抑制 MEK/ERK 以增強Docetaxel 及 Cytosine deaminase/5-FC對三陰性乳癌的療效

乳癌是一種好發於女性的癌症，發生率有逐年提升的現象，所以乳癌成為女性死亡率上昇的一項主因。乳癌細胞大部分帶有 estrogen receptors (ER)、 progesterone receptors (PR) 或 HER2 這三個細胞表面受體。但是有 15% 的乳癌細胞族群同時都不表現 ER 和 HER2，且這種乳癌細胞往往也不表現 PR，因此稱作三陰性乳癌 (triple-negative breast cancers, TNBC)。對於此種乳癌而言，因為 ER 與 HER2 皆不表現，所以用於抑制 ER 或抑制 HER2 的等標靶藥物的治療效果會顯著降低。因此對此類型病患，臨床上只能使用傳統化學治療藥物來處理。目前有研究指出，TNBC 中的 MEK/ERK 訊號路徑具有高度活性，易造成許多傳統化療藥的抗藥性。而在我們過去的研究中證實，若使細胞表達 cytosine deaminase (CD)，便可將本身不具細胞毒性的前藥 5-flucytosine (5-FC) 轉換成化療藥 5-flourouracil (5-FU)，進而有效抑制老鼠皮下乳癌腫瘤的生長。且有文獻指出，抑制 MEK/ERK 的活性後可以增強 5-FU 與 docetaxel 的治療效果。因此，在本研究中，我們利用 lentiviral-vector 攜帶 CD 基因，使其在乳癌細胞中長期且穩定地大量表現，並將前藥 5-FC 轉化成 5-FU 以毒殺乳癌細胞。另外，我們也利用 selumetinib 抑制乳癌細胞中 MEK/ERK的訊號傳遞路徑，然後再以 docetaxel 處理。由實驗結果發現，當同時使用三種治療方式時，可以比單獨一種或是兩種的治療方式達到更好的療效。期待未來可以此種複合型策略對乳癌細胞進行治療，進而減少化療藥的劑量且達到較好的治療效果，同時降低化療藥物引起的副作用。

關鍵字

5-氟胞嘧啶；胞嘧啶脱氨酶；歐洲紫杉醇；三陰性乳癌

並列摘要

Epidemiological studies have indicated that breast cancer is one of the leading cancers of death for women in Taiwan. About 75% of breast cancers are estrogen receptor-positive (ER-positive, or ER+). About 65% of ER-positive breast cancers are also progesterone receptor-positive (PR-positive, or PR+). The HER2 marker is present in about 20% of cases of invasive breast cancer. If the cells lack the three proteins, they are called triple-negative breast cancers (TNBCs). Therefore, TNBC cannot be efficiently inhibited by target-therapy with ER inhibitor and HER2 inhibitor. Fortunately, some reports have determined that TNBC have high activity of MEK/ERK pathway resulting in resistance to traditional chemotherapy. If MEK/ERK pathway was down-regulated, the cell viability can be inhibited, and the drug-sensitivity to 5-fluorouracil (5-FU) or docetaxel can be restored. In our previous study, we have shown that in the breast cancer cells, the cytosine deaminase (CD) can convert the nontoxic prodrug 5-fluorocytosine (5-FC) to the highly toxic metabolite 5-FU and therefore inhibit the cell proliferation. In this study, we used lentiviral-vector to overexpress CD in breast cancer cells, then treated the cells with 5-FC followed by treatment of selumetinib and docetaxel. Then, cell viabilitywas assayed to determine thatthecombination therapy CD/5-FC/docetaxel/selumetinibis more effective than single or dual of these therapies. We wish the combination therapy could be a new approach to TNBCs with low side effect of chemotherapy.

並列關鍵字

Cytosine deaminase ； Docetaxel ； MEK/ERK ； 5-FC ； Triple-negative Breast Cancers

參考文獻

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抑制 MEK/ERK 以增強Docetaxel 及 Cytosine deaminase/5-FC對三陰性乳癌的療效

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