CaSki ). Int J Cancer 91, 840-845.
Qian, W., Liu, J., Jin, J., Ni, W., Xu, W., 2007. Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via up-regulation of Beclin-1. Leuk Res 31, 329-339.
Roboz, G.J., Dias, S., Lam, G., Lane, W.J., Soignet, S.L., Warrell, R.P., Jr., Rafii, S., 2000. Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis. Blood 96, 1525-1530.
Scherz-Shouval, R., Shvets, E., Fass, E., Shorer, H., Gil, L., Elazar, Z., 2007. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26, 1749-1760.
Shen, Z.X., Chen, G.Q., Ni, J.H., Li, X.S., Xiong, S.M., Qiu, Q.Y., Zhu, J., Tang, W., Sun, G.L., Yang, K.Q., Chen, Y., Zhou, L., Fang, Z.W., Wang, Y.T., Ma, J., Zhang, P., Zhang, T.D., Chen, S.J., Chen, Z., Wang, Z.Y., 1997. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89, 3354-3360.
Shimizu, S., Kanaseki, T., Mizushima, N., Mizuta, T., Arakawa-Kobayashi, S., Thompson, C.B., Tsujimoto, Y., 2004. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 6, 1221-1228.
Skubitz, K.M., D'Adamo, D.R., 2007. Sarcoma. Mayo Clin Proc 82, 1409-1432.
Soignet, S.L., Frankel, S.R., Douer, D., Tallman, M.S., Kantarjian, H., Calleja, E., Stone, R.M., Kalaycio, M., Scheinberg, D.A., Steinherz, P., Sievers, E.L., Coutre, S., Dahlberg, S., Ellison, R., Warrell, R.P., Jr., 2001. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19, 3852-3860.
Szumiel, I., 1998. Monitoring and signaling of radiation-induced damage in mammalian cells. Radiat Res 150, S92-101.
Tallman, M.S., Andersen, J.W., Schiffer, C.A., Appelbaum, F.R., Feusner, J.H., Woods, W.G., Ogden, A., Weinstein, H., Shepherd, L., Willman, C., Bloomfield, C.D., Rowe, J.M., Wiernik, P.H., 2002. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 100, 4298-4302.
Tallman, M.S., Lefebvre, P., Baine, R.M., Shoji, M., Cohen, I., Green, D., Kwaan, H.C., Paietta, E., Rickles, F.R., 2004. Effects of all-trans retinoic acid or chemotherapy on the molecular regulation of systemic blood coagulation and fibrinolysis in patients with acute promyelocytic leukemia. J Thromb Haemost 2, 1341-1350.
Tardito, S., Bussolati, O., Gaccioli, F., Gatti, R., Guizzardi, S., Uggeri, J., Marchio, L., Lanfranchi, M., Franchi-Gazzola, R., 2006. Non-apoptotic programmed cell death induced by a copper(II) complex in human fibrosarcoma cells. Histochem Cell Biol 126, 473-482.
VanderWaal, R.P., Griffith, C.L., Wright, W.D., Borrelli, M.J., Roti, J.L., 2001. Delaying S-phase progression rescues cells from heat-induced S-phase hypertoxicity. J Cell Physiol 187, 236-243.
Verma, A., Mohindru, M., Deb, D.K., Sassano, A., Kambhampati, S., Ravandi, F., Minucci, S., Kalvakolanu, D.V., Platanias, L.C., 2002. Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide. J Biol Chem 277, 44988-44995.
Wang, D., Kreutzer, D.A., Essigmann, J.M., 1998. Mutagenicity and repair of oxidative DNA damage: insights from studies using defined lesions. Mutat Res 400, 99-115.
Xie, L.X., Lin, X.H., Li, D.R., Chen, J.Y., Hong, C.Q., Du, C.W., 2007. Synergistic therapeutic effect of arsenic trioxide and radiotherapy in BALB/C nude mice bearing nasopharyngeal carcinoma xenografts. Exp Oncol 29, 45-48.
Yang, J., Wu, L.J., Tashino, S., Onodera, S., Ikejima, T., 2008. Reactive oxygen species and nitric oxide regulate mitochondria-dependent apoptosis and autophagy in evodiamine-treated human cervix carcinoma HeLa cells. Free Radic Res 42, 492-504.
Zhang, Q.Y., Hammerberg, C., Baldassare, J.J., Henderson, P.A., Burns, D., Ceska, M., Voorhees, J.J., Fisher, G.J., 1992. Retinoic acid and phorbol ester synergistically up-regulate IL-8 expression and specifically modulate protein kinase C-epsilon in human skin fibroblasts. J Immunol 149, 1402-1408.
Zhang, W., Anker, L., Law, R.E., Hinton, D.R., Gopalakrishna, R., Pu, Q., Gundimeda, U., Weiss, M.H., Couldwell, W.T., 1996. Enhancement of radiosensitivity in human malignant glioma cells by hypericin in vitro. Clin Cancer Res 2, 843-846.
Zhang, W., Yamada, H., Sakai, N., Nozawa, Y., 1993. Sensitization of C6 glioma cells to radiation by staurosporine, a potent protein kinase C inhibitor. J Neurooncol 15, 1-7.
Zhu, J., Koken, M.H., Quignon, F., Chelbi-Alix, M.K., Degos, L., Wang, Z.Y., Chen, Z., de The, H., 1997. Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. Proc Natl Acad Sci U S A 94, 3978-3983.
行政院衛生署，臺灣。2008。http://www.doh.gov.tw/。
陳碧芳。2005。癌症新探。台灣癌症臨床研究發展基金會。台灣。
林宜賢。認識放射線治療。財團法人振興復健醫學中心放射治療科。台灣。
陳建安。淺談癌症的放射線治療。敏盛醫院放射腫瘤科。台灣
黃叔牧。1997。高醫醫訊17(5)。高雄醫學大學附設醫院。台灣。
季匡華、柯卉玲。2006。癌症治療新領域。新光吳火獅紀念醫院。台灣。