Gemcitabine-(C4-amide)-[anti-HER2/neu] Anti-Neoplastic Cytotoxicity in Dual Combination with Mebendazole against Chemotherapeutic-Resistant Mammary Adenocarcinoma.
Gemcitabine-(C4-amide)-[anti-HER2/neu] Anti-Neoplastic Cytotoxicity in Dual Combination with Mebendazole against Chemotherapeutic-Resistant Mammary Adenocarcinoma.
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DOI：
10.4172/2324-9110.1000109
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发表时间：
2013-03
期刊：
影响因子：
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通讯作者：
Coyne Cp;Toni Jones;Ryan Bear
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作者：
Coyne Cp;Toni Jones;Ryan Bear
吉西他滨是一种嘧啶核苷类似物，可被三磷酸化并竞争性抑制胞苷掺入DNA链。二磷酸化吉西他滨不可逆地抑制核糖核苷酸还原酶，从而阻止脱氧核糖核苷酸合成。作为一种有效的化疗药物，吉西他滨可降低肿瘤细胞增殖并诱导细胞凋亡，这是其在临床治疗几种白血病和癌细胞类型中有效的原因。由于快速脱氨、化疗耐药和后遗症导致的短暂血浆半衰期限制了吉西他滨在临床肿瘤学中的应用。选择性"靶向"吉西他滨递送代表了延长其血浆半衰期和最小化无辜组织/器官暴露的分子策略。方法应用先前描述的有机化学方案来合成用于生产吉西他滨-（C4-酰胺）-[抗HER2/neu]的UV-光活化的吉西他滨中间体。应用免疫检测分析（蛋白质印迹）检测任何降解性片段化或聚合的存在。使用高度过表达HER2/neu营养膜受体的化疗耐药乳腺癌（SKBr-3）群体，通过细胞ELISA测定吉西他滨-（C4-酰胺）-[抗HER2/neu]的保留结合亲合力检测。确定了吉西他滨-（C4-酰胺）-[抗HER2/neu]和苯并咪唑微管蛋白/微管抑制剂阿苯达唑、氟苯达唑和甲苯达唑对化疗耐药乳腺癌（SKBr-3）的细胞毒性抗肿瘤效力。相关研究评价了吉西他滨-（C4-酰胺）-[抗-HER2/neu]与甲苯咪唑双重联合治疗与吉西他滨-（C4-酰胺）-[抗-HER2/neu]相比引起细胞毒性抗肿瘤效力水平升高的可能性。结果共价吉西他滨-（C4-酰胺）-[anti-HER2/neu]免疫化疗剂和每种苯并咪唑（n = 3）对化疗耐药乳腺癌（SKBr-3）具有细胞毒性抗肿瘤效力。共价吉西他滨-（C4-酰胺）-[抗-HER2/neu]免疫化疗或吉西他滨与甲苯咪唑双重组合产生的细胞毒性抗肿瘤效力水平增加，高于吉西他滨-（C4-酰胺）-[抗-HER2/neu]或吉西他滨单独给药所达到的水平。结论吉西他滨-（C4-酰胺）-[抗HER2/neu]与苯并咪唑类药物双重联合治疗可产生更高水平的细胞毒性抗肿瘤活性，并可能为具有更宽安全范围的治疗方案提供基础。这些益处可能通过以下的集体性质而实现：[i]选择性"靶向"吉西他滨递送;[ii]与许多（如果不是大多数）常规化疗剂相比，苯并咪唑的毒性相对较低;[iii]通过相加或协同抗癌性质而降低的总剂量需求;[iv]与其他化疗剂相比，苯并咪唑的毒性相对较低。和[iv]与苯并咪唑微管蛋白/微管抑制剂相比，吉西他滨-（C4-酰胺）-[抗HER2/neu]的后遗症差异。
INTRODUCTION Gemcitabine is a pyrimidine nucleoside analog that becomes triphosphorylated and competitively inhibits cytidine incorporation into DNA strands. Diphosphorylated gemcitabine irreversibly inhibits ribonucleotide reductase thereby preventing deoxyribonucleotide synthesis. Functioning as a potent chemotherapeutic, gemcitabine decreases neoplastic cell proliferation and induces apoptosis which accounts for its effectiveness in the clinical treatment of several leukemia and carcinoma cell types. A brief plasma half-life due to rapid deamination, chemotherapeutic-resistance and sequelae restrict gemcitabine utility in clinical oncology. Selective "targeted" gemcitabine delivery represents a molecular strategy for prolonging its plasma half-life and minimizing innocent tissue/organ exposure. METHODS A previously described organic chemistry scheme was applied to synthesize a UV-photoactivated gemcitabine intermediate for production of gemcitabine-(C4-amide)-[anti-HER2/neu]. Immunodetection analysis (Western-blot) was applied to detect the presence of any degradative fragmentation or polymerization. Detection of retained binding-avidity of gemcitabine-(C4-amide)-[anti-HER2/neu] was determined by cell-ELISA using populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) that highly over-express the HER2/neu trophic membrane receptor. Cytotoxic anti-neoplastic potency of gemcitabine-(C4-amide)-[anti-HER2/neu] and the benzimidazole tubulin/microtubule inhibitors, albendazole, flubendazole and mebendazole was established against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Related investigations evaluated the potential for gemcitabine-(C4-amide)-[anti-HER2/neu] in dual combination with mebendazole to evoke increased levels of cytotoxic anti-neoplatic potency compared to gemcitabine-(C4-amide)-[anti-HER2/neu]. RESULTS Covalent gemcitabine-(C4-amide)-[anti-HER2/neu] immunochemotherapeutic and each benzimidazole (n=3) exerted cytotoxic anti-neoplastic potency against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Covalent gemcitabine-(C4-amide)-[anti-HER2/neu] immunochemotherapeutic or gemcitabine in dual combination with mebendazole created increased levels of cytotoxic anti-neoplastic potency that were greater than attained with gemcitabine-(C4-amide)-[anti-HER2/neu] or gemcitabine alone. CONCLUSION Gemcitabine-(C4-amide)-[anti-HER2/neu] in dual combination with benzimidazoles can produce enhanced levels of cytotoxic anti-neoplastic activity and potentially provide a basis for treatment regimens with a wider margin-of-safety. Such benefits would be possible through the collective properties of; [i] selective "targeted" gemcitabine delivery; [ii] relatively lower toxicity of benzimidazoles compared to many if not most conventional chemotherapeutics; [iii] reduced total dosage requirements faciliated by additive or synergistic anti-cancer properties; and [iv] differences in sequelae for gemcitabine-(C4-amide)-[anti-HER2/neu] compared to benzimidazole tubulin/microtubule inhibitors.