肺癌專一性標的胜肽之尋找及標的治療之發展

Abstract

全世界，每年約有一千萬人被診斷出患有癌症，而一年之中，更有超過六百萬人死於此疾病。而其中最為普遍的癌症分別為，佔12.3%的肺癌、10.4%的乳癌、以及9.4%的結腸直腸癌。肺癌於工業化國家中擁有高致死率，是所有因癌症死亡的病例中最為顯著的。人們患有非小細胞肺癌的病患其五年的存活率低於15%。缺乏癌細胞專一性標的物質一直是化學療法中的一重大問題，由於不具有專一性而使得副作用的產生，進而限制了藥物的劑量而無法根除癌細胞。在此研究中，我們運用噬菌體展示法，分離出能專一性結合非小細胞肺癌之十二個胺基酸胜肽。表現此特殊胜肽〈P5-2〉的噬菌體〈PC5-2〉具有專一性結合至非小細胞肺癌細胞株，且不會與正常細胞有結合現象。而針對移植非小細胞肺癌的SCID老鼠，此PC5-2噬菌體能專一性地瞄準腫瘤組織結合。此外，PC5-2噬菌體的導向能力，能進一步地被合成的P5-2胜肽所競爭而失去結合能力。更甚之，當將包含VNB抗癌藥物的微脂體連接P5-2胜肽〈P5-2-Lipo-VNB〉後，抑制腫瘤的生長能力較只帶有VNB的微脂體〈Lipo-VNB〉佳，且不會產生副作用。這些結果都指出P5-2胜肽將抗癌藥物送到癌組織並加強了藥物殺死SCID老鼠中肺癌組織的效力。此腫瘤專一性胜肽深具標的治療肺癌的潛力，並且可以發展肺癌的診斷試劑。

The most common cancers worldwide are lung (12.3 % of all cancers), breast (10.4 %) and colorectal cancer (9.4 %). Lung cancer is the predominant cause of cancer deaths in industrialized countries with a high death rate. The five-year survival rate is less than 15 % for patients with advanced non-small-cell lung cancer (NSCLC). Lack of tumor specificity remains a major problem with chemotherapies in that side effects prevent the delivery of essential dosages of drugs to eliminate majority cancer cells. In this report, we describe the isolation of a 12-mer peptide (P5-2) specifically binding to NSCLC from peptide-presenting phage libraries. The phage displayed P5-2 (PC5-2) were able to bind to NSCLC cell lines and did not bind to normal cells. In SCID mice bearing NSCLC xenografts, the PC5-2 could target to the tumor mass specifically. The homing activity of PC5-2 clones could be further competitively inhibited by synthetic P5-2. Furthermore, the P5-2-Lipo-vinorelbine (VNB) repressed tumor growth better than Lipo-VNB and without side effect. These results indicate that P5-2 enhanced the therapeutic efficacy of the drug against lung cancer xenografts in SCID mice. This tumor-specific peptide has a potential for targeted drug delivery to treat lung cancer and may be useful for designing targeted gene transfer vectors as well as diagnostic tools for this disease.