Paclitaxel alters the expression and specific activity of deoxycytidine kinase and cytidine deaminase in non-small cell lung cancer cell lines

<p>Abstract</p> <p>Background</p> <p>We observed that paclitaxel altered the pharmacokinetic properties of gemcitabine in patients with non-small cell lung cancer (NSCLC) and limited the accumulation of gemcitabine and its metabolites in various primary and immortalized human cells. Therefore, we classified the drug-drug interaction and the effects of paclitaxel on deoxycytidine kinase (dCK) and cytidine deaminase (CDA) in three NSCLC cell lines. These enzymes are responsible for the metabolism of gemcitabine to its deaminated metabolite dFdU (80% of the parent drug) and the phosphorylated metabolites dFdCMP, dFdCDP and dFdCTP. These metabolites appear to relate to sensitivity and tolerability of gemcitabine based on previous animal and laboratory studies.</p> <p>Methods</p> <p>Three immortalized human cells representative of the most common histological subtypes identified in patients with advanced NSCLC were exposed to the individual drugs or combinations to complete a multiple drug effect analysis. These same cell lines were exposed to vehicle-control or paclitaxel and the mRNA levels, protein expression and specific activity of dCK and CDA were compared. Comparisons were made using a two-tailed paired t-test or analysis of variance with a P value of < 0.05 considered significant.</p> <p>Results</p> <p>The multiple drug effect analysis indicated synergy for H460, H520 and H838 cells independent of sequence. As anticipated, paclitaxel-gemcitabine increased the number of G2/M cells, whereas gemcitabine-paclitaxel increased the number of G0/G1 or S cells. Paclitaxel significantly decreased dCK and CDA mRNA levels in H460 and H520 cells (40% to 60%, P < 0.05) and lowered dCK protein (24% to 56%, P < 0.05) without affecting CDA protein. However, paclitaxel increased both dCK (10% to 50%) and CDA (75% to 153%) activity (P < 0.05). Paclitaxel caused substantial declines in the accumulation of the deaminated and phosphorylated metabolites in H520 cells (P < 0.05); the metabolites were not measurable in the remaining two cell lines. The ratio of dCK to CDA mRNA levels corresponded to the combination index (CI) estimated for sequential paclitaxel-gemcitabine.</p> <p>Conclusion</p> <p>In summary, paclitaxel altered the mRNA levels and specific activity of dCK and CDA and these effects could be dependent on histological subtype. More cell and animal studies are needed to further characterize the relationship between mRNA levels and the overall drug-drug interaction and the potential to use histological subtype as a predictive factor in the selection of an appropriate anticancer drug regimen.</p

Echinacea purpurea Significantly Induces Cytochrome P450 3A Activity but Does Not Alter Lopinavir‐Ritonavir Exposure in Healthy Subjects

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90291/1/phco.30.8.797.pd

The roles of herbal remedies in survival and quality of life among long-term breast cancer survivors - results of a prospective study

<p>Abstract</p> <p>Background</p> <p>Few data exist on survival or health-related quality of life (QOL) related to herbal remedy use among long-term breast cancer survivors. The objective of this report is to examine whether herbal remedy use is associated with survival or the health-related QOL of these long-term breast cancer survivors.</p> <p>Methods</p> <p>In 1999-2000, we collected the information of herbal remedy use and QOL during a telephone interview with 371 Los Angeles Non-Hispanic/Hispanic white women who had survived more than 10 years after breast cancer diagnosis. QOL was measured using the Medical Outcomes Study Short Form-36 (SF-36) questionnaire. Patients were followed for mortality from the baseline interview through 2007. 299 surviving patients completed a second telephone interview on QOL in 2002-2004. We used multivariable Cox proportional hazards methods to estimate relative risks (RR) and 95% confidence intervals (CI) for mortality and applied multivariable linear regression models to compare average SF-36 change scores (follow-up - baseline) between herbal remedy users and non-users.</p> <p>Results</p> <p>Fifty-nine percent of participants were herbal remedy users at baseline. The most commonly used herbal remedies were echinacea, herbal teas, and ginko biloba. Herbal remedy use was associated with non-statistically significant increases in the risks for all-cause (44 deaths, RR = 1.28, 95% CI = 0.62-2.64) and breast cancer (33 deaths, RR = 1.78, 95% CI = 0.72-4.40) mortality. Both herbal remedy users' and non-users' mental component summary scores on the SF-36 increased similarly from the first survey to the second survey (<it>P </it>= 0.16), but herbal remedy users' physical component summary scores decreased more than those of non-users (-5.7 vs. -3.2, <it>P </it>= 0.02).</p> <p>Conclusions</p> <p>Our data provide some evidence that herbal remedy use is associated with poorer survival and a poorer physical component score for health-related QOL among women who have survived breast cancer for at least 10 years. These conclusions are based on exploratory analyses of data from a prospective study using two-sided statistical tests with no correction for multiple testing and are limited by few deaths for mortality analysis and lack of information on when herbal remedy use was initiated or duration of or reasons for use.</p