Theodore D.K. Chung

Characterization of the role of IL‐6 in the progression of prostate cancer

We recently identified IL‐6, a pleiotropic cytokine implicated in the neoplastic process of a variety of neoplasms, as a mediator of prostate cancer morbidity. In the present study, we investigated the expression of members of the IL‐6 supergene family and related cytokines and the potential role of IL‐6 in prostate cancer growth regulation.

Concomitant Infusional Paclitaxel and Fluorouracil, Oral Hydroxyurea, and Hyperfractionated Radiation for Locally Advanced Squamous Head and Neck Cancer

PURPOSE To improve local disease control and survival with organ preservation, we conducted a phase II multi-institutional trial with a concomitant taxane-based chemotherapy and hyperfractionated radiation regimen. PATIENTS AND METHODS Sixty-four patients with locally advanced squamous cancers (stage IV, 98%; N2/3, 81%) were treated on an intensive regimen consisting of 5-day (120-hour) infusions of paclitaxel (20 mg/m(2)/d) and fluorouracil (600 mg/m(2)/d), oral hydroxyurea 500 mg every 12 hours for 11 doses, and radiation 1.5 Gy bid (T-FH2X). Chemoradiation was administered concomitantly on days 1 to 5 of each 14-day cycle. A full treatment course consisted of five cycles during a 10-week period to a total radiation dose of 72 to 75 Gy. RESULTS The median follow-up for the group is 34 months. At 3 years, progression-free survival is 63%, locoregional control is 86%, and systemic control is 79%; overall survival is 60%. Seventeen patients died of recurrent cancer, two died of second primary cancers, and four died of other causes. Side effects observed include anemia (22% required transfusion), leucopenia (34%, grade 3 to 4), and mucositis (84%, grade 3 to 4). Organ preservation principles were maintained. At 1 year posttreatment, 61% of patients had severe xerostomia and 47% had compromised swallowing. There was little disturbance of speech quality in 97% of patients at the same follow-up point. CONCLUSION T-FH2X is a highly active and tolerable concomitant chemotherapy and hyperfractionated radiation regimen that induces sustained local tumor control and holds promise for improved survival with organ preservation in high-risk patients. Identification of less toxic therapy and improved distant disease control are needed. T-FH2X should be tested in a randomized trial and compared with a less intensive concomitant regimen that uses once-daily radiation fractionation.

STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells .

In the human prostate cancer cell line LNCaP, interleukin (IL)‐6 has been shown to regulate both growth and neuroendocrine (NE) differentiation.. We recently observed that IL‐6 mediated growth arrest in LNCaP by activating STAT 3. Since differentiation and growth arrest are often associated processes, we investigated whether STAT3 also mediated NE differentiation in this prostate cancer cell line.

STAT3 mediates IL-6-induced growth inhibition in the human prostate cancer cell line LNCaP

In prostate cancer, we and others have observed distinct phenotypic responses to interleukin‐6 (IL‐6), which acts either as a paracrine growth inhibitor in the LNCaP cell line or as an autocrine growth stimulator in PC‐3, DU145, and TSU cell lines. To understand the underlying mechanism responsible for this phenotypic difference, we investigated differences in the IL‐6‐induced Janus kinase‐signal tranducers and activators of transcription (JAK‐STAT) signal transduction pathway between these two phenotypes.

Interleukin-6 activates phosphatidylinositol-3 kinase, which inhibits apoptosis in human prostate cancer cell lines†

A number of recent studies have identified interleukin (IL)‐6 as an important regulator of prostate cancer growth. Here, we investigate the potential interaction of IL‐6 with phosphatidylinositol (PI)‐3 kinase, a key growth regulatory enzyme, in prostate cancer cell lines.

