BMVC及相關光感物質所引發細胞毒性及機制探討

Abstract

現今癌症的治療方式，最主要障礙是在於化學治療藥劑的非專一性毒殺細胞而造成的副作用。絕大部分的癌細胞藉由端粒酶來維持端粒的長度而生存及進行不正常增生，而大多數的正常細胞缺乏端粒酶。倘若能藉由抑制端粒酶作用，選擇性地對癌細胞產生毒殺，而不對正常細胞有威脅，此種策略不啻為可行的方法。 BMVC 【3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide】可與人類端粒上四股結構 (G-quadruplex)中的d(T2AG3)序列形成穩定的鍵結。在本研究中，我們利用人類子宮頸癌上皮細胞(HeLa)，經由BMVC處理下，來探討所造成生物效應變化之情形。研究結果顯示：（1）BMVC會明顯抑制癌細胞的生長。（2）長時間與BMVC培養的細胞，其生長會受到抑制，但主要原因非衰老此單一因素所造成。（3）BMVC進入癌細胞的量為正常細胞的兩倍以上。（4）BMVC在細胞中累積的位置，在癌細胞中主要在細胞核。（5）經BMVC培養的癌細胞，其細胞週期由G1 phase 進入 S phase有受到延遲的現象。（6）BMVC會影響Topoisomerase II解開超螺旋DNA。 由於BMVC具有抑制癌細胞生長的能力，可利用此種性質，來研究BMVC相關光感物質對癌細胞的生物機制。探討PS-BMVC與meto-tera (hydroxyphenyl) porphyrin衍生物在細胞存在的量與位置，及光動力治療效果。

Presently, the major obstacle of cancer chemotherapy is the non-specific cytotoxicity of chemotherapeutic drugs. Over 80% of cancer cells maintain telomere length by telomerase, which are not found in normal somatic cells. Therefore telomerase inhibitor could induce selective cytotoxicity on tumor cell. 3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide (BMVC) has been synthesized and shown to stabilize the G-quadruplex structure of human telomeric sequence of d(T2AG3). The purpose of this study is to investigate the biological effects of BMVC on HeLa cell. We found: (1) The growth of tumor cells was inhibited by BMVC. (2) The long-term effects in population doubling showed that the growth inhibition of BMVC and the shortening of telomere by BMVC might not play the major role in the inhibition of cell growth. (3) Compared to normal cells, cancer cells have higher uptake of BMVC. (4) BMVC was mainly localized in the nucleus of cancer cells (5) BMVC suppressed the cell progression cycle into S-phase. (6) BMVC could interfere to form relax induced by Topoisomerase II. Furthermore, we investigated the cellular location, uptake, and photodynamic effects of BMVC analogs and Meto-tera (hydroxyphenyl) porphyrin derived analogs.