Effect Of SASP Research Articles

Sulfasalazine‐induced cystine starvation: Potential use for prostate cancer therapy

Certain cancers depend for growth on uptake of cystine/cysteine from their environment. Here we examined advanced human prostate cancer cell lines, DU-145 and PC-3, for dependence on extracellular cystine and sensitivity to sulfasalazine (SASP), a potent inhibitor of the x(c)(-) cystine transporter. Cultures were evaluated for growth dependence on exogenous cystine, x(c)(-) transporter expression, response to SASP (growth and glutathione content). In vivo, effect of SASP was determined on subrenal capsule xenograft growth. Cystine omission from culture medium arrested DU-145 and PC-3 cell proliferation; both cell lines expressed the x(c)(-) transporter and were growth inhibited by SASP (IC(50)s: 0.20 and 0.28 mM, respectively). SASP-induced growth inhibition was associated with vast reductions in cellular glutathione content - both effects based on cystine starvation. SASP (i.p.) markedly inhibited growth of DU-145 and PC-3 xenografts without major toxicity to hosts. SASP-induced cystine/cysteine starvation leading to glutathione depletion may be useful for therapy of prostate cancers dependent on extracellular cystine.

Effects of sulfasalazine on biopsy mucosal pathologies and histological grading of patients with active ulcerative colitis

To investigate the mechanisms of sulfasalazine (SASP) in the treatment of ulcerative colitis (UC). Changes of pathological signs and histological grading of 106 patients with active UC were observed before and after the treatment with SASP, 1 g, thrice daily for 6 wk. The effect of SASP on the vasculitis in lamina propria was 48.2% and 17.4% in the mild active UC (P<0.001) and 68% and 26.7% in the moderate active UC (P<0.001) before and after treatment. Fibroid necrosis of vessel wall was found in one case of mild UC and two cases of moderate UC before treatment and was not found after treatment. No thrombosis was found in mild UC before and after treatment, while thrombosis was found in one case of moderate UC before treatment. The effect on mucosal glandular abnormality was 30.4% and 13.0% in mild UC (P<0.05), and 42% and 40% in moderate UC (P>0.05) before and after treatment. The rate of eosinophil infiltration was 98.2% and 80.4% in mild UC (P<0.01), and 100% and 91.1% in moderate UC (P<0.05) before and after treatment. The effect on crypt abscess was 21.4% and 4.4% in mild UC (P<0.05), and 48% and 13.3% in moderate UC (P<0.001) before and after treatment. The effect on mucosal pathohistological grading was 2.00+/-0.84 and 0.91+/-0.46 in mild UC (P<0.001), and 2.49+/-0.84 and 1.31+/-0.75 in moderate UC (P<0.001) before and after treatment. SASP can improve small vessel lesions and crypt abscesses and reduce neutrophilic and eosinophilic leukocyte infiltration in inflammatory mucosa of UC.

Regulation of phospholipase isozymes by nuclear factor-kappaB in human gestational tissues in vitro.

Phospholipid-derived mediators are implicated in the initiation and progression of human labor and delivery, particularly in relation to infection-induced preterm labor. We previously demonstrated that, in human intrauterine tissues, lipopolysaccharide (LPS)-stimulated nuclear factor-kappaB (NF-kappaB) DNA binding activity, and subsequent cytokine release can be suppressed by sulfasalazine (SASP) concentrations greater than 5 mM. The aim of this study was to elucidate the effect the SASP on secretory type II phospholipase A(2) (PLA(2)), cytosolic PLA(2) (cPLA(2)), cyclooxygenase (COX) isozymes, and subsequent prostaglandin F(2alpha) (PGF(2alpha)) production in human gestational tissues. Human placenta, amnion, and choriodecidua (n = 4-9 separate placentas) were incubated in the presence of SASP (0.1, 1, 5, and/or 10 mM) under either basal or LPS (10 microg/ml) conditions. After 6 h incubation, the tissues were collected and assayed for type II PLA(2) by ELISA and cPLA(2), COX-1, and COX-2 content by Western blotting. The incubation medium was collected and assayed for type II PLA(2) and 13,14-dihydro-15-keto PGF(2alpha) release by ELISA and PGF(2alpha) by RIA. Treatment of placenta, amnion, and choriodecidua with SASP concentrations greater than 5 mM significantly inhibited basal and/or LPS-stimulated type II PLA(2) content and release, 13,14-dihydro-15-keto PGF(2alpha) release, and cPLA(2) protein content (ANOVA, P < 0.05); however, no effect of SASP was observed on basal or LPS-stimulated COX-1 or COX-2 protein. Although no effect of SASP was observed on basal and LPS-stimulated PGF(2alpha) release from placenta and amnion, it significantly increased both basal and LPS-stimulated PGF(2alpha) release from choriodecidua. In addition, SASP concentrations of 5 mM or greater significantly suppressed NF-kappaB DNA binding activity. These data are consistent with the hypothesis that NF-kappaB regulates the expression and release of phospholipase isozymes.

ＲＡに対するサラゾスルファピリジン使用例の検討

Twenty-seven patients with rheumatoid arthritis were evaluated for the effect of salazosulphapyridine (SASP) administration over a 5 month period. Twenty-two patients continued with administration of SASP but 5 patients failed. Lansbury's articular index was significantly improved and morning stiffness, grip strength, Lansbury's systemic index and CRP tended to improve. However ESR and rheumatoid factor did not change. The effect of SASP was independant of subsets of rheumatoid arthritis classified by Ochi, and disease duration, but associated with therapy duration and Lansbury's systemic index. In the SASP effective group, CRP was significantly high.

SULPHASALAZINE IN RHEUMATOID ARTHRITIS: HAEMATOLOGICAL PROBLEMS AND CHANGES IN HAEMATOLOGICAL INDICES ASSOCIATED WITH THERAPY

This prospective study documents the haematological responses in 300 rheumatoid patients (RA) treated with sulphasalazine (SASP) for between 1 and 9 years. It also examines the effect of SASP on the total white cell and platelet counts over 2 years in relation to disease activity in 80 RA patients. Neutropenia occurred in six (2%) (three severe--neutrophil count less than 0.8 X 10(9)/l) after 3 and 12 weeks. The drug was withdrawn in six immediately and in one patient after 21 months when the neutrophil count fell to 0.7 X 10(9)/l. An additional 11 (3.7%) developed mild or transient leucopenia between 2 weeks and 24 months, and eight continued therapy. Thrombocytopenia occurred in one patient at 18 weeks associated with other reactions. Four with Felty's syndrome developed a further fall in the total WBC associated with thrombocytopenia in two. A rise in mean cell volume was common (72%), and macrocytosis (MCV greater than 98 fl) occurred in 27 (9%). Macrocytic anaemia was rare (less than 1%). All haematological problems were reversible. In 80 patients treated with SASP for 2 years there was a significant fall in the median white cell and platelet counts at 3 months associated with improvement in disease activity.