Evaluate the effectiveness of Cordyceps sinensis as remedy medicine following cancer therapy and its working mechanism
08/01/2007 ~ 07/31/2009 (NSC95-2320-B007-009)
Cordyceps sinensis (CS) is a fungal parasite of moth larvae (Lepidoptera) in the genera Hepitalus and Thitarodes that has been widely used in traditional Chinese medicine as a tonic agent. In the past 20 years, as the result of the pass of the “Dietary Supplement Health and Education Act of 1994” by the Center for Food Safety and Applied Nutrition, FDA, there has been phenomenal growth in the interest and use of complementary or alternative medicine that has promoted CS as a popular remedy for cancer treatment in Chinese society. A broad spectrum of pharmacological actions in modulating the hepatic, renal, cardiovascular, immune, nervous, endocrine and steroid systems has been reported in addition to its anticancer activity. In my previous NSC grant entitled “Effect of Cordyceps Sinensis on the Immunity of Tumor Vaccine”, we have found that CS can enhance the effectiveness of tumor vaccine for prostate cancer. During the period of this study, we accidentally found that CS can enhance the recovery of radiation-induced blood cell depletions. Moreover, we found that CS can stimulate the differentiation of bone marrow stem cells. Those indicate that CS is a potential reagent to rescue conventional cancer therapy-caused stem cell damage. We therefore propose to extend these findings to explore the effect of CS as remedy medicine following cancer therapy and examine its working mechanism. To achieve this goal, we will first compare the effectiveness of CS as remedy medicine in anti-tumor as well as immune and physiological modulator following various forms of cancer therapy. The next step is to dissect the working mechanism of each function of CS.
The specific aims of this proposal are.
1. To compare the effectiveness of CS as remedy medicine for various forms of cancer therapy.
2. To study the role of immune cells on Cordyceps sinensis effects as remedy medicine following chemo- or radio-therapy.
3. To examine the role of bone marrow stem cells on Cordyceps sinensis effects as remedy medicine following chemo- or radio-therapy.
Accomplishment of this proposal should provide valuable information on the role of Cordyceps sinensis as a remedy medicine in various forms of cancer therapy. This study will also provide a well-defined system to gain an insight into the working mechanisms of Cordyceps sinensis as remedy medicine, and ultimately lead to strategies to include Cordyceps sinensis as a main complementary component in cancer treatment.
Effect of Cordyceps Sinensis on the Immunity of Tumor Vaccine
08/01/2003 ~ 07/31/2006 (NSC92-2320-B007-009)
Cordyceps sinensis (CS), a herb medicine, has been used as a popular remedy in Chinese Medicine for more than two hundred years. It is a fungus parasitic on the larvae of Lepidopteral. A broad spectrum of its pharmacological functions in hepatic function, renal function, cardiovascular function, immunomodulation, endocrine and steroid system, nervous system, and anticancer activity has been reported. Among of these effects, the immunomodulation-related antitumor activities are most promising and deserve great attention. Early studies had shown that Cordyceps sinensis is an important immune modulator. CS could modulate cellular immunity and was potentially useful to overcome the immunosuppression. This study will focus on the study of whether CS could enhance the immunity of tumor vaccine by overcome the immunosuppresion caused by primary tumor. Except to evaluate the efficacy of CS as immunomodulator for tumor vaccine, we will also test whether CS can be an effective chemopreventive agent against cancer progression. To test this hypothesis, a unique transgenic adenocarcinoma mouse prostate (TRAMP) will be used. TRAMP is an excellent model of prostate cancer that mimics progressive forms of human disease in as much as 100% of males develop histological PIN by 8-12 weeks of age that progress to adenocarcinoma with distant site metastases by 24-28 weeks of age.
In this proposal, we hypothesize that Cordyceps sinensis is an effective immunomodulator of tumor vaccine and effective chemopreventive agent against cancer progression. To test this hypothesis, following specific aims are proposed.
1. To evaluate the potential of Cordyceps sinensis as the immune modulator of tumor vaccine.
2. To evaluate the feasibility of Cordyceps sinensis as an immune boosting agent following cancer therapy.
3. To examine the potential of Cordyceps sinensis as chemopreventive agent against cancer progression using a TRAMP transgenic mouse model.
4. To find a best formula of combining of Cordyceps sinensis with cytokine gene-transfected tumor vaccine for cancer therapy and prevention.
5. To elucidate the mechanisms of Cordyceps sinensis as immune modulator.
Accomplishment of this proposal should provide valuable information of the role of Cordyceps sinensis in cancer immunotherapy. This study will also provide a well-defined system to gain an insight into the mechanisms of Cordyceps sinensis on the modulation of immunity against prostate cancer, ultimately leading to strategies for using Cordyceps sinensis in immunotherapy for human prostate cancer.
探討冬蟲夏草對癌症疫苗免疫力之影響
08/01/2003 ~ 07/31/2006 (NSC92-2320-B007-009)
冬蟲夏草是一種寄生在Lepidopteral幼蟲上的菌類，在中醫學裡是一味盛行多年的治療草藥。許多研究報告指出其藥理作用的範圍，包括了肝、腎、心血管功能，並可影響神經及內分泌系統，且對於免疫力的調控及抑制癌症有相當的功效；其中認為最值得探討的就是調控免疫系統以對抗癌症發生的能力。在早期的研究中指出冬蟲夏草是一個重要的免疫調控因子，可以影響細胞免疫的反應來克服免疫力被抑制的問題。因此本計畫將探討當冬蟲夏草與癌症疫苗結合後，是否可以藉由其影響免疫系統的能力，來增進癌症疫苗治療初生腫瘤的效果。除此之外也會評估在腫瘤持續增生的時候，此草藥能否成為有效的化學抑制藥劑。為證實以上假說，我們擬建立一套獨特的基因轉殖鼠模式transgenic adenocarcinoma mouse prostate (TRAMP)來進行實驗；在此老鼠體內會像人類男性一樣自發性地產生射護腺癌，其8-12週大小時即可觀察到組織型態之變化，且隨著腺癌的增長在24-28週會發生遠端轉移的情況。
本計畫之具體目標為：
1. 評估使用癌症疫苗治療癌症時，加入冬蟲夏草後其調控免疫系統的能力。
2. 探討在癌症治療後，冬蟲夏草作為免疫增強劑的可能性。
3. 利用TRAMP基因轉殖鼠來探討冬蟲夏草作為化學抑制劑的可能性。
4. 在冬蟲夏草藥與帶有細胞激素的癌症疫苗兩者結合後，找出最適合於癌症治療及預防的方式。
5. 研究冬蟲夏草作為免疫調控因子的機制。
本實驗不僅說明在癌症治療上冬蟲夏草所扮演的角色，並充分瞭解此草藥特定於射護腺癌其調控免疫系統的機制，未來並可發展成為人類射護腺癌治療之方法。
Application of Micro-PET on the Effects of Gene Therapy for Prostate Radiotherapy
01/01/2004 ~ 12/31/2006 (NSC93-2623-7007-013-NU)
Gene therapy has been a most popular and advanced approach for many forms of diseases including cancer. How to monitor the efficacy of gene therapy during radiotherapy in vivo has been a critical issue for the translation of this technique to clinical application. To date, combining thymidine kinase (tk) gene therapy with PET imaging has proved to be a useful model for monitoring the efficacy of gene therapy in animals and humans non-invasively and repetitively. It is the intension of this proposal to study the pre-clinical application of micro-PET system, in the Institute of Nuclear Energy Research, on the combining effects of radiotherapy, suicide gene therapy, and IL-3 gene immunotherapy for prostate cancer. The reason for choosing prostate cancer is that we have a unique transgenic mouse model (TRAMP) for prostate cancer. These mice develop prostate cancer spontaneously and progress in a process similar to human prostate cancer. This will provide an excellent pre-clinical model for the study of prostate cancer therapy. Currently, the micro-PET system for prostate cancer therapy only uses the transplant tumor in nude mice model. This study will be the first to use micro-PET system for studying the prostate cancer in situ. In this proposal, we propose a new type of multi-modality (cocktail) therapy for prostate cancer. As our knowledge, this is the first intend to combine the radiotherapy, suicide gene therapy, and immunogene therapy for prostate cancer. Moreover, the suicide gene that we will use can also be used as a reporter gene for PET image.
