caa a22 4500 397566085 CHVBK 20180308164828.0 cr unu---uuuuu 161202e19960619xx s 000 0 eng 10.1093/jnci/88.12.794 doi (NATIONALLICENCE)oxford-10.1093/jnci/88.12.794 Suramin-Induced Decrease in Prostate-Specific Antigen Expression With No Effect on Tumor Growth in the LNCaP Model of Human Prostate Cancer [Elektronische Daten] [George N. Thalmann, Robert A. Sikes, Shi-Ming Chang, Dennis A. Johnston, Andrew C. von Eschenbach, Leland W. K. Chung] Background: Suramin, a polysulfonated naphthylurea and a recognized antitrypanosomal agent, has shown some promise in phase II clinical trials in the management of hormone-refractory human prostate cancer. Reduction of serum prostate-specific antigen (PSA) levels has been proposed as an end point for evaluating the antitumor efficacy of treatments for hormone-refractory prostate cancer. Purpose: We examined the antitumor effect of suramin in an in vivo mouse model of hormone-refractory human prostate cancer to determine whether a decrease in PSA levels reflects a reduction in tumor growth (volume). The tumors were induced in castrated, athymic nude mice by use of the androgen-independent, tumorigenic human prostate cancer cell line C4-2, which is a subline of the androgen-de-pendent, parental nontumorigenic cell line LNCaP. We also evaluated the effects of suramin in vitro on cell growth and the expression of PSA messenger RNA (mRNA) in both LNCaP and C4-2 cells. Methods: For the in vivo studies, 24 mice were given a subcutaneous injection of 5 x 106 C4-2 cells at each of four sites. Animals (n = 20) with tumor volumes greater than 1 mm3 or less than 5 mm3 were divided equally into two groups. Drug treatment was initiated in one group by administration of 1 mg suramin in-traperitoneally, followed by 0.1 mg suramin at 10-day intervals to maintain constant serum levels. Tumor growth and PSA expression levels were monitored. For the in vitro studies, both LNCaP and C4-2 cells were exposed to 100-400 pg/μL suramin, and cell growth was monitored by a quantitative crystal violet assay. PSA mRNA expression was assessed by northern blot analysis in cells treated with either 250 μg/mL suramin, 400 ng/mL dihydrotestosterone (DHT) (positive control), or 0.5-75 μg/mL hydrocortisone (to mimic the clinical use of hydrocortisone during suramin treatment to compensate for the loss of adrenocortical function). In some studies, the combined effect of DHT and suramin on PSA mRNA expression was also evaluated. A two-way analysis of variance was performed to evaluate the treatment differences, and P values were obtained from two-sided tests for statistical significance. Results: In vivo, suramin did not significantly affect the growth of androgen-independent C4-2 tumors (relative to the growth of tumors in 5% glucose-treated control animals; P = .76). However, suramin significantly decreased the ratio of PSA level to tumor volume (ng/mL PSA per mm3 of tumor) (P<.001). Mice developed bone metastases in both treatment arms. Suramin affected the in vitro growth of LNCaP cells but not of C4-2 cells. Suramin diminished PSA mRNA expression in both LNCaP and C4-2 cells grown in vitro. Hydrocortisone had no effect on PSA mRNA levels. Conclusions: Although suramin inhibited the growth of androgen-dependent LNCaP cells, it did not inhibit the growth of androgen-independent C4-2 cells either in vitro or in vivo. Suramin significantly decreased PSA mRNA expression in both cell lines in vitro and depressed serum PSA levels in mice bearing androgen-independent C4-2 tumors. Implications: PSA level should be used with caution as an end point in clinical trials using suramin therapy for hormone-refractory prostate cancer. © Oxford University Press ARTICLES nationallicence Thalmann George N. Department of Urology The University of Texas M. D. Anderson Cancer Center Houston aut Sikes Robert A. Department of Urology The University of Texas M. D. Anderson Cancer Center Houston aut Chang Shi-Ming Department of Urology The University of Texas M. D. Anderson Cancer Center Houston aut Johnston Dennis A. Department of Biomathematics The University of Texas M. D. Anderson Cancer Center Houston aut von Eschenbach Andrew C. Department of Urology The University of Texas M. D. Anderson Cancer Center Houston aut Chung Leland W. K. Department of Urology The University of Texas M. D. Anderson Cancer Center Houston aut JNCI: Journal of the National Cancer Institute Oxford University Press 88/12(1996-06-19), 794-801 0027-8874 88:12<794 1996 88 jnci https://doi.org/10.1093/jnci/88.12.794 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/jnci/88.12.794 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Thalmann George N. Department of Urology The University of Texas M. D. Anderson Cancer Center Houston aut NATIONALLICENCE 700 1- Sikes Robert A. Department of Urology The University of Texas M. D. Anderson Cancer Center Houston aut NATIONALLICENCE 700 1- Chang Shi-Ming Department of Urology The University of Texas M. D. Anderson Cancer Center Houston aut NATIONALLICENCE 700 1- Johnston Dennis A. Department of Biomathematics The University of Texas M. D. Anderson Cancer Center Houston aut NATIONALLICENCE 700 1- von Eschenbach Andrew C. Department of Urology The University of Texas M. D. Anderson Cancer Center Houston aut NATIONALLICENCE 700 1- Chung Leland W. K. Department of Urology The University of Texas M. D. Anderson Cancer Center Houston aut NATIONALLICENCE 773 0- JNCI: Journal of the National Cancer Institute Oxford University Press 88/12(1996-06-19), 794-801 0027-8874 88:12<794 1996 88 jnci Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford