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Biomedical subjects

A S Belldegrun

Publications and source records attributed to A S Belldegrun.

At least 37 records · Page 2Linked to original sources
PubMed2000

Gene therapy for prostate cancer at the University of California, Los Angeles: preliminary results and future directions.

The treatment options for patients with advanced prostate cancer are limited. Because of recent advances in the understanding of the molecular biology of prostate cancer, the accessibility of the prostate for injection, and the availability of gene promotors that allow tissue-specific expression of therapeutic gene products, gene therapy for prostate cancer has realized significant achievements in recent years. What once belonged to the realm of basic science is now entering the domain of phase II clinical trials. In this review, current results and future directions in prostate gene therapy at the University of California, Los Angeles, are discussed.

California↗
PubMed2000

Intermittent androgen deprivation therapy: schedule modifications based on a novel in vivo human xenograft model.

In most clinical trials of intermittent androgen deprivation (IAD), the decision to stop androgen withdrawal is based on monitoring PSA levels, waiting for its drop to nadir. Based on in vitro pre-clinical studies, a modified 'on-off' schedule of short intervals of androgen deprivation, designated pulsed androgen deprivation (PAD), is proposed to destroy androgen dependent (AD) cells more gradually and to conserve their androgen-independent (AI) inhibitory potential for longer periods, resulting in an overall prolongation of time to hormone resistant progression.Prostate Cancer and Prostatic Diseases (2000) 3, 280-282

Journal Article↗
PubMed2000

CL1-GFP: an androgen independent metastatic tumor model for prostate cancer.

PURPOSE: The mechanisms responsible for tumor progression to androgen independence in prostate cancer (CaP) remain unknown. To characterize these changes and provide a basis for rational therapeutic strategies for advanced CaP, an in vivo model from a highly aggressive androgen independent CaP cell line with distinct cellular and molecular properties was developed. MATERIALS AND METHODS: An aggressive androgen-independent cell line designated CL1 was derived from a slow-growing, and androgen-dependent, parental LNCaP cell line through in-vitro androgen-deprivation and selection. CL1 was stably transfected with a green fluorescence protein gene (CL1-GFP) and orthotopically injected into SCID mice. The pathologic behavior, histology, and molecular determinants of CL1 tumor and metastases were determined and characterized by standard light and fluorescent microscopy, and quantitative RT-PCR analysis. RESULTS: CL1 is an anaplastic prostate cancer cell line which demonstrates extensive local invasion and metastases to various organs that can be visualized via GFP expression. When compared with parental LNCaP cells, RT-PCR analysis of the tumor revealed an over-expression of EGFR, b-FGF, VEGF, TGF-beta, IL-8, IL-6, and bcl-2 and a down regulated expression of the p53, E-cadherin and PTEN. In contrast to LNCaP cells, CL1 tumors express lower levels of androgen receptor and barely detectable PSA mRNA. CONCLUSIONS: CL1-GFP represents an aggressive androgen-independent CaP tumor model derived through androgen deprivation whose pathologic development and molecular properties in animals resembles the clinical characteristics of hormone refractory prostate cancer (HRPC). Metastatic sites of CL1-GFP can be visualized with fluorescence microscopy offering a unique therapeutic model for the evaluation of drug sensitivity and other therapeutic modalities.

Androgens↗
PubMed1999

Gene therapy for prostate cancer. New perspectives on an old problem.

Recent advances in molecular biology have made the prospect of gene therapy for prostate cancer a reality. A wide variety of genetic strategies, vector designs, and delivery modalities are currently in use. This article examines the state of the art prostate cancer gene therapy and details the various options available to clinicians.

Cancer Vaccines↗
PubMed1999

Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma.

PURPOSE: To prospectively evaluate in a multicenter randomized trial the antitumor activity of CD8(+) tumor-infiltrating lymphocytes (TILs) in combination with low-dose recombinant interleukin-2 (rIL-2), compared with rIL-2 alone, after radical nephrectomy in metastatic renal cell carcinoma patients. PATIENTS AND METHODS: Between December 1994 and March 1997, 178 patients with resectable primary tumors were enrolled at 29 centers in the United States and Europe. Patients underwent total nephrectomy, recovered, and were randomized to receive either CD8(+) TILs (5 x 10(7) to 3 x 10(10) cells intravenously, day 1) plus rIL-2 (one to four cycles: 5 x 10(6) IU/m(2) by continuous infusion daily for 4 days per week for 4 weeks) (TIL/rIL-2 group) or placebo cell infusion plus rIL-2 (identical regimen) (rIL-2 control group). Primary tumor specimens were cultured at a central cell-processing center in serum-free medium containing rIL-2 to generate TILs. RESULTS: Of 178 enrolled patients, 160 were randomized (TIL/rIL-2 group, n = 81; rIL-2 control group, n = 79). Twenty randomized patients received no treatment after nephrectomy because of surgical complications (four patients), operative mortality (two patients), or ineligibility for rIL-2 therapy (14 patients). Among 72 patients eligible for TIL/rIL-2 therapy, 33 (41%) received no TIL therapy because of an insufficient number of viable cells. Intent-to-treat analysis demonstrated objective response rates of 9.9% v 11.4% and 1-year survival rates of 55% v 47% in the TIL/rIL-2 and rIL-2 control groups, respectively. The study was terminated early for lack of efficacy as determined by the Data Safety Monitoring Board. CONCLUSION: Treatment with CD8(+) TILs did not improve response rate or survival in patients treated with low-dose rIL-2 after nephrectomy.

Adolescent↗
PubMed1998

Superficial bladder cancer: the role of interferon-alpha.

PURPOSE: We evaluate the clinical experience with recombinant interferon-alpha in superficial transitional cell carcinoma and discuss the most rational use of recombinant interferon-alpha in the context of current treatment options. MATERIALS AND METHODS: The available data were reviewed and discussed at a consensus conference in August 1996. The conclusions and recommendations are those of the authors based on the consensus reached at that meeting. RESULTS: While bacillus Calmette-Guerin (BCG) is recognized as the most efficacious intravesical agent in the prophylaxis and treatment of superficial transitional cell carcinoma, it is associated with significant toxicities and a 20 to 40% relapse rate. Interferons, particularly recombinant interferon-alpha, have demonstrated efficacy against primary and recurrent papillary transitional cell carcinoma and carcinoma in situ with minimal toxicity, although the response and relapse rates are inferior to BCG. Intravesical recombinant interferon-alpha therapy has also produced responses in patients who failed to respond or were refractory to BCG or chemotherapy. CONCLUSIONS: The clinical experience suggests that recombinant interferon-alpha has an important role in the treatment of superficial transitional cell carcinoma, particularly as second line therapy following failure of BCG or chemotherapy, and it may have synergistic effects when combined with chemotherapy or BCG. We propose a prospective randomized study comparing the efficacy of recombinant interferon-alpha, BCG and BCG plus recombinant interferon-alpha as maintenance following complete response to primary BCG therapy. The proposed study would also investigate the efficacy of BCG plus recombinant interferon-alpha as second line therapy following BCG failure. This study will be important to determine the most effective strategy to integrate recombinant interferon-alpha into current treatment options for superficial bladder cancer.

Administration, Intravesical↗
PubMed1997

Identification of a positive regulatory element responsible for tissue-specific expression of prostate-specific antigen.

The prostate-specific antigen (PSA) promoter (PSA-P) has been identified, characterized, and determined to be tissue specific. Compared with high expression of the genomic PSA gene in prostate cells, expression of the transgene driven by the putative PSA promoter is low. This suggests that the identified promoter may be incomplete or may function optimally with additional regulatory elements. To identify the presence of additional regulatory elements, we screened sequences upstream of the PSA promoter and identified a DNA fragment of 822 bp, which enhances PSA gene expression. Combining the newly identified PSA gene regulatory sequence (PSAR) with our previously identified PSA promoter (PCPSA-P) exhibited enhanced expressional activity in the PSA-producing LNCaP cell line. With the addition of 10 to 100 nM dihydrotestosterone, a more than 1000-fold increase in expression was observed as compared to androgen-negative controls. Furthermore, although the combined regulatory element (PSAR)-PSA promoter (PCPSA-P) sequence resulted in high transgene expression in LNCaP cell lines, the combined regulatory element-promoter sequence resulted in minimal expression in the non-PSA-producing prostate cell line PC-3, renal tumor cell line R11, and cervical adenocarcinoma cell line HeLa. The newly identified 822 bp alone could also function as a promoter. Compared with the combined promoter, however, the 822-bp fragment alone demonstrated lower activity and lower responsiveness to androgen stimulation. Our results suggest that coupling the PSA promoter with an upstream regulatory element results in a marked increase in PSA expression, suggesting that the complete PSA promoter contains two functional domains: a proximal promoter and a distal promoter, which can also function as an enhancer. The enhanced gene expression of the new construct, combined with its tissue specificity and androgen responsiveness, in turn provides a foundation for the development of tissue-specific vectors for prostate cancer gene therapy.

Base Sequence↗
PubMed1997

Health related quality of life outcomes in patients treated for metastatic kidney cancer: a pilot study.

PURPOSE: We assessed health related quality of life in patients with advanced renal cell carcinoma treated with nephrectomy and tumor infiltrating lymphocyte therapy in combination with interleukin-2. MATERIALS AND METHODS: A total of 20 patients with advanced renal cell carcinoma who underwent nephrectomy and combination immunotherapy with tumor infiltrating lymphocytes and interleukin-2 completed a retrospective, cross-sectional health related quality of life instrument. Established reference populations with other chronic medical conditions, or breast, prostate or other cancers were used for comparison of health related quality of life scores. General health related quality of life was measured with a RAND 36-Item Health Survey 1.0. Cancer targeted quality of life was measured with the Cancer Rehabilitation Evaluation System-Short Form. Sociodemographic and co-morbidity variables were also collected. RESULTS: General health related quality of life in patients treated with tumor infiltrating lymphocytes and interleukin-2 was significantly better than that in heart failure patients on 1 of 8 scales but significantly worse than in the general population on 6 of 8 scales. General health related quality of life in the former patients was also significantly worse than in those with hypertension on 5 of 8 scales and significantly worse than in diabetics on 2 scales. Cancer targeted health related quality of life in patients given immunotherapy was significantly better than in men with prostate cancer on 1 of 5 scales, significantly better than in women with breast cancer on 2 of 5 scales and significantly better than patients with other cancers (nonbreast and nonprostate) on 3 of 5 scales. CONCLUSIONS: Patients undergoing nephrectomy and adjuvant tumor infiltrating lymphocytes plus interleukin-2 therapy for advanced renal cell carcinoma report better health related quality of life than those with other malignancies and better physical function than patients with congestive heart failure. However, health related quality of life is worse than in the general population and similar or worse than in patients with hypertension or type II diabetes. This surveyed population is selective and may represent the best responders among survivors of a highly toxic therapy. Nevertheless, quality and quantity of life should be addressed with patients when considering immunotherapy for metastatic kidney cancer.

Carcinoma, Renal Cell↗
PubMed1996

In vitro modulation of tumor progression-associated properties of hormone refractory prostate carcinoma cell lines by cytokines.

BACKGROUND: Cytokines exert cytostatic and immunomodulatory effects on carcinoma cells. Growth inhibition of human prostate carcinoma by cytokines has been demonstrated both in vitro and in vivo, whereas the cellular and molecular changes in prostate carcinoma properties after cytokine treatment have never been characterized. We have thus investigated whether the intrinsic properties of prostate carcinoma cells that are associated with tumor development and progression can be altered by direct cytokine treatment. METHODS: LNCaP, DU-145, and PC-3 cell lines were treated with tumor necrosis factor-alpha (TNF-alpha) (200 U/mL), interferon-gamma (IFN-gamma) (500 U/mL), human leukocyte interferon (IFN-alpha) (500 U/mL), and interleukin-2 (IL-2) (400 U/mL). The expression of (prostate-specific antigen [PSA] and prostate-specific membrane [PSM]), androgen receptor (AR), growth factors, oncogenes, collagenase, cell adhesion molecules, HLA antigens, cell adhesion to human bone marrow stroma, and cell growth were determined by quantitative polymerase chain reaction (PCR) analysis, fluorescence-activated cell sorter (FACS) analysis, and cell attachment and proliferation assays, and were compared with non-treated cells. RESULTS: PCR analysis indicated that only LNCaP cells expressed PSA, PSM, and AR mRNA. Cytokine treatment did not alter PSM mRNA expression, whereas a 15-fold decrease in PSA and a 5-fold reduction in AR mRNA expression was detected in TNF-alpha-treated cells. The down regulation of PSA production was also demonstrated at the protein level in a dose-dependent fashion. A fivefold decrease in PSA mRNA was also detected in IL-2-treated LNCaP cells but without a reduction in AR. Down regulated epidermal growth factor receptor (EGF-R) and basic fibroblast growth factor (b-FGF) mRNA expressions were detected in TNF-alpha- and IFN-alpha-treated DU-145 and PC-3 cells, whereas, only reduced EGF-R expression was observed in LNCaP cells. IFN-gamma and IL-2 treatment down regulated the expression of collagenase Type IV mRNA in DU-145 and PC-3 cells, whereas tumor transforming growth factor-beta (TGF-beta) and IL-6 mRNA expressions did not exhibit any essential changes after cytokine treatment. A reduction in c-myc mRNA expression was observed in TNF-alpha- and IFN-alpha-treated cells, whereas no change in HER-2 expression was noted in any cytokine treated cells. Up regulated P-cadherin, but not E-cadherin, mRNA expression was detected in TNF-alpha- and IFN-gamma-treated PC-3 cells. FACS analysis revealed that all but IL-2-treated cells had enhanced HLA Class I expression, with the maximum effect seen in TNF-alpha-treated LNCaP cells (threefold increase). Up regulated HLA Class II expression was seen only in IFN-gamma-treated cells. All cytokine-treated DU-145 and PC-3 cells expressed reduced levels of alpha3, but not beta1, integrin. Up regulated of ICAM-1 expression was seen in all cytokine treated DU-145 and PC-3 cells, whereas no change in CD44 occurred. Cytokine treatment reduced the binding affinity of LNCaP and DU-145, but not of PC-3 cells, to human bone marrow stromal cells, and all cytokines but IL-2 showed a mild to moderate growth inhibition to prostate cancer cells, with a marked inhibition only observed in TNF-alpha-treated LNCaP cells. CONCLUSIONS: Cytokine treatment can effectively alter several prostate carcinoma properties that are closely associated with tumor invasion and a metastatic phenotype, suggesting that immunotherapy via the local delivery of cytokines may have a potentially therapeutic role in the treatment of hormone-refractory prostate cancer through both direct and indirect antitumor mechanisms.

Antigens, Neoplasm↗
PubMed1996

In vivo trafficking of adoptively transferred interleukin-2 expanded tumor-infiltrating lymphocytes and peripheral blood lymphocytes. Results of a double gene marking trial.

Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and IL-2 appears to produce dramatic regressions in patients with metastatic melanoma and renal cancer. However, the in vivo mechanism of TIL function is not known. We conducted an UCLA Human Subject Protection Committee, Recombinant DNA Advisory Committee, and FDA-approved clinical trial using genetically-marked TIL to test the hypothesis that these cells have unique, tumor-specific in vivo trafficking patterns. TIL and PBL (as a control effector cell population) were isolated and expanded in parallel in vitro in IL-2-containing medium for 4-6 wk. During the expansion, TIL and PBL were separately transduced with the amphotropic retroviral vectors LNL6 and G1Na. Transduced TIL and PBL were coinfused into patients and their respective numbers measured in tumor, peripheral blood, and normal tissues; integrated provirus could be quantitated and distinguished by DNA PCR. Nine patients were treated (six melanoma, three renal) and received between 4.5 x 10(8) and 1.24 x 10(10) total cells. Both "marked" TIL and PBL could be detected circulating in the peripheral blood, in some patients for up to 99 d after infusion. Marked TIL and/or PBL could be detected in tumor biopsies in six of nine patients as early as day 6 and as late as day 99 after infusion. No convincing pattern of preferential trafficking of TIL vs. PBL to tumor was noted. Moreover, concurrent biopsies of muscle, fat, and skin demonstrated the presence of TIL/PBL in comparable or greater numbers than in tumor in five patients. The results of this double gene marking trial provide interesting insights into the life span and trafficking of adoptively transferred lymphocytes, but do not support the hypothesis that TIL specifically traffic to tumor deposits.

Adult↗
PubMed1995

Prostate tissue specificity of the prostate-specific antigen promoter isolated from a patient with prostate cancer.

We have cloned and characterized a 620-bp fragment of DNA that flanks 5' of the prostate-specific antigen (PSA) gene from a prostate cancer patient. Using DNA transfection, the efficacy of this putative promoter in regulating gene expression was quantitated in several prostate and nonprostate tissue cell lines. Our results demonstrated that the 620-dp DNA fragment actively drives gene expression in LNCaP, a PSA-producing prostate tumor cell line. No promoter activity was detected in the non-PSA-producing prostate tumor lines, DU145 and PC-3, nor in a renal (R11) or breast (MCF-7) cancer cell line. Furthermore, the promoter activity could be regulated in vitro by androgen stimulation. Dihydrotestosterone (DHT) concentrations between 3 and 30 nM induced the highest promoter activity in the transfected LNCaP cells, which parallels the expression profile of the androgen receptor in LNCaP cells. In addition, our PSA promoter exhibited competitive inhibition of the endogenous genomic PSA promoter in transfected LNCaP cells, suggesting that prostate cell-specific DNA-binding proteins are required to activate the PSA promoter. increased its potency four- to five-fold while retaining tissue specificity. Our data suggest that a strong tissue-specific negative regulatory element capable of overriding the nonspecific CMV promoter is present in the PSA promoter and confers its tissue specificity. The use of a highly specific promoter-driven gene vector will allow selective expression of therapeutic genes within PSA-producing prostate cancer cells, providing a unique strategy for prostate cancer gene therapy.

Antigens, Neoplasm↗