In vitro evaluation of calphostin C as a novel agent for photodynamic therapy of bladder cancer

OBJECTIVES Calphostin C, a highly specific protein kinase C inhibitor, induces apoptosis in the presence of visible light. We report the photoactivatable cytotoxicity of calphostin C in a series of well-characterized human bladder cancer cell lines: RT4, UM-UC-3, and 5637. METHODS The human bladder cancer cell lines RT4, UM-UC-3, and 5637 were chosen on the basis of their p53, pRb and 9p21 deletion status. Using standard tissue culture techniques, the cytotoxicity of 10 to 100 nM calphostin C in combination with increasing exposures of visible light was examined. Controls consisted of cells treated with calphostin C without visible light and cells exposed to visible light without calphostin C treatment. Cell viability was determined by MTT assay. The induction of apoptosis by activated calphostin C was determined by 4,6-diamidino-2-phenylindole (DAPI) staining/fluorescence microscopy of nuclei. RESULTS In the absence of light, calphostin C did not demonstrate a cytotoxic effect on any of the cell lines tested. Increasing the duration of light exposure resulted in a concomitant decrease in cell viability. Significant cell death was seen with calphostin C concentrations as low as 10 nM. These studies also demonstrated that calphostin C induced apoptosis by a mechanism independent of p53 and pRb status and the presence or absence of 9p21 deletions. CONCLUSIONS We demonstrated the ability of activated calphostin C to induce apoptosis in a light-dependent and concentration-dependent fashion in a bladder cancer model system. Activated calphostin C cytotoxicity is independent of tumor genetic background and the status of p53 and pRb. Further development of calphostin C as a photosensitizer for photodynamic therapy of superficial bladder cancer may be warranted.

Interleukin-6 activates phosphatidylinositol-3 kinase, which inhibits apoptosis in human prostate cancer cell linesPresented at the American Association for Cancer Research Special Conference “New Research Approaches in the Prevention and Cure of Prostate Cancer,” December 2–6, 1998, Indian Wells, CA.

BACKGROUND A number of recent studies have identified interleukin (IL)-6 as an important regulator of prostate cancer growth. Here, we investigate the potential interaction of IL-6 with phosphatidylinositol (PI)-3 kinase, a key growth regulatory enzyme, in prostate cancer cell lines. METHODS Tyrosine phosphorylation of p85, the regulatory subunit of PI-3 kinase, in the human prostate cancer cell lines LNCaP and PC-3 was assessed by sequential immunoprecipitation with anti-p85 antibody and immunoblotting with anti-phosphotyrosine. The effects of wortmannin, an inhibitor of PI-3 kinase, and/or IL-6 on cell growth were assessed by MTT assays. DNA laddering experiments were performed to assay for programmed cell death. RESULTS Tyrosine phosphorylation of p85 is upregulated by IL-6 in both LNCaP and PC-3. IL-6 promotes coprecipitation of p85 with gp130, the signal-transducing component of the IL-6 receptor. Inhibition of PI-3 kinase with wortmannin induces programmed cell death in PC-3 cells. In contrast, wortmannin has no effect on LNCaP growth when used alone; however, combined with IL-6, wortmannin promotes apoptosis in these cells. CONCLUSIONS PI-3 kinase is involved in IL-6 signal transduction and delivers an antiapoptotic signal in human prostate cancer cell lines.

Television and news print media are effective in recruiting potential participants in a prostate cancer chemoprevention trial.

Theodore D.K. Chung, MD, PhD,1,2 Irwin I. Park,1 Lani Ignacio, BSN,3 Rose Catchatourian, MD,4 Mitchell Kopnick, MD,5 Evelyn Davison,3 Geraldine Conrad,6 Azhar M. Awan, MD,1,7 David Crawford, MD,8 and Srinivasan Vijayakumar, MD1,2,3,8* 1Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois 2Department of Radiation Oncology, University of Illinois at Chicago, Chicago, Illinois 3Department of Radiation Oncology, Michael Reese Hospital and Medical Center, Chicago, Illinois 4Division of Hematology−Oncology, Michael Reese Hospital and Medical Center, Chicago, Illinois 5Division of Urology, Michael Reese Hospital and Medical Center, Chicago, Ilinois 6Office of Public Relations, Michael Reese Hospital and Medical Center, Chicago, Ilinois 7Department of Radiation Oncology, LaGrange Memorial Hospital, LaGrange, Ilinois 8Southwest Oncology Group, San Antonio, Texas