Formulation Dependent Help Interactions with Chemothera*

描述(申请人提供)：由于我们在癌症药理、药物新陈代谢方面的经验，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，以调查癌症患者常用的细胞毒性癌症化疗和草药补充剂之间潜在的药效学和药代动力学相互作用。对于这一R21应用，我们建议归因于来自一种特定植物的草药产品的不良反应不一定适用于由同一植物生产的其他配方。这个由两部分组成的试点项目将重点放在以DNA拓扑异构酶II(TOPO II)为靶标的抗癌药物依托泊苷(VP-16)和圣约翰草(SJW)的三种最广泛使用的商业制剂贯叶连翘上。 生姜丸的抗抑郁活性最初归因于萘二酮金丝桃素，但最近的数据更强烈地涉及到其他成分(包括金丝桃素和其他成分)。无论如何，大多数商业化的SJW产品都标准化为0.3%的金丝桃素。金丝桃素在结构上类似于针对Topo II的抗肿瘤药物，Topo II是一种核酶，在肿瘤细胞增殖过程中需要DNA复制和染色体分离。初步研究表明，金丝桃素与DNA结合，但不像依托泊苷(VP-16)那样产生Topo H依赖的DNA损伤或激活DNA损伤反应基因的表达。相反，金丝桃素抑制Topo II酶活性的步骤先于抗Topo II化疗药物，导致对依托泊苷和另一种Topo II靶向抗肿瘤药物安萨克林所需的DNA损伤活性的有效、剂量依赖性拮抗。由于癌症患者通常会被开出抗抑郁药的处方或自行服用草药产品，我们建议研究生姜丸提取物在体外和培养的人类肿瘤细胞中对Topo II活性的类似影响，并确定在复杂提取物的背景下，这些作用是否发生在生理上可达到的单个成分浓度。 我们的第一个假设是，SJW提取物的作用类似于纯金丝桃素，并在体外和体内拮抗Topo II导向的化疗药物；鉴于金丝桃素似乎具有抗抑郁活性，抑郁的癌症患者可能安全地使用不含金丝桃素的SJW产品。生姜丸提取物还可能通过诱导或抑制细胞色素P3A4活性与癌症化疗药物发生药代动力学相互作用，具体取决于暴露时间和所用生姜丸配方。细胞色素P3A4代谢依托泊苷以及长春新碱、长春新碱、伊立替康(CPT-11)和他莫昔芬。金丝桃素似乎是导致这些效果的SJW成分，但同样，它可能不是该草药的抗抑郁原理。最近SJW配方富含金丝桃苷的推广活动引起了人们的担忧，即如果长期使用SJW导致细胞色素P3A4的产生，某些SJW产品可能会对抗肿瘤药物的疗效产生不利影响。因此，我们的第二个假设是测试SJW提取物通过主要的CYP3A4调节蛋白孕烷X受体(PXR)转录激活以及直接改变培养的人肝细胞的CYP3A4含量的配方依赖性。对这一应用至关重要的研究组件是RTI天然产品表征核心(NPCC)，其分析化学能力将确定负责任何观察到的生物终点的SJW成分(S)的身份和浓度。这些研究的目的是为了公众健康和精神，即癌症患者应该被引导远离有害的草药产品，同时确保安全地获得相同草药的替代配方。

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.