INTRODUCTION Gemcitabine is a pyrimidine nucleoside analog that becomes triphosphorylated and in this form it 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, chemotherapeuticresistance and sequelae restricts 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 for 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. Anti-neoplastic cytotoxicity of gemcitabine-(C4-amide)-[anti-HER2/neu] and the tubulin/microtubule inhibitor, griseofulvin 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 griseofulvin to evoke increased levels of anti-neoplastic cytotoxicity compared to gemcitabine-(C4-amide)-[anti-HER2/neu]. RESULTS Covalent gemcitabine-(C4-amide)-[anti-HER2/neu] immunochemotherapeutic and griseofulvin exerted anti-neoplastic cytotoxicity against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Covalent gemcitabine-(C4-amide)-[anti-HER2/neu] immunochemotherapeutic or gemcitabine in dual combination with griseofulvin created increased levels of anti-neoplastic cytotoxicity that were greater than was attainable with gemcitabine-(C4-amide)-[anti-HER2/neu] or gemcitabine alone. CONCLUSION Gemcitabine-(C4-amide)-[anti-HER2/neu] in dual combination with griseofulvin can produce enhanced levels of anti-neoplastic cytotoxicity 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 griseofulvin 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 griseofulvin functioning as a tubulin/microtubule inhibitor.

中文翻译：

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吉西他滨-（C4-酰胺）-[抗-HER2 / neu]与灰黄霉素联用对化疗耐药的乳腺腺癌（SKBr-3）的抗肿瘤细胞毒性。

简介吉西他滨是一种嘧啶核苷类似物，已被三磷酸化，并以此形式竞争性抑制胞苷掺入DNA链中。二磷酸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的合成。吉西他滨起着有效的化学治疗作用，可减少肿瘤细胞的增殖并诱导凋亡，这解释了其在几种白血病和癌细胞类型的临床治疗中的有效性。由于快速脱氨，抗化学治疗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”吉西他滨递送代表延长其血浆半衰期并最大程度减少无辜组织/器官暴露的分子策略。方法采用先前描述的有机化学方案合成紫外光活化的吉西他滨中间体，用于生产吉西他滨-（C4-酰胺）-[抗-HER2 / neu]。免疫检测分析（Western-blot）用于检测任何降解片段或聚合反应的存在。吉西他滨-（C4-酰胺）-[抗-HER2 / neu]保留的结合亲和力的检测通过细胞ELISA进行，使用了高度过表达HER2 / neu的对化疗药物耐药的乳腺腺癌（SKBr-3）群体营养膜受体。吉西他滨-（C4-酰胺）-[抗-HER2 / neu]和微管蛋白/微管抑制剂，灰黄霉素的抗肿瘤细胞毒性被建立为对化疗药物耐药的乳腺腺癌（SKBr-3）。相关研究评估了吉西他滨-（C4-酰胺）-[抗-HER2 / neu]与灰黄霉素双联使用与吉西他滨-（C4-酰胺）-[抗-HER2 /相比]引起增加的抗肿瘤细胞毒性的潜力neu]。结果共价吉西他滨-（C4-酰胺）-[抗-HER2 / neu]免疫化学疗法和灰黄霉素对抗化疗药性的乳腺腺癌（SKBr-3）具有抗肿瘤细胞毒性作用。共价吉西他滨-（C4-酰胺）-[抗-HER2 / neu]免疫化学疗法或吉西他滨与灰黄霉素的双重结合产生的抗肿瘤细胞毒性水平高于吉西他滨-（C4-酰胺）-[抗- HER2 / neu]或吉西他滨单用。结论吉西他滨-（C4-酰胺）-[抗-HER2 / neu]与灰黄霉素双重组合可产生更高水平的抗肿瘤细胞毒性，并有可能为更安全的治疗方案提供基础。通过以下方面的集体财产可能获得这些利益：[i]选择性“靶向”吉西他滨给药；[ii]与许多（如果不是大多数）常规化疗药物相比，灰黄霉素的毒性相对较低；[iii]通过累加或协同抗癌特性降低总剂量需求；[iv]吉西他滨-（C4-酰胺）-[抗-HER2 / neu]与灰黄霉素起微管蛋白/微管抑制剂作用的后遗症差异。通过以下方面的集体财产可能获得这些利益：[i]选择性“靶向”吉西他滨给药；[ii]与许多（如果不是大多数）常规化疗药物相比，灰黄霉素的毒性相对较低；[iii]通过累加或协同抗癌特性降低总剂量需求；[iv]吉西他滨-（C4-酰胺）-[抗-HER2 / neu]与灰黄霉素起微管蛋白/微管抑制剂作用的后遗症差异。通过以下方面的集体财产可能获得这些利益：[i]选择性“靶向”吉西他滨给药；[ii]与许多（如果不是大多数）常规化疗药物相比，灰黄霉素的毒性相对较低；[iii]通过累加或协同抗癌特性降低总剂量需求；[iv]吉西他滨-（C4-酰胺）-[抗-HER2 / neu]与起微管蛋白/微管抑制剂作用的灰黄霉素相比后遗症的差异。