Antiangiogenic effect of ZD1839 against murine renal cell carcinoma (RENCA) in an orthotopic mouse model.

INTRODUCTION: ZD1839 (Iressa) is a selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). We evaluated the antitumor and antiangiogenesis activities of ZD1839 in a murine renal cell carcinoma (RENCA) model. MATERIALS AND METHODS: The effect of ZD1839 on the cellular proliferation of RENCA cells in vitro was measured by colorimetric assay. For the in vivo studies, RENCA cells were adsorbed in Gelfoam and implanted into BALB/cJ mouse parenchyma with an agarose bar. Mice were treated with ZD1839 (40 mg/kg/day s.c.), genistein or saline for 14 days. Western blot analysis was performed to observe EGFR expression in RENCA cells and tumor tissues. Microvessel density (MVD) was quantified by immunostaining for factor VIII-related antigens and VEGF level was assayed by ELISA. RESULTS: ZD1839 showed a dose-dependent inhibition of RENCA cellular proliferation. ZD1839 treatment resulted in a marked decrease in tumor growth compared with saline treatment. The MVD and VEGF in the RENCA tumors were decreased significantly by ZD1839 (p<0.01 and p>0.05, respectively). Genistein also suppressed tumor growth and decreased MVD and VEGF level, but the efficacies were less than with ZD1839. CONCLUSION: The suppressive activity of ZD1839 on RENCA tumor growth was accompanied by decreases in the MVD and VEGF production. These results suggest that the antitumor effect of ZD1839 in a RENCA model is mediated partially by the inhibition of tumor angiogenesis.

Association of cyclooxygenase-2 expression with prognosis of stage T1 grade 3 bladder cancer.

OBJECTIVES: To determine whether the expression of cyclooxygenase-2 (COX-2) has prognostic significance in Stage T1G3 transitional cell carcinoma of the bladder, the most unfavorable subgroup in terms of recurrence and disease progression. METHODS: Thirty-seven consecutive patients with initial T1G3 transitional cell carcinoma, who had undergone complete transurethral resection, followed by 6 weeks of intravesical instillation of bacille Calmette-Guérin (BCG), and with at least 1 year of follow-up, were enrolled in the study. Paraffin-embedded cancer tissue samples were immunohistochemically stained for COX-2, and possible correlations with clinicopathologic features, such as age, shape and multiplicity of tumor, recurrence, and progression were examined. RESULTS: The median follow-up was 27 months (range 12 to 67). Sixteen patients (43.2%) experienced recurrence and 6 (16.2%) had progression defined as muscle invasion. Of 37 specimens, 16 (43.2%) stained positive for COX-2, defined as 5% or greater of positively stained cancer cells. COX-2 expression was statistically significant in predicting both recurrence (P = 0.0493) and disease progression (P = 0.0272). Patient age and the shape and multiplicity of tumors were not significantly predictive of recurrence or progression. CONCLUSIONS: In a pathologically homogeneous group of T1G3 transitional cell carcinoma of the bladder, the expression of COX-2 correlated with recurrence and progression. Thus, patients with COX-2 positive superficial bladder cancer may need to be followed up more vigorously. Additional studies on the mechanistic implications of COX-2 with respect to recurrence and progression and the possible application of a COX-2 inhibitor to prevent recurrence and progression of superficial bladder cancer are warranted.

Comparative study of concentration of isoflavones and lignans in plasma and prostatic tissues of normal control and benign prostatic hyperplasia.

OBJECTIVE: Isoflavones and lignans are phytoestrogens that have recently gained interest as dietary factors related to prostatic diseases. However, no data on the concentrations in prostate tissue in humans is available. Therefore, the concentrations of isoflavones and lignans in plasma and prostatic tissues according to the prostate volume were compared to determine their possible effect on the benign prostatic growth. METHODS: Fasting plasma and prostatic tissue specimens were acquired from 25 men over 50 years of age with similar normal dietary habits and no previous history of drug intake that could affect the isoflavones and lignans levels. The tissue was acquired either during a transurethral resection of the prostate in 15 patients with benign prostatic hyperplasia (BPH) with prostate volume over 40 ml or during a radical cystoprostatectomy in 10 patients with bladder cancer with a prostate volume < 25 ml, who were used as the controls. Quantitative analysis of the isoflavones, specifically equol, daidzein and genistein and lignans, particularly enterodiol and enterolactone, was performed by gas chromatography-mass spectrometry. RESULTS: The mean prostatic concentrations of enterodiol, enterolactone, equol and daidzein in the BPH and the control groups were similar. However, the mean prostatic concentration of genistein was significantly lower in the BPH group than in the control group (65.43 +/- 17.05 vs 86.96 +/- 37.75 ng/ ml, respectively, p=0.032). The plasma concentration of isoflavones and lignans in the two groups were comparable. CONCLUSION: Isoflavones, but not lignans, have some influence the benign prostatic growth, and the prostatic concentration of genistein possibly has the closest association among them. More studies to further clarify the roles and mechanisms of isoflavone action on BPH including pharmacokinetic studies are recommended.