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Formulation Dependent Help Interactions with Chemothera*

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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.

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