PubMed · 11022732
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A Shiono, K Kurokawa, K Ito, H Yamanaka. 2000. [Step up therapy].. https://pubmed.ncbi.nlm.nih.gov/11022732/
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A new fully automated method for the quantitative analysis of an antiandrogenic substance, cyproterone acetate (CPA), in plasma samples has been developed using on-line solid-phase extraction (SPE) prior to the determination by reversed-phase liquid chromatography (LC). The automated method was based on the use of a precolumn packed with an internal-surface reversed-phase packing material (LiChrospher RP-4 ADS) for sample clean-up coupled to LC analysis on an octadecyl stationary phase using a column-switching system. A 200-microL volume of plasma sample was injected directly on the precolumn packed with restricted access material using a mixture of water-acetonitrile (90:10, v/v) as washing liquid. The analyte was then eluted in the back-flush mode with the LC mobile phase which consisted of a mixture of phosphate buffer, pH 7.0-acetonitrile (54:46, v/v). The elution profiles of CPA and blank plasma samples on the precolumn and the time needed for analyte transfer from the precolumn to the analytical column were determined. Different compositions of washing liquid and mobile phase were tested to reduce the interference of plasma endogenous components. UV detection was achieved at 280 nm. Finally, the developed method was validated using a new approach, namely the application of the accuracy profile based on the interval confidence at 90% of the total measurement error (bias+standard deviation). The limit of quantification of cyproterone acetate in plasma was determined at 15 ng mL(-1). The validated method should be applicable to the determination of CPA in patients treated by at least 50 mg day(-1).
BACKGROUND: In vitro studies of CWR22 tumor cells lack steroid specificity. We sought to determine if CWR22 xenografts also lack steroid specificity. METHODS: We injected castrated nude mice with CWR22 tumor cells (6 x 10(6) cells) and implanted Alzet osmotic pumps that delivered approximately 1 mg steroid/kg body weight/day. RESULTS: Serum PSA levels were detectable in intact mice and castrated mice treated with testosterone (T), but not in those treated with estradiol (E(2)), progesterone (P), or flutamide (F). T maintained mean tumor weight similar to that in intact mice (P = NS). We observed no tumors in castrated mice or mice treated with E(2), P, or F, and tumor histology was consistent with weights. CONCLUSIONS: The mutation of the androgen receptor (H874Y) that occurs in the CWR22 xenograft model of human prostate cancer does not significantly affect in vivo steroid specificity for E(2), P, or F.
Androgen receptor (AR) plays an important role in the development and progression of prostate cancer upon the action of androgen through the binding of the androgen-responsive elements (AREs) on the target genes. Abnormal activation of the AR by nonandrogen has been implicated in the progression of androgen-independent prostate cancer. The levels of interleukin-4 (IL-4) are significantly elevated in sera of patients with hormone refractory prostate cancer. The potential role of IL-4 on the activation of AR was investigated in prostate cancer cells. IL-4 enhances AR-mediated prostate-specific antigen (PSA) expression and ARE-containing gene activity through activation of the AR in the androgen ablation condition in human prostate cancer cells. The AR can also be sensitized by IL-4 and activated by significantly lower levels of androgen (10 pM of R1881) in prostate cancer cells. IL-4 enhances nuclear translocation of AR and increases binding of the AR to the ARE in LNCaP prostate cancer cells. Blocking of the Akt pathway by an Akt-specific inhibitor LY294002 abrogates IL-4-induced PSA expression and AR signaling. These results demonstrate that IL-4 enhances PSA expression through activation of the AR and Akt signaling pathways in LNCaP prostate cancer cells. Understanding IL-4-induced signaling leading to abnormal activation of AR will provide insights into the molecular mechanisms of androgen-independent progression of prostate cancer cells.