動物正子照相系統於攝護腺放射基因治療之應用研究
01/01/2004 ~ 12/31/2006 (NSC93-2623-7007-013-NU)
基因治療為目前各式癌症療法中最前瞻及最有潛力之治療法，但如何追蹤基因治療於治療過程中基因之表現及體內之分佈情況及其效果是影響基因治療能否進入臨床階段的一主要因素。在目前的研究中，結合thymidine kinase (tk)基因治療及正子照相系統已能初步達到非侵入性並可連續追蹤基因治療之療效之目的，此一技術目前正開始應用於動物研究模型及臨床試驗中。本研究的主要目的，在於應用於核能研究所新購之動物正子照相系統，以評估結合放射治療與自殺基因治療合併細胞激素三之基因治療法對攝戶腺癌之療效。於研究攝戶腺癌方面，我們擁有一研究攝戶腺癌非常特殊、珍貴之基因轉植鼠-TRAMP；此一基因轉植鼠戶於成長的過程中會自然發生攝戶腺癌，且其發生之形式與人類攝戶腺癌形成之方式非常類似，此鼠是目前研究攝戶腺癌治療法中之最佳動物模型。目前以動物正子照相法追蹤攝戶腺癌基因治療法療效都還停留在將腫瘤轉植至裸鼠的動物模式，本計畫將會是第一個以動物正子照相術研究原發性攝戶腺癌基因治療法的研究計畫。於此計畫書中我們並提議一新型的攝戶腺癌雞尾酒療法，於此療法中我們將首次嘗試將放射線治療法、自殺基因治療法、及細胞激素三基因免疫療法結合在一起，期望能對攝戶腺癌之治療提供一更加之治療模式；治療期間之自殺基因亦可提供為正子照相系統之追蹤基因，以達到一舉數得之目的。
Combining gene immunotherapy for prostate cancer
01/01/2002 ~ 12/31/2004 (NHRI-EX93-9121BI)
Abstract
Combining Gene Immunotherapy for Prostate Cancer Abstract: The increasing rate (13.6%) of the incidence of Prostate cancer has become the highest among all malignant cancers in Taiwan. Although prostate cancer is generally being diagnosed at an earlier stage than ever before, which may explain the high increasing rate, it still carries an overall cancer-specific, disease-free survival rate of only 51%. It is curable only when localized and amenable to surgery and/or radiotherapy. However, of those individuals treated for local disease, 30% will develop local recurrence or metastases, which usually are incurable by current conventional therapies. Clearly, there is a need to develop strategies that will both increase local tumor control and treat systemic disease. Among many strategies for prostate cancer therapy, combining immunotherapy with other forms of therapy is an ideal strategy for this goal. In many ways, prostate cancer presents an ideal setting for the study and use of immunotherapy because prostate cancer cells express a well-characterized antigen, prostate-specific antigen (PSA), whose expression is widely used clinically as a marker and target for prostate cancer. The study of PSA as a potential target antigen for immunotherapy has been hampered by the lack of appropriate animal tumor models. I therefore intend to initiate a research program to establish a mouse prostate cancer cell line (TRAMP) expressing probasin protein (similar to human PSA) and an androgen refractory TRAMP cell lines and use these models for testing the feasibility of combining gene immunotherapy with other forms of therapy. The overall aim of this study is to find a best combination of multi-forms of therapy to enhance the curing rate of prostate cancer. The specific aims of this proposal are: 1. To develop hormone-refractory murine prostate cancer model. 2. To compare the gene expression profiles of the host and cancer cells on the process of the development of hormone-refractory prostate cancer using the approach of microarray. 3. To evaluate the feasibility of immunotherapy for prostate cancer at different stages using above tumor models. 4. To enhance tumor immunogenicity by transduction of cytokine genes and the unique gene identified on aim 2. 5. To develop a best strategies against primary and hormone-refractory recurrent or metastatic prostate cancers. Accomplishment of this proposal should provide a valuable murine prostate tumor model for the study of various forms of prostate cancer therapy. This model will also provide a well-defined system to gain an insight into the mechanisms of development of hormone-refractory prostate cancer, ultimately leading to strategies for immunotherapy of human prostate cancer using new identified target antigens. It will open new doors for new strategies against hormone-refractory prostate cancers, which account for the major failure of current clinical prostate cancer therapy.
結合基因免疫治療以治療攝護腺癌
01/01/2002 ~ 12/31/2004 (NHRI-EX93-9121BI)
結合基因免疫治療以治療攝護腺癌攝護症近年來其發生率增加13.6%，已跨居台灣惡性癌症之首。雖然攝護比起以前更容易在前期診斷出來(其實這可以解釋攝護腺癌發生率上升13.6%的現象)，但腫瘤完全治癒率卻只有51%。攝護腺癌若只是在局部生長，可用手術或放射線治療之。然而，診斷出有局部腫瘤的病人接受目前的臨床的治療後，有百分之三十的病人發生局部復發或轉移的情形，而局部復發或轉移卻往往不能用現在臨床用的方法來治療。相當明顯的，發展一套可治療方法增加對局部腫瘤及治療全身腫瘤的控制是有必要的。在攝護腺癌的治療方法中，結合免疫治療及其他方式的治療應是最理想的。因為攝護腺癌會表現特有的抗原(攝護腺特別抗原; PSA)，此抗原在臨床上常用於診斷攝護腺癌，所以對不同方面來說，攝護腺癌在研究及使用免疫治療上是一個理想的模型。由於缺乏適當的動物模式，利用攝護腺特別抗原來刺激免疫系統有效攻擊腫瘤的研究不能順利進行。所以此次所提的研究計畫是建立一個表現probasin蛋白質(類似攝護腺特別抗原)的老鼠攝護腺癌細胞(TRAMP)及對雄性激素(androgen)有抗性的細胞株，並利用這系統來評估結合免疫治療及其他治療對攝護腺癌的治療可行度。此計畫總目標是找一個結合不同治療方法的一個最佳組合來增加攝護腺癌的治癒率。 此計畫的特定目標為： 1. 建立抗賀爾蒙的鼠類攝護模型。 2. 在腫瘤發展出抗賀爾蒙的性質時，用微陣列基因技術來比較其寄主及腫瘤細胞基因表現。 3. 利用上述腫瘤模型來評估免疫治療對不同時期的的攝護腺癌治療可行度。 4. 利用植入細胞激素基因來增加腫瘤免疫生成性(tumor immunogenicity)。 5. 發展一套最佳策略來治療原位及抗賀爾蒙復發或轉移的攝護腺癌。 此計畫成後，對研究多樣的攝護腺癌治療方法，可提供一個有用的鼠類攝護腺腫瘤模式。此模式也可提供一個明確的系統，且可以得知腫瘤產生賀爾蒙抗性的機制，進一步可以發展利用一個特殊的抗原的免疫治療來治療攝護腺癌。此計畫將目前臨床上治療失敗主因抗賀爾蒙攝護腺癌發展一個的新策略。
細胞激素-3 植入的癌症疫苗基因治療
許多的臨床實驗證明癌症疫苗基因治療能有效對抗腎臟癌、攝護腺癌及黑色素癌等病人。但是一個好的癌症疫苗必須能夠增強癌細胞的免疫抗原性 （immunogenicity），並產生長期記憶性的免疫記憶 （immunological memory）。細胞激素基因植入的癌症疫苗顯然有這方面的效果，但哪一種細胞激素最好呢?在一般的觀念中以為能直接刺激免疫系統中T-淋巴球細胞的細胞激素應具有最佳的效果。
可是一些實驗發現療效最好的卻是經由間接作用的顆粒極巨嗜細胞生長激素 (GM-CSF) 及細胞激素-3 (IL-3) 。目前對於為何這兩種激素可以產生如此有效的免疫效應的機制還不是很清楚。我的最近一些實驗證據顯示細胞激素-3可能是和TNF-a 相互合作而刺激抗原表現細胞 (Antigen Presenting Cells) 的功能因而激發了體內的免疫系統。本實驗的目的即在進一步探討細胞激素-3植入的癌症疫苗基因治療的作用機制，並進一步發展體內基因植入的技術。
本計畫的特定目標為: