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A Belldegrun

Publications and source records attributed to A Belldegrun.

At least 73 records · Page 4Linked to original sources
PubMed1997

Sensitization of renal carcinoma to radiation using alpha interferon (IFNA) gene transfection.

The rationale for this study was that local delivery of interferon-alpha (IFN-alpha) by gene transfection may be of value during radiotherapy. To investigate the feasibility of this approach, cells of the human renal carcinoma cell line R11 were transfected with the IFNA gene and evaluated for radiation responses in vitro by clonogenic assays. R11 cells expressing IFN-alpha after gene transfection were more sensitive to radiation than R11 control cells (SF2 = 0.33 and 0.51, respectively). In addition to increasing radiosensitivity, IFNA gene transfection slowed cellular growth and reduced the plating efficiency in clonogenic assays. The addition of exogenous rhIFN-alpha to cells at different times relative to irradiation showed that its presence during the postirradiation period was critical for radiosensitization, but repair of sublethal damage did not seem to be affected. No apoptosis of R11 cells was found 1-5 days after exposure to 2-25 Gy with or without IFN-alpha. Extensive formation of multinuclear giant cells was present beginning 2 days after irradiation; however, IFN-alpha did not cause any major alterations in the yield of radiation-induced giant cells. These studies suggest that gene transfection might be an effective means of delivering IFN-alpha for clinical use in radiotherapy of cancer.

Carcinoma, Renal Cell↗
PubMed1997

Interleukin-2-based immunotherapy for the treatment of metastatic renal cell carcinoma: an analysis of 203 consecutively treated patients.

PURPOSE: This article analyzes the long-term results of 203 consecutive patients with metastatic renal cell carcinoma who were treated with various recombinant interleukin-2 (rIL-2) -based immunotherapy regimens, and describes factors that may influence response to therapy and long-term survival. PATIENTS AND METHODS: The response and survival of 203 patients with metastatic renal cell carcinoma treated consecutively between July 1987 and October 1995 at the UCLA Medical Center Kidney Cancer Program with rIL-2-based immunotherapy were analyzed. Patients were divided into four groups: (1) no prior nephrectomy (n = 24), (2) nephrectomy > 6 months prior to rIL-2 therapy (n = 76), (3) nephrectomy < or = 6 months prior to rIL-2 therapy (n = 47), and (4) nephrectomy followed by treatment with rIL-2 and tumor-infiltrating lymphocytes +/- interferon-alpha (n = 56). Response and survival for each of these patient groups and survival per response to therapy were compared. RESULTS: The overall median survival for all patients was 18 months, and survival at 1, 2, and 3 years after therapy was 61%, 40%, and 31% percent, respectively. A total of 12 patients (6%) achieved a complete response, and all were alive at 3 years. Of 36 patients (18%) who achieved a partial response and 41 patients (20%) with stable disease, 3-year survival was 37% and 50%, respectively. The survival of patients with a partial response or stable disease was significantly better than that of patients who exhibited progressive disease. Patients with nephrectomy > 6 months prior to rIL-2 therapy had a 46% 3-year survival rate, compared with a 9% 3-year survival rate for patients with nephrectomy < or = 6 months prior to rIL-2 therapy and a 4% 3-year survival rate for patients with no nephrectomy. Patients treated with tumor-infiltrating lymphocytes had a 38% 3-year survival rate, which was also significantly better than patients treated with nephrectomy < or = 6 months prior to rIL-2 therapy or with no nephrectomy. CONCLUSION: This analysis demonstrated that rIL-2-based therapy offers a significant survival benefit to patients with advanced metastatic renal cell carcinoma, compared with historical controls. Furthermore, we have shown that nephrectomy > 6 months prior to rIL-2 therapy and nephrectomy followed by treatment with tumor-infiltrating lymphocytes/rIL-2 +/- interferon-alpha was associated with the greatest survival benefit. Tumor response to rIL-2-based therapy and time from nephrectomy to treatment were the most important predictors of survival. Randomized studies in a large group of patients are needed to confirm these observations.

Adult↗
PubMed1997

Chemosensitization of human prostate carcinoma cell lines to anti-fas-mediated cytotoxicity and apoptosis.

Androgen ablation has been an effective treatment in patients with advanced prostate cancer. However, most treated patients develop hormonally resistant disease and do not respond to conventional chemotherapy. Immunotherapy against prostate cancer is an alternative approach in overcoming hormonal/drug-resistant prostate cancer. Cytotoxic immune lymphocytes kill target cells via the perforin/granzyme and the Fas-ligand (Fas-L) pathways. We hypothesize that tumor cells respond poorly to immunotherapy by developing resistance to killing by the Fas-L mechanism. This study investigated whether prostate tumor cells are sensitive to Fas-mediated killing. The human prostate carcinoma cell lines DU145, PC-3, and LnCAP were examined for their sensitivity to killing and apoptosis by the Fas-L agonist anti-Fas antibody and CTLs. All three lines moderately expressed the Fas antigen on the cell surface; however, all three lines were relatively resistant to cytotoxicity mediated by anti-Fas (CH-11) antibody. Pretreatment of DU145 and PC-3 with subtoxic concentrations of drugs followed by anti-Fas antibody resulted in synergistic cytotoxicity and apoptosis, whereas only an additive effect was obtained with LnCAP. Chemosensitization with drugs and anti-Fas was completely blocked by the addition of neutralizing anti-Fas antibody. The murine CTL hybridoma, PMMI, which kills only via the Fas-L pathway, was able to kill chemosensitized PC-3 and DU145 but not LnCAP cells. Furthermore, this cytotoxicity was blocked by anti-Fas neutralizing antibody. Chemosensitization of PC-3 and DU145 prostate tumor cells was not due to up-regulation of Fas-receptor antigen expression. Treatment of tumor cells with cisplatin did not down-regulate the antiapoptotic genes bcl-2, FAP-1, and c-myc. Further, there was no induction by cisplatin of Fas-L on the tumor cells, thus ruling out Fas/Fas-L-mediated autologous killing. These findings demonstrate that pretreatment of drug-resistant/CTL-resistant prostate DU145 and PC-3 tumor cells with subtoxic concentrations of certain chemotherapeutic drugs sensitizes the tumor cells to Fas-mediated cytotoxicity. These findings suggest that chemosensitization of tumor cells should optimize the response to immunotherapeutic interventions in the treatment of hormone-resistant/drug-resistant prostate cancer.

Animals↗
PubMed1996

An association between renal cell carcinoma and lymphoid malignancies. A case series of eight patients.

BACKGROUND: Second primary malignancies have been described in patients with both solid tumors and hematologic malignancies. However, an association between renal cell carcinoma and lymphoid malignancies has rarely been described. Eight patients with both disorders are described and possible explanations for the association are reviewed. METHODS: A retrospective review of records from patients with renal cell carcinoma, lymphoma, leukemia, or myeloma discharged from the University of California at Los Angeles between July 1, 1993 and June 30, 1995 was performed. Renal cell carcinoma was diagnosed in 186 patients, whereas 405 had a lymphoid malignancy. Eight patients with both disorders were identified. RESULTS: In four of the eight patients, the renal cell carcinoma was diagnosed prior to their hematologic malignancy, whereas in the remaining four patients, the lymphoid malignancy was diagnosed first. Renal cell carcinoma is observed in the general population in 12.5 persons per 100,000 and hematologic malignancies in 31.8 per 100,000. The number of cases of lymphoid malignancies expected in the 186 renal cell carcinoma patients is lower than the 4 cases actually observed (P < 0.01). Likewise, the number of renal tumors expected in the 405 patients with hematologic malignancies is fewer than the 4 cases observed (P < 0.01). CONCLUSIONS: The incidence of renal cell carcinoma and lymphoid malignancy occurring in the same patient is higher than that expected in the general population. This association cannot be explained by treatment-related development of a second malignancy. A common genetic mutation or an immunomodulatory role of the first malignancy predisposing to the second are possibilities but further investigation is warranted.

Aged↗
PubMed1996

Natural immune reactivity-associated therapeutic response in patients with metastatic renal cell carcinoma receiving tumor-infiltrating lymphocytes and interleukin-2-based therapy.

Combination therapy with systemically administered interleukin-2 (IL-2) and tumor infiltrating lymphocytes (TIL) demonstrates significant clinical activity in some patients with metastatic renal cell carcinoma (RCC). The objective of this study was to identify predictors of therapeutic response in patients with IL-2- and TIL-based immunotherapy. We characterized and compared immunologic properties of tumors, TILs, peripheral blood lymphocytes (PBLs) and sera of responding (R, n = 8) with nonresponding patients (NR, n = 9). Before undergoing nephrectomy, responding patients exhibited a higher percentage of circulating natural killer (NK) cells (CD56+ CD3-) (43 +/- 20%) as compared with nonresponders (18 +/- 16%) (p < 0.01). After nephrectomy, the CD56+ CD3-/CD56- CD3+ ratio in responding patients (pre: 2.60 +/- 2.24; post: 0.28 +/- 0.19; p < 0.05) significantly decreased and was similar to that of patients not responding to therapy (0.42 +/- 0.36). Sera from patients responding to immunotherapy, obtained before and after completion of therapy, contained natural killer (NK)-enhancing factor(s) that significantly enhanced the proliferation (3.2 x 10(3) +/- 25%/ 3.6 x 10(3) +/- 13% counts/min) and cytotoxicity [17.6 +/- 4.0/18.0 +/- 1.9 lytic units (LU)] of fresh PBLs as compared with normal serum (1.8 x 10(3) +/- 8% counts/min; 13.4 +/- 2.5 LU) or sera from nonresponders (1.6 x 10(3) +/- 25%/1.5 x 10(3) +/- 20% counts/min; 8.3 +/- 5.9/6.8 +/- 4.8 LU). In contrast to noncultured tumor suspension, IL-2 cultivation induced TIL growth, cytotoxicity, and multicytokine synthesis, and a complete clearance of tumor cells. No significant differences were observed between responders and nonresponders in the in vitro characteristics of tumor/TIL, which include the degree of intratumoral lymphocytic infiltrate, TIL expansion, specific lysis of autologous tumor, phenotype, expansion time, quantity of TIL infused, cytokine release, and degree of tumor aggressiveness. We conclude that clinical response to TIL and IL-2-based immunotherapy is associated with patients' baseline natural immune status. The percentage of circulating NK cells and the presence of serum NK-cell-enhancing factors may serve as potential predictors of response in patients with advanced RCC. The in vitro study of RCC-TIL suggests that activated TIL may provide a synergistic effect to that of administered IL-2 on activation of cellular immune response in situ, rendering a tumor eradication, while the clinical outcome is largely dependent on the pretreatment immune status of patient.

Adult↗
PubMed1996

Suramin in hormone-refractory metastatic prostate cancer: a drug with limited efficacy.

PURPOSE: To confirm the previously reported high response rates and prolonged survival in hormone-refractory prostate cancer treated with suramin. PATIENTS AND METHODS: Thirty-six eligible patients with hormone-refractory prostate cancer with either measurable disease or bone disease only and a prostate-specific antigen (PSA) level greater than 50 ng/mL were enrolled. Treatment consisted of two 8-week courses of outpatient-based therapy with an interposed rest period. A bayesian adaptive control strategy and a three-compartment pharmacokinetic model that accommodates clearance changes was used to guide individual dosing. A rapid infusion of 1,000 mg/m2 suramin was followed by five daily infusions that targeted 285 micrograms/mL peak plasma levels during the first week. All patients received concomitant hydrocortisone. For the next 7 weeks, patients received one to two doses per week that targeted levels in the 150 to 285 micrograms/mL range and integrated weekly averages of 200 ug/mL. RESULTS: Nine patients (28%) had a partial response to suramin based on a > or = 50% decrease in PSA levels coupled with either relief of bone pain or by a 50% decrease in measurable disease. The median overall survival time for all patients is 31 weeks (95% confidence interval [CI], 23 to 51). Treatment was generally well tolerated, with fatigue being the most common significant toxicity, but fatal idiosyncratic myelosuppression (grade V) was observed in one patient. CONCLUSION: Using this dosing schedule, suramin has limited activity against hormone-refractory metastatic prostate cancer. Recent data suggest that hydrocortisone administered with suramin may be partly responsible for the benefit attributed to the drug. Although a small cohort of patients appeared to benefit, we were unable to confirm the previously reported high rate of activity and durability of remission using this agent.

Adenocarcinoma↗
PubMed1996

Quantitative polymerase chain reaction does not improve preoperative prostate cancer staging: a clinicopathological molecular analysis of 121 patients.

PURPOSE: To improve on current staging and monitoring methods for prostate cancer, we applied the technique of quantitative polymerase chain reaction to measure the degree of tumor burden in the circulation and correlate this with pathological tumor stage. A reproducible, highly sensitive and specific, reverse transcriptase-polymerase chain reaction amplification technique to quantify prostate specific antigen (PSA) and prostate specific membrane antigen gene expression in the peripheral circulation was developed. Using a 32phosphorus-gamma-adenosine triphosphate-5'PSA and prostate specific membrane antigen primer incorporation assay, the ribonucleic acid signal extracted from a single neoplastic cell (LNCaP) premixed in 10 cc normal whole blood could be amplified. PSA and prostate specific membrane antigen polymerase chain reaction indexes have been created for clinical application. MATERIALS AND METHODS: From September 1994 through July 1995 specimens from 121 patients were prospectively analyzed for PSA and prostate specific membrane antigen signals. RESULTS: Circulating PSA producing cells were present in 29 of 33 patients (88%) with metastatic prostate cancer. Two of 19 patients (11%) with no known prostate cancer exhibited positive signals (1 later had prostate cancer), establishing a sensitivity of 88% and specificity of 94% for our assay. Positive PSA polymerase chain reaction signals were detected in 30 of 51 patients (59%) with stages pT1 and pT2 disease and in 13 of 18 (72%) with stage pT3 cancer. No statistically significant relationship of a positive PSA polymerase chain reaction signal to pathological stage, tumor grade, apical involvement or positive surgical margins was found, and no benefit was derived by measuring the quantity of circulating PSA polymerase chain reaction signals. Circulating prostate specific membrane antigen polymerase chain reaction signals were identified mostly in patients with advanced prostate cancer and offered no benefit to preoperative staging. CONCLUSIONS: Given the high incidence of false positive signals in patients with pathologically determined localized disease, in our experience polymerase chain reaction based assays offer no immediate benefit for preoperative prostate cancer staging. The prognostic significance of detecting circulating prostate specific signals awaits longer followup in this cohort of patients, which is currently under study.

Antigens, Neoplasm↗
PubMed1996

Renal cell carcinoma: basic biology and clinical behavior.

The incidence of renal cell carcinoma (RCC) has gradually increased, and approximately 40% of all patients diagnosed with this disease will die of it. With the increasing availability of ultrasonography and computed tomography (CT) scanning, incidental renal tumors are more frequently diagnosed. Overall, conflicting evidence still exists to support a trend towards early diagnosis and/or a change in the natural history of the disease. The localization of the von Hippel-Lindau (VHL) tumor suppressor gene and other regions on chromosome 3p have contributed significantly to our understanding of the molecular genetics of both familial and sporadic RCC. Moreover, distinction between different cell types of RCC are being made at the molecular and genetic level. A relationship between environmental factors, such as cigarette smoking, and these genetic disturbances has yet to be determined. Although different determinants of nuclear grading are being proposed as prognostic factors, no convincing evidence has been identified to support the use of other molecular markers, such as the p53 tumor suppressor gene and epidermal growth factor. With regard to treatment, beyond the role of surgery in organ-confined RCC, other therapies for RCC are limited. Furthermore, immunotherapy has shown the best promise by providing durable responses in patients with advanced disease.

Carcinoma, Renal Cell↗
PubMed1996

Cytoreductive surgery in the management of metastatic renal cell carcinoma: the UCLA experience.

We assessed the role of cytoreductive surgery in patients with metastatic renal cell carcinoma (RCC) selected for interleukin-2 (IL-2)-based immunotherapy. Sixty-three consecutive newly diagnosed patients with metastatic RCC were treated at our institution between April, 1990 and October, 1994. The patients were selected based on their ability to undergo a radical nephrectomy and to receive a combination of interleukin-2 and interferon alfa (IFN-alpha). The mean age was 58.7 years (range, 34-74 years). All but one patient had an Eastern Cooperative Oncology Group performance status of 0 or 1, and presented with metastatic disease and locally advanced primary tumors. All patients successfully underwent cytoreductive nephrectomy, but 6 patients (10%) required concomitant resection of caval thrombus, 3 (5%) required partial hepatectomy, 2 (3%) needed duodenal repairs, and 1 (2%) required a splenectomy. Postoperative complications were observed in 8 patients (12.7%). There were no postoperative mortalities. Seven patients (11%) could not undergo immunotherapy because of myocardial infarctions (n = 2), no growth of tumor infiltrating lymphocytes (TILs) (n = 1), deterioration of performance status (n = 1), transient ischemic attack (n = 1), chronic renal failure (n = 1), and a diagnosis other than RCC (n = 1). Overall, 56 of 63 (88%) patients selected underwent immunotherapy. Among these 56 patients, a response rate of 33.9% [7 (12.5%) complete, and 12 (21.4%) partial] was observed. Moreover, the 2- and 3-year survival rates were 43% and 38%, respectively. Our results support the argument for an aggressive approach (surgery combined with IL-2-based immunotherapy including TILs) in the management of metastatic RCC. Further studies are needed to elucidate the individual contributions of these therapeutic processes.

Adult↗
PubMed1996

Immunotherapy and gene therapy.

Currently, there are many options for the treatment of metastatic renal cell carcinoma (RCC). Being a mostly chemoresistant malignancy, renal cell carcinoma is usually treated with immunotherapy. These therapies are generally based on interleukin-2 (IL-2) or interferon alfa (IFN-alpha), or involve more novel techniques such as gene therapy. IL-2 is a biological agent that has been approved by the U.S. Food and Drug Administration and leads to durable remissions in a subset of patients with metastatic RCC. Patients presenting with a good performance status and without serious concomitant cardiac or pulmonary disorders should be considered for IL-2-based therapy as first-line treatment.

Carcinoma, Renal Cell↗
PubMed1995

Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines.

Hormonal treatment of advanced prostatic cancer patients generally results in an initially beneficial response, but the treated patients develop hormonally resistant disease in which no curative therapy is currently available. Recent studies have revealed that interleukin 6 (IL-6) is a growth factor for myeloma, renal cell carcinoma, and certain T-cell lymphomas. Further, IL-6 has been shown to block apoptosis induced by p53, transforming growth factor beta, and certain cancer chemotherapeutic compounds. The objective of the present study was to determine whether IL-6 is a growth factor for two human prostate cancer lines and whether it protects the tumor cells from drug-induced cell death. Two hormone-independent prostate cell lines were used in this study, namely PC-3 and DU145, and these have been shown to be relatively resistant to cis-diamminedichloroplatinum (CDDP), etoposide (VP-16), and adriamycin (ADR). Both cell lines express IL-6 mRNA and secrete IL-6 constitutively. The addition of anti-IL-6 antiserum to the cell lines resulted in a significant inhibition of cell growth up to day 2, and when additional antibody was added at day 2 the inhibition persisted for 4 days. The coaddition of anti-IL-6 antiserum and CDDP or VP-16 resulted in synergy in cytotoxicity in both cell lines, whereas the combination of antibody and ADR or suramin resulted only in additive effects. Sequential treatment revealed that anti-IL-6 antibody was required to achieve synergy, whereas either sequence of pretreatment resulted in synergy with anti-IL-6 and CDDP but not with VP-16. CDDP treatment of tumor cells down-regulated IL-6 mRNA expression and IL-6 secretion. The present findings demonstrate that IL-6 is an autocrine/paracrine growth factor for DU145 and PC-3 prostate lines. Additionally, the secretion of this cytokine protects the tumor cells against the cytotoxic effect of CDDP and VP-16 and its neutralization sensitizes the cells to cytotoxicity. Overall, the studies suggest that agents that can down-regulate or inhibit protective factors in tumors may overcome drug resistance.

Antineoplastic Agents↗
PubMed1995

The effects of granulocyte-macrophage colony-stimulating factor on tumour-infiltrating lymphocytes from renal cell carcinoma.

It has been shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) can induce specific and non-specific anti-tumour cytotoxicity and also stimulates the proliferation and function of peripheral lymphocytes and thymocytes. GM-CSF and interleukin 2 (IL-2) act synergistically on peripheral lymphocytes for the induction of a highly effective cytotoxic cell population. Thus, the goal of our investigation was to study the effects of GM-CSF upon expansion, proliferation and in vitro killing activity of tumour-infiltrating lymphocytes (TILs) from renal cell carcinoma (RCC). TILs from seven consecutive tumours were cultured with GM-CSF (500 or 1000 nmol ml-1) without IL-2 supplementation, with suboptimal doses of IL-2 (8 and 40 U ml-1) plus GM-CSF (1000 nmol ml-1), and with a dose of IL-2 (400 U ml-1) which sufficed alone to induce TIL development plus GM-CSF (500 or 1000 nmol ml-1). GM-CSF alone or together with suboptimal doses of IL-2 was not able to induce or facilitate TIL development in these cultures. When GM-CSF at both concentrations studied was added to optimal doses of IL-2 the resulting TIL populations proliferated significantly better and faster (+66%), resulting in a higher cell yield (+24%) at the time of maximal expansion of the TIL cultures. The length of the culture periods of TILs was not affected by GM-CSF when compared with the control cultures supplemented with IL-2 alone. In vitro killing activity of TIL populations stimulated with IL-2 and GM-CSF remained unspecific, but lysis of the autologous tumour targets as well as the allogeneic renal tumour targets was significantly enhanced (+138%) as compared with the corresponding control TILs stimulated with IL-2 alone. Lysis of the natural killer (NK)-sensitive control cell line K562 and the NK-resistant Daudi cell line remained unchanged even though FACS analysis of TILs cultured with IL-2 and 1000 nmol of GM-CSF demonstrated a significantly higher proportion of cells expressing the CD56 molecule (+50%). Specific receptors for GM-CSF could not be demonstrated on TILs from RCC. Our data demonstrate that GM-CSF alters the biological behaviour of IL-2-activated TILs from renal cell carcinoma in terms of proliferation, in vitro killing activity and cell-surface molecule expression.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinoma, Renal Cell↗
PubMed1995

Gene therapy: principles and potential.

Gene therapy is a new and provocative means of treating human malignancy. Insight into the mechanisms of growth and growth regulation within cancer cells has offered multiple potential methods for genetic intervention. The application of gene therapy to prostate cancer is in its infancy. The development of both adenoviral and retroviral replication deficient vectors has provided the ability consistently to transfer genes into cancer cells. Although the ideal gene for transfer has not yet been clearly identified, many genes capable of altering the biological behaviour of prostate cancer exist. Selection of the appropriate gene is highly dependent on the desired therapeutic outcome. A gene therapy strategy, whether dependent on ex vivo or in vivo transfection, must ultimately be tailored to meet the specific needs of the disease to be treated. The potential to treat locally confined disease, preventing subsequent metastasis, or widespread metastatic disease exists. The ultimate success of a prostate cancer gene therapy strategy will rely on comprehensive investigation of the biology of the tumour and careful planning of an effective intervention.

Cytokines↗
PubMed1995

Surgery from a US perspective.

Prostate screening has made it possible to detect organ confined prostate carcinoma in men with a life expectancy of 20 years and longer. These clinically significant malignancies may be successfully eradicated by means of anatomical dissection of the prostate, which minimizes both morbidity and mortality. In a retrospective series of patients with clinically localized prostate cancer who were treated with a radical retropubic prostatectomy and lymph node dissection, 5 and 10 year crude survival rates were 96% and 86%. Survival was compromised by penetration of tumour through the prostatic capsule, and even more significantly by involvement of the seminal vesicles. The use of prostate specific antigen (PSA) concentrations to monitor disease progression before any clinical manifestation revealed that disease free survival was less than previously reported. Patients diagnosed and treated more recently had longer disease free survival than the overall group mainly because of earlier detection with PSA, with consequent lower tumour volumes and stage. In addition, 92 +/- 3(SD)% patients with pathologically organ confined tumours, without capsular or seminal vesicle invasion, are clinically disease free with non-detectable PSA at 5 years. Our data therefore show that radical prostatectomy can cure patients with organ confined prostate cancer, with acceptable morbidity. Although the need for cure may be questioned in many patients, young patients with prostate cancer almost certainly benefit from eradication of the malignancy.

Adult↗