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151.
The effects of the rationally designed JAK3 inhibitor JANEX-1 on the development of intestinal tumors in the APCmin mouse model of familial adenomatous polyposis were examined. At a non-toxic dose level, >4 times lower than its day 30 LD10, JANEX-1 was highly effective in preventing intestinal tumor development in Min mice, resulting in markedly improved survival outcomes. JAK3 inhibitors may, therefore, be useful in the chemoprevention of colorectal cancer. Here, an overview regarding the potential of JANEX-1 as a chemopreventive agent is provided. 相似文献
152.
153.
Waddick KG; Myers DE; Gunther R; Chelstrom LM; Chandan-Langlie M; Irvin JD; Tumer N; Uckun FM 《Blood》1995,86(11):4228-4233
B-cell precursor (BCP) leukemia is the most common form of childhood cancer and represents one of the most radiation-resistant forms of human malignancy. In this study, we examined the antileukemic efficacy of the B43 (anti-CD19)-pokeweed antiviral protein (B43-PAP) immunotoxin against radiation-resistant BCP leukemia cells. B43-PAP caused apoptosis of radiation-resistant primary BCP leukemia cells, killed greater than 99% of radiation-resistant primary leukemic progenitor cells from BCP leukemia patients, and conferred extended survival to severe combined immunodeficiency (SCID) mice xenografted with radiation- resistant human BCP leukemia. Furthermore, the combination of B43-PAP and total body irradiation (TBI) was more effective than TBI alone in two SCID mouse bone marrow transplantation models of radiation- resistant human BCP leukemia. Thus, B43-PAP may prove useful in the treatment of radiation-resistant BCP leukemia. 相似文献
154.
Lisa Tuel-Ahlgren Xiao Jun Kevin G. Waddick Jizhong Jin Joseph Bolen Fatih M. Uckun 《Leukemia & lymphoma》1996,20(5):417-426
Here we provide experimental evidence that ionizing radiation induces inhibitory tyrosine phosphorylation of the p34cdc2 kinase in human leukemic B-cell precursors. Herbimycin A markedly reduced tyrosine phosphorylation of p34cdc2 in irradiated leukemic B-cell precursors, thereby preventing radiation-induced cell cycle arrest at the G2-M transition checkpoint. Thus, tyrosine phosphorylation is directly responsible for the inactivation of p34cdc2 in irradiated human leukemic B-cell precursors and activation of protein tyrosine kinases is a proximal and mandatory step in radiation-induced G2-arrest arrest at the G2-M checkpoint. Human WEE1 kinase isolated from unirradiated or irradiated leukemic B-cell precursors had minimal tyrosine kinase activity towards p34cdc2. We detected no increase of human WEE 1 kinase activity after radiation of leukemic B-cell precursors, as measured by (a) autophosphorylation, (b) tyrosine phosphorylation of a synthetic peptide derived from the p34cdc2 amino-terminal region or (c) recombinant human p34cdc2-cyclin B complex. Thus the signaling pathway leading to inhibitory tyrosine phosphorylation of p34cdc2 and G2-arrest in irradiated human leukemic B-cell precursors functions independent of p49WEE1Hu and enzymes which augment the tyrosine kinase activity of p49WEE1Hu. 相似文献
155.
The zidovudine derivative, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxy alaninyl phosphate (WHI-07), is a dual-function spermicidal and anti-HIV agent with contraceptive and microbicidal activity. In previous two subchronic toxicity studies, intravaginal application of 0.5-2.0% WHI-07, for up to 13 weeks, was shown to cause no local, systemic or reproductive toxicity. To evaluate the toxicity and carcinogenic potential of long-term exposure to WHl-07, groups of 50 female B(6)C(3)F(1) mice were given no treatment or exposed intravaginally to a gel-microemulsion formulation with and without 2.0% WHI-07, 5 days per week for 2 years. The dose of WHI-07 was equivalent to 5700 times its spermicidal EC(50) and 5.7x10(6) times its anti-HIV IC(50). The endpoints that were evaluated included survival, body weight, hematologic and clinical chemistry profiles, absolute and relative organ weights, and histopathology. No significant differences in mean body weight gain and survival were found among the groups of untreated control, placebo control, and 2% WHI-07-treated mice at the end of the 2-year study. The hematological and clinical chemistry profiles did not reveal any toxicologically significant changes that could be attributed to WHI-07 treatment. No clinically significant changes in absolute and relative organ weights were noted in the WHI-07 group. A variety of neoplastic and nonneoplastic lesions which were considered incidental, related to aging, or procedural, were observed in both the untreated and intravaginally treated groups. The proportion of animals with malignant tumors, the total number of malignant tumors, as well as the types of malignant tumