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R Nasr

Publications and source records attributed to R Nasr.

14 recordsLinked to original sources
PubMed2004

N-(4-hydroxyphenyl)retinamide induces growth arrest and apoptosis in HTLV-I-transformed cells.

N-(4-hydroxyphenyl)retinamide (HPR) is a synthetic retinoid that inhibits growth and induces apoptosis in many human cell lines. We explored the effects of HPR on human T-cell lymphotropic virus type I (HTLV-I)-positive and HTLV-I-negative malignant T-cell lines, most of which are resistant to all-trans retinoic acid. Clinically achievable concentrations of HPR caused a dramatic inhibition of cell proliferation, G(0)/G(1) arrest, and massive apoptosis in all tested malignant T cells, while no effect was observed on resting or activated normal lymphocytes. Interestingly, HTLV-I-negative cell lines were significantly more sensitive to HPR compared to HTLV-I-positive and Tax-transfected cells. In HTLV-I-negative cells only, HPR-induced apoptosis was associated with ceramide accumulation, sharp decrease in mitochondrial membrane potential, and activation of caspases 8, 9 and 3, and could be partially reverted by the caspase inhibitor z-VAD suggesting that Tax protects infected cells from ceramide accumulation and caspase-mediated apoptosis. In HTLV-I-positive cells, HPR treatment rapidly induced proteasomal-mediated degradation of p21, downregulated cyclin D(1), and upregulated bax protein levels. These findings support a potential therapeutic role for HPR in both HTLV-I-associated adult T-cell leukemia/lymphoma (ATL) and HTLV-I-negative peripheral T-cell lymphomas.

Antineoplastic Agents↗
PubMed2001

Retinoic acid dramatically enhances the arsenic trioxide-induced cell cycle arrest and apoptosis in retinoic acid receptor alpha-positive human T-cell lymphotropic virus type-I-transformed cells.

INTRODUCTION: Adult T-cell leukemia/lymphoma, caused by the human T-cell lymphotropic virus type I, is an aggressive neoplasm of mature activated T cells that is generally resistant to conventional therapy. While arsenic trioxide (As) inhibits the growth and induces apoptosis in HTLV-I-infected T cells, synergistically, when combined with interferon-alpha, variable effects on growth with all trans retinoic acid treatment have been reported in ATL-derived cell lines and fresh ATL cells. In this study, we investigate the effects of ATRA alone or in combination with As in HTLV-I-transformed cells. MATERIALS AND METHODS: Four HTLV-I-transformed cell lines (HuT-102, MT2, C8166 and C91PL) were treated with different doses of ATRA alone or in combination with As for one to three days. Cell growth was assessed by cell count with 3H-thymidine incorporation. Cell cycle distribution was assessed by propidium iodine-labeled DNA content by flow cytometry. Apoptosis was evaluated by Hoechst nuclear staining and annexin-V binding assays. Expression of retinoid receptors, the viral transactivator Tax, and the proteins bcl-2 and IkappaB-alpha proteins, was analysed by Western blot. RESULTS: Only C8166 cells were sensitive to the ATRA-induced growth inhibitory effect while HuT-102, MT2, and C91PL were resistant to ATRA treatment (up to 10(-5) M). The retinoid X receptor alpha and the retinoic acid receptor gamma (RARgamma) proteins were expressed in all four cell lines, while RARalpha protein was only detected in the HuT-102 and C8166 cells. The combination ATRA/As showed a highly synergistic effect on HuT-102 cells, and, to a lesser extent, on C8166 cells and resulted in a dramatic inhibition of cell proliferation and induction of massive apoptosis in HuT-102 cells, associated with caspase activation. While ATRA alone had no effect on Tax and IkappaB-alpha protein levels, ATRA increased the As-induced Tax degradation and the up-regulation of IkappaB-alpha protein. In contrast, the expression of bcl-2 protein was not significantly affected by any of the treatments. CONCLUSION: Our data provide a rationale for combined ATRA and As-therapies in ATL patients refractory to conventional therapy and expressing RARalpha in their leukemic cells.

Antineoplastic Agents↗
PubMed2001

The value of cystoscopy, prostate biopsy and frozen-section urethral biopsy prior to orthotopic neobladder substitution.

INTRODUCTION: The traditional criteria for selecting suitability of male patients with bladder cancer for othtopic neobladder substitution includes: patient motivation, negative transurethral (TUR) prostate biopsy prior to cystectomy, and/or tumor-free biopsy of the urethral margin at the time of cystectomy. In this report we evaluate the value of these preoperative and intraoperative biopsies in the cystoscopically normal prostatic urethra. METHODS: During a 5-year period, cystectomies were performed on 54 men and 13 women with invasive bladder cancer. Prior to this procedure, all of the men had TUR biopsy of the prostate. Forty men with cystoscopically normal prostatic fossa had negative prostatic biopsies, and. had orthotopic neobladder substitution. RESULTS: Pathological examination showed that 3 out of these 40 men had transitional cell carcinoma (TCC) involving the prostate. In all 40 patients, the prostatic apical resection margin was negative. To date, none of the patients developed urethro-neobladder recurrence. CONCLUSION: TUR biopsy of the prostatic urethra prior to cystectomy, or biopsy of the prostatic urethral margin at the time of cystectomy in patients with cystoscopically normal, tumor free prostatic urethra has limited value in selecting candidates for orthotopic neobladder substitution.

Adult↗
PubMed2001

Rising prostate specific antigen after radical prostatectomy: a case based review.

Prostate specific antigen (PSA) has been proven to be a valuable tool in the diagnosis and staging of early prostate cancer and as a sensitive marker of residual or recurrent cancer after curative therapy. In 1998, 200 000 new cases of prostate cancer were reported in the SEER database. Two-thirds of these, or 134 000 men, underwent definitive therapy for localized cancer, including approximately 75 000 radical prostatectomies. It has been reported that 20%-50% of radical prostatectomy patients will have a PSA only recurrence. One can therefore estimate that every year 15 000 to 38 000 men will have a rising PSA following definitive surgical therapy. This elevation of PSA often precedes clinical failure by many years and poses a difficult management problem for which there are not, as yet, definitive management guidelines. This paper will review the definition of PSA recurrence, the natural history, diagnostic options and the therapeutic choices, as illustrated by several genuine cases.

Adenocarcinoma↗
PubMed2000

Arsenic-interferon-alpha-triggered apoptosis in HTLV-I transformed cells is associated with tax down-regulation and reversal of NF-kappa B activation.

Human T-cell lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature activated T cells resistant to conventional chemotherapy. The viral transactivator protein Tax plays a critical role in HTLV-I-induced transformation and apoptosis resistance by inducing I kappa B-alpha degradation, resulting in the activation of the NF-kappa Bpathway. In these HTLV-I-transformed cells, arsenic trioxide (As) and interferon (IFN)-alpha synergize to induce cell cycle arrest and apoptosis. We demonstrate that cell death induction is only partly dependent upon caspase activation and is not associated with modulation of bcl-2, bax, or p53 expression. However, combined As and IFN induce the degradation of Tax, associated with an up-regulation of I kappa B-alpha resulting in a sharp decrease in RelA DNA binding nuclear factor (NF)-kappa B complexes because of the cytoplasmic retention of RelA. Taken the role of Tax in HTLV-I-induced transformation, its down-regulation probably accounts for cell death induction through inactivation of the NF-kappa B pathway. Such specific targeting of the viral oncoprotein by As-IFN treatment, reminiscent of As targeting of promyelocytic leukemia/retinoic acid receptor-alpha in acute promyelocytic leukemia, provides strong rational for combined As-IFN therapy in ATL patients. (Blood. 2000;96:2849-2855)

Apoptosis↗
PubMed2000

Interferon alpha is an effective therapy for congenital dyserythropoietic anaemia type I.

The efficacy of interferon-alpha (IFN) was reported in three patients with congenital dyserythropoietic anaemia (CDA) type I. We describe two additional cases treated with IFN, which normalized the haemoglobin level in both patients with a dramatic decrease in the size of the spleen in one. Haemoglobin remained stable more than 6 months after discontinuation of treatment. IFN induced more than 50% decrease in the number of BFU-E in both patients' bone marrow cultures, suggesting an indirect effect of IFN on erythropoiesis in vivo. We conclude that a trial of IFN therapy should be considered in patients with CDA type I.

Adult↗
PubMed2000

Evidence against a direct cytotoxic effect of alpha interferon and zidovudine in HTLV-I associated adult T cell leukemia/lymphoma.

The combination of the anti-viral agents, zidovudine (AZT) and interferon-alpha (IFN), is a potent treatment of HTLV-I-associated adult T cell leukemia/lymphoma (ATL). In this study we investigate the possible mechanism of action of this combination by examining several cellular parameters including cell proliferation, cell cycle distribution and apoptosis. The ATL-derived T cell lines HuT-102 and MT-2 served as models. HTLV-I negative T cell lines (CEM and Jurkat) were used as controls. No significant modification of cell growth was observed except at suprapharmacological doses of AZT and IFN. Moreover, these effects were less pronounced in HTLV-I-infected cell lines compared to control cell lines. AZT and IFN treatment did not induce any significant modification of the expression of bcl-2 and p53. Interestingly no in vitro cytotoxic effect of AZT/IFN combination was observed on fresh leukemic cells derived from an acute ATL patient at diagnosis despite achievement of in vivo complete remission using the same therapy. These results suggest that the therapeutic effect of AZT and IFN is not through a direct cytotoxic effect of these drugs on the leukemic cells.

Aged↗
PubMed1999

Arsenic trioxide and interferon-alpha synergize to induce cell cycle arrest and apoptosis in human T-cell lymphotropic virus type I-transformed cells.

Human T-cell lymphotropic virus type I (HTLV-I) is the causative agent of adult T-cell leukemia/lymphoma (ATL). ATL is an aggressive proliferation of mature activated T cells associated with a poor prognosis. The combination of the antiviral agents, zidovudine (AZT) and interferon (IFN), is a potent treatment of ATL. Recently, arsenic trioxide (As) was shown to be an effective treatment of acute promyelocytic leukemia (APL). We have tested the effects of the combination of As and IFN on cell proliferation, cell cycle phases distribution, and apoptosis in ATL-derived or control T-cell lines. A high synergistic effect between IFN and As was observed in ATL-derived cell lines in comparison to the control cell lines, with a dramatic inhibition of cell proliferation, G1 arrest, and induction of apoptosis. Similar results were obtained with fresh leukemia cells derived from an ATL patient. Although the mechanisms involved are unclear, these results could provide a rational basis for combined As and IFN treatments in ATL.

Antineoplastic Agents↗
PubMedDate not supplied

The value of free and total prostate specific antigen in identifying patients for prostatic biopsy and its relationship to Gleason score and number of positive cores.

INTRODUCTION AND OBJECTIVES: The percentage of free over total prostate specific antigen (%F/T PSA) seems to enhance the predictive value of PSA in diagnosing prostate cancer. We evaluated the value of F/T PSA in 50 consecutive patients who underwent prostate needle biopsy, its relationship to the Gleason score and number of positive cores. MATERIAL AND METHODS: 50 patients underwent prostate needle biopsy for abnormal PSA and/or abnormal digital rectal examination (DRE). There were 8 patients with PSA equal or less than 4 ng/ml, 6 with F/T PSA < 20%, group I (GI). 27 patients with PSA between 4.1 ng/ml and 10.0 ng/ml, 20 with F/T PSA < 20%, group II (GII) and 15 patients with PSA > 10.1 ng/ml (13 with F/T PSA < 20%), group III (GIII). At least six needle biopsies were obtained guided by transrectal ultrasound selectively or randomly. Pathological evaluation included Gleason grade and number of cores involved. RESULTS: 21/50 patients (42%) had positive biopsies, 3/8 in GI, 8/27 in GII (6 had negative DRE) and 10/15 in GIII (9 had positive DRE). 19/21 patients with positive biopsies had F/T PSA < 20%. The sensitivity, specificity and positive predictive value of PSA between 4-10 ng/ml and F/T PSA < 20% was 87.5%, 31% and 35% respectively. Stratifying patients with positive biopsies to F/T PSA < 10%, F/T PSA > 10% and the three PSA groups, there was no relationship to either Gleason score or number of positive cores. CONCLUSION: With a cutoff of 20%, F/T PSA seems to be an important parameter in selecting patients with abnormal PSA for biopsy. It will be helpful mostly with PSA 4-10 ng/ml. No relationship was observed between the level of F/T PSA, grade or number of positive cores.

Adult↗