It is suggested that health care professionals and consumers should be aware of the potential for adverse interactions with these herbs, question their patients on their use of them, especially among patients whose disease is not responding to treatments as expected, and urge patients to avoid herbs that could confound their cancer care.

The MS-275 oral formulation on the daily schedule was intolerable at a dose and schedule explored. The q14-day schedule is reasonably well tolerated. Histone deacetylase inhibition was observed in peripheral-blood mononuclear-cells. Based on PK data from the q14-day schedule, a more frequent dosing schedule, weekly x 4, repeated every 6 weeks is presently being evaluated.

The epigenome is defined by DNA methylation patterns and the associated post-translational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The histone deacetylases (HDACs) play a major role in keeping the balance between the acetylated and deacetylated states of chromatin and eventually regulate gene expression. Recent developments in understanding the cancer cell cycle, specifically the interplay with chromatin control, are providing opportunities for developing mechanism-based therapeutic drugs. Inhibitors of HDACs are under considerable exploration, in part because of their potential roles in reversing the silenced genes in transformed tumor cells by modulating transcriptional processes. This review is an effort to summarize the nonclinical and clinical status of HDAC inhibitors currently under development in anticancer therapy.In eukaryotic cells, DNA has been conserved over evolution in a condensed and densely packed higher order structure called chromatin. Chromatin, present in the interphase nucleus, is composed of regular repeating units of nucleosomes, which represent the principal protein-nucleic acid relationship. The major components of chromatin are nucleic acids (DNA and RNA), which are negatively charged; associated proteins, including histones, that are positively charged at neutral pH; and nonhistone chromosomal proteins, which are acidic at neutral pH. Within the nucleus, chromatin can exists in two different forms: heterochromatin, which is highly compact and transcriptionally inactive, or euchromatin, which is loosely packed and accessible to RNA polymerases for involvement in transcriptional processes and gene expression. A nucleosome is a complex of 146 nucleotide base pairs of DNA wrapped around the core histone octamer that helps organize chromatin. The histone octamer is composed of two copies each of H2A, H2B, H3, and H4 proteins, which are very basic, mainly because of positively charged amino-terminal side chains rich in the amino acid lysine. Post-translational and other changes in chromatin, such as acetylation/deacetylation at lysine residues, methylation at lysine or arginine residues, phosphorylation at serine resides, ubiquitylation at lysines, and/or ADP ribosylation, are mediated by chemical modification of various sites on N-terminal tail .The structural modification of histones is regulated mainly by acetylation/deacetylation of the N-terminal tail and is crucial in modulating gene expression, because it affects the interaction of DNA with transcription-regulatory non-nucleoArticle, publication date, and citation information can be found at

Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response is extensive, and largely unexplained. We hypothesized that this is due to affinity of taxanes for an uptake transporter that indirectly regulates elimination pathways. Here, we studied accumulation of [3H]docetaxel and [3H]paclitaxel in Xenopus laevis oocytes injected with cRNA of the liver-specific organic anion transporting polypeptide (OATP) family members OATP1B1 (OATP2) or OATP1B3 (OATP8). Taxane transport by OATP1B1 expressing oocytes was not significantly different from that by water-injected controls, whereas uptake by OATP1B3 was 2.2-fold higher for docetaxel (p = 0.0007) and 3.3-fold higher for paclitaxel (p < 0.0001). OATP1B3-mediated paclitaxel transport was saturable (Michaelis-Menten constant, 6.79 microM), time-dependent, and highly sensitive to chemical inhibition. Paclitaxel uptake was not inhibited by ketoconazole or tariquidar. However, uptake was inhibited by the formulation excipient Cremophor (74.4% inhibition, p < 0.0001), cyclosporin A (25.2%, p = 0.005), glycyrrhizic acid (24.6%, p = 0.012), and hyperforin (28.4%, p = 0.003). Consistent with this finding, Cremophor was found to significantly affect the hepatic uptake of paclitaxel in mice. These data suggest that OATP1B3 is a key regulator of hepatic uptake, and may therefore play a role in the variable response to treatment with taxanes.

No abstract

Purpose Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses. Methods Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m2, days 1, 4, 8, 11, for up to eight 21-day treatment cycles (n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected. Results Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102–112 L/h for first dose; 15–32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m2 group. Conclusions Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m2 doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.

This phase I study compared pharmacokinetics and pharmacodynamics, and assessed safety and efficacy of intravenous and subcutaneous administration of bortezomib. Relapsed or refractory multiple myeloma patients were randomized to receive bortezomib by standard intravenous bolus (n=12) or subcutaneous injection (n=12) at the recommended dose and schedule (1.3 mg/m 2 , days 1, 4, 8, 11; eight 21-day cycles). Plasma bortezomib concentration and percent 20S proteasome inhibition were measured at multiple time points on days 1 and 11, cycle 1. Systemic bortezomib exposure was similar between arms. As expected, mean maximum plasma concentration was lower and took longer to reach following subcutaneous administration. Overall 20S proteasome inhibition was similar between arms. Safety profile and response rate for the subcutaneous arm did not appear inferior to the intravenous arm, with good local tolerance of subcutaneous injection. Based on these exploratory findings, subcutaneous administration offers an alternative option to intravenous injection (ClinicalTrials.gov identifier: NCT00291538).

ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein) and ABCG2 (breast cancer-resistance protein [BCRP], mitoxantrone-resistance protein [MXR], or ABC transporter in placenta [ABCP]), are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenetics of the ABC transporters ABCB1 and ABCG2, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer.