Formulation Dependent Help Interactions with Chemothera*

与 Chemothera* 的配方依赖性帮助相互作用

• 批准号: 6769285
• 负责人: David J Kroll
• 金额: $ 27.75万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6769285
• 关键词: DNA topoisomerases; St Johns wort; alternative medicine; antidepressants; biological products; cytochrome P450; cytotoxicity; depression; drug interactions; high performance liquid chromatography; human tissue; liver cells; mass spectrometry; medicinal plants; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; pharmacokinetics; plant extracts; pregnane compound; statistics /biometry; tissue /cell culture

DESCRIPTION (provided by applicant): As a result of our experience in cancer pharmacology, drug metabolism, and interest in therapeutic natural products (prescription drugs and dietary supplements), preliminary work was conducted to investigate potential pharmacodynamic and pharmacokinetic interactions between cytotoxic cancer chemotherapy and herbal supplements used commonly by cancer patients. For this R21 application, we propose that adverse actions attributed to herbal products derived from one specific plant may not necessarily hold true for other formulations manufactured from the same plant. This two-part pilot project will focus on the DNA topoisomerase II (topo II)-targeted anticancer agent etoposide (VP-16) and three of the most-widely used commercial formulations of St. John's wort (SJW), Hypericum perforatum. The antidepressant activity of SJW was originally attributed to the naphthodianthrone hypericin but recent data have more strongly implicated other components (including hyperforin and others). Regardless, most commercial SJW products are standardized to 0.3% hypericin. Hypericin is structurally similar to antitumor agents that target topo II, a nuclear enzyme required for DNA replication and chromosomal segregation during tumor cell proliferation. Preliminary studies revealed that hypericin bound to DNA but did not produce topo H-dependent DNA damage or activate the expression of DNA damage response genes as does etoposide (VP-16). Instead, hypericin inhibited topo II enzyme activity at a step prior that of anti-topo II chemotherapeutics resulting in potent, dose-dependent antagonism of the desired DNA damaging activity of etoposide and that of another topo II-targeted antitumor drug, amsacrine. Since cancer patients are often prescribed antidepressants or self-medicate with herbal products, we propose to investigate SJW extracts for similar effects on topo II activity in vitro and in cultured human tumor cells and determine whether these effects occur at physiologically achievable concentrations of individual components in the context of a complex extract. Our first hypothesis is that SJW extracts will act similar to pure hypericin and antagonize topo II- directed chemotherapeutics in vitro and in vivo; given that hypericin seems dispensible for antidepressant activity, depressed cancer patients might be directed safely toward hypericin-free SJW products. SJW extracts may also interact pharmacokinetically with cancer chemotherapeutics by inducing OR inhibiting CYP3A4 activity depending upon the duration of exposure and the SJW formulation used. CYP3A4 metabolizes etoposide as well as vincristine, vinblastine, irinotecan (CPT-11) and tamoxifen. Hyperforin appears to be the SJW component responsible for these effects but again, it may not be the antidepressant principle of the herb. Recent promotion of SJW formulations enriched for hyperforin raises concerns that certain SJW products may adversely compromise antitumor drug efficacy if CYP3A4 is induced by chronic SJW use. Therefore our second hypothesis is to test the formulation-dependence of SJW extracts in transcriptional activation via the primary CYP3A4 regulatory protein, pregnane X receptor (PXR), and in directly altering CYP3A4 content of cultured human hepatocytes. The research component central to this application is the RTI Natural Product Characterization Core (NPCC) whose analytical chemistry capabilities will determine the identity and concentrations of SJW constituent(s) responsible for any observed biological endpoints. These studies are designed in the interest of public health and the spirit that cancer patients should be steered away from harmful herbal products while being assured safe access to alternative formulations of the same herb.

描述（由申请方提供）：由于我们在癌症药理学、药物代谢方面的经验以及对治疗性天然产品（处方药和膳食补充剂）的兴趣，我们进行了初步工作，以研究癌症患者常用的细胞毒性癌症化疗和草药补充剂之间的潜在药效学和药代动力学相互作用。对于这项R21申请，我们提出，源自一种特定植物的草药产品的不良反应不一定适用于同一植物生产的其他制剂。这一由两部分组成的试点项目将侧重于DNA拓扑异构酶II（topo II）靶向抗癌剂依托泊苷（VP-16）和三种最广泛使用的圣约翰麦芽汁（SJW）、贯叶连翘的商业制剂。 SJW的抗抑郁活性最初归因于萘二蒽酮金丝桃素，但最近的数据更强烈地涉及其他成分（包括贯叶金丝桃素等）。无论如何，大多数商业SJW产品标准化为0.3%金丝桃素。金丝桃素在结构上类似于靶向topo II的抗肿瘤剂，topo II是肿瘤细胞增殖期间DNA复制和染色体分离所需的核酶。初步研究表明，金丝桃素结合DNA，但不产生拓扑H依赖的DNA损伤或激活DNA损伤反应基因的表达，如依托泊苷（VP-16）。相反，金丝桃素抑制拓扑异构酶II酶活性的步骤之前，导致有效的，剂量依赖性的拮抗剂所需的DNA损伤活性的依托泊苷和另一个拓扑异构酶II靶向的抗肿瘤药物，安吖啶的抗拓扑异构酶II化疗。由于癌症患者经常开抗抑郁药或自我安慰与草药产品，我们建议调查SJW提取物的拓扑异构酶II活性在体外和培养的人类肿瘤细胞的类似效果，并确定这些效果是否发生在生理上可实现的浓度的单个组件的背景下，复杂的提取物。 我们的第一个假设是，SJW提取物将采取类似于纯金丝桃素和拮抗拓扑异构酶II-定向化疗药物在体外和体内;鉴于金丝桃素似乎是必不可少的抗抑郁活性，抑郁的癌症患者可能会安全地指向金丝桃素自由SJW产品。SJW提取物也可能通过诱导或抑制CYP 3A 4活性与癌症化疗药物发生药代动力学相互作用，具体取决于暴露持续时间和所用SJW制剂。CYP 3A 4代谢依托泊苷以及长春新碱、长春碱、伊立替康（CPT-11）和他莫昔芬。贯叶金丝桃素似乎是造成这些作用的SJW成分，但同样，它可能不是草药的抗抑郁原理。最近推广的富含贯叶金丝桃素的SJW制剂引起了人们的担忧，即如果长期使用SJW诱导CYP 3A 4，某些SJW产品可能会对抗肿瘤药物的功效产生不利影响。因此，我们的第二个假设是测试SJW提取物在通过主要CYP 3A 4调节蛋白、胆甾烷X受体（PXR）的转录激活以及直接改变培养的人肝细胞的CYP 3A 4含量方面的制剂依赖性。本申请的核心研究部分是RTI天然产物表征核心（NPCC），其分析化学能力将确定负责任何观察到的生物学终点的SJW成分的身份和浓度。这些研究的目的是为了公众健康的利益和精神，即癌症患者应远离有害的草药产品，同时确保安全获得相同草药的替代制剂。