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Prostate Cancer Chemoprevention Agents Exhibit Selective Activity Against Early Stage Prostate Cancer Cells

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Prostate Cancer Chemoprevention Agents Exhibit Selective Activity Against Early Stage Prostate Cancer Cells Prostate Cancer and Prostatic Diseases (2001) 4, 81±91 ß 2001 Nature Publishing Group All rights reserved 1365±7852/01 $15.00 www.nature.com/pcan Prostate cancer chemoprevention agents exhibit selective activity against early stage prostate cancer cells YQ Liu1, E Kyle2, S Patel2, F Housseau3, F Hakim2, R Lieberman4, M Pins5, MV Blagosklonny2 & RC Bergan1* 1Division of Hematology/Oncology, Department of Medicine, Northwest University Medical School and the Robert H. Lurie Cancer Center of Northwestern University, Chicago, USA; 2Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, National Institutes, National Institutes USA; 3Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; 4Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; and 5Department of Pathology, Northwestern University Medical School and the Robert H. Lurie Cancer Center of Northwestern University, Chicago, USA Preclinical models for the identi®cation of prostate cancer chemoprevention agents are lacking. Based upon the notion that clinically useful chemoprevention agents should exhibit selective activity against early stage disease, studies were undertaken to assess whether chemoprevention agents selectively inhibited the growth of early stage prostate cancer, as compared to late stage cancer. First, a series of cell and molecular studies were performed, which, when taken together, validated the use of a panel of prostate cell lines as a model of the different stages of carcinogenesis. Next, therapeutic responsiveness to ten different cytotoxic or chemoprevention agents was evaluated. Chemoprevention agents exhibited selective activity against normal and early transformed prostate tissue, whereas cytotoxic agents were non-speci®c. Selective activity against early versus advanced prostate cancer cells is identi®ed as a potential screening method for chemoprevention agents. Prostate Cancer and Prostatic Diseases (2001) 4, 81±91. Keywords: prostate cancer; chemoprevention; preclinical models; cell growth; treatment Introduction supporting therapeutic intervention at a very early stage in the disease process, using a chemopreventive-type Prostate cancer is a prevalent disease which historically approach. First, recent advances in cancer biology suggest has been resistant to chemotherapy, and is incurable in that prostate cancer develops as a result of a multi-step advanced stages.1 Prostate cancer will be diagnosed in an process, with late stage steps dependent upon initial estimated 180 400 Americans in 2000, causing death in changes.4±6 Thus, therapeutic intervention at an early approximately 31 900 of them, world wide these numbers stage would prevent late stage disease. Advances in are much higher.2 Though initially responsive to hormone awareness, detection and in our understanding of early therapy, relapse is inevitable once bony metastasis have clinical stages has expanded the ability to correlate clin- developed. Chemotherapy has not improved overall ther- ical stages with changes at the molecular level. Impor- apeutic outcome over the past four decades.1,3 Signi®cant tantly, early clinical processes develop in the context of a advances in this area will require approaches other than process characterized by both distinct pathological enti- those historically undertaken. ties, as well as one characterized by linear progression.1,6,7 While most systemic therapeutic interventions are per- The earliest pathologic change, low grade prostatic intrae- formed in late stage disease, there are a number of reasons pithelial neoplasia (PIN), is observed in the third decade of life, while invasive cancer is observed in the sixth decade. Likewise, invasive cancer runs a well recognized *Correspondence: RC Bergan, Olson 8524, Division of Hematology/ Oncology, Northwestern University, 710 N. Fairbanks, Chicago, IL course of latency within the prostate gland, followed by 60611-3008, USA. local invasion, seeding of local lymph nodes, and then the Received 9 August 2000; accepted in revised form 5 December 2000 development of wide spread metastasis. Identi®cation of prostate chemoprevention drugs YQ Liu et al 82 Another advantage to early therapeutic intervention Normal prostate epithelial cells (NPECs) were obtained relates to the fact that systemic pharmaceuticals are from Clonetics (Palo Alto, CA). Human papillomavirus directed towards a ®nite number of molecular targets. (HPV) transformed normal epithelial and primary cancer Signi®cant in that the number of molecular abnormalities cells were obtained from prostate glands as described.14 of any cancer, including prostate, increase with time and Brie¯y, normal and cancer cells from the same patient advances in the clinical stage. In fact, abnormalities at the were microdissected and transformed yielding paired molecular level are believed to be responsible for disease normal and cancer transformed cell lines. Paired lines progression.8,9 This means that in more advanced stages from two patients were available: 1532NPTX (normal) of disease, therapeutic interventions must effectively and 1532CPTX (cancer), and 1542NPTX (normal) and reverse a much larger number of molecular aberrations 1542CP3TX (cancer). HPV transformed cell lines were a than in the early stages. Finally, patients have fewer generous gift from S Topolian (National Cancer Institute, comorbid conditions at early stages of the disease, as Bethesda, MD). Normal diploid peripheral blood mono- compared to those with late stages. This is not only an nuclear cells were harvested as previously described from important prognosticator of therapeutic responsiveness, normal volunteers.15,16 but also de®nes a patient population more tolerant of side PC3 and PC3-M cells were grown in RPMI 1640 media effects of therapy. (Gibco BRL, Grand Island, NY) supplemented with 10% One of the dif®culties with developing prostate cancer fetal bovine serum (FBS; Bio¯uids, Rockville, MD). DU- chemopreventive agents, however, relates to the manner 145 cells were cultured in Dulbecco's modi®ed Eagle's by which potentially active agents are identi®ed in the medium (DMEM), supplemented with 5% FBS. NPECs preclinical setting. Currently, there is no standard meth- were cultured according to the manufacturer. 1532NPTX, odology for the identi®cation of such agents. In part this 1542NPTX, 1532CP1TX and 1542CP3TX cells were grown relates to the historic dif®culty in identifying agents in keratinocyte-serum free medium, supplemented with which have clinical activity against prostate cancer. That bovine pituitary extract and human recombinant epider- is, it has been dif®cult to develop meaningful preclinical mal growth factor according to the manufacturer (Gibco), models for prostate cancer.10 This problem is com- and with 5% FBS and 2 mM glutamine (Bio¯uids, Rock- pounded when one is considering an early intervention/ ville, MD). All cells were maintained at 37C in a humi- chemoprevention strategy.11 This is because endpoints for di®ed atmosphere of 5% carbon dioxide, with biweekly chemoprevention trials differ from those sought in more media changes. conventional clinical trials which seek to accrue a cohort of patients with advanced disease. An effective chemoprevention agent should be selec- Cell cycle and DNA ploidy analysis tive and should have activity at early stages of the disease Exponentially growing subcon¯uent cells were subjected process. It was therefore hypothesized that chemopreven- to ¯ow cytometric analysis as previously described.17 tive agents should exhibit selective activity against less Brie¯y, cells were ®xed in 70% ethanol at 4C, overnight. carcinogenic cell lines, as compared to cell lines indicative Cells were then resuspended in PBS containing 50 kunit/ of more advanced stages of carcinogenesis. In addition, ml type III-A RNase (Sigma, St. Louis, MD) and incu- the spectrum of activity of chemopreventive agents bated for 30 min at 37C; DNA was then stained by the should be distinct from that observed with conventional addition of propidium iodide. The intensity of nuclear cytotoxic agents. A series of investigations were under- staining was analyzed on a FACSCAN (Becton Dickinson, taken to test this hypothesis. Taken together current San Jose, CA). The proportion of cells in G0 ± G1, S and ®ndings support the notion that chemopreventive G2 ± M was then determined from the resultant DNA agents exert selective activity against early prostate histogram using a Mod®t-LT software package (Verity cancer, as compared to late stage disease. Software House, Inc., Topsham, ME). DNA ploidy of prostate cells was analyzed by comparing the position Materials and methods of the G0 ± G1 peak of prostate cells to that of the corresponding peak for normal diploid peripheral blood Materials mononuclear cells. In these experiments, prostate and peripheral blood mononuclear cells were analyzed sepa- Adriamycin, vinblastine, tamoxifen and 4-hydroxytamox- rately (ie, individual cell types were analyzed separately ifen were obtained from Sigma Chemical Company (St. in consecutive runs), as well as together (ie, individual Louis, MO). Genistein, 43% and 90% preparations, were cell types were mixed and run together). obtained from Protein Technologies International (St. Louis, MO), perillyl alcohol (PAL), perillic acid (PAC) and perillyl alcohol methylester (PALME) were obtained Cell adhension assay from McKesson BioServices (Rockville, MD). Toremifene citrate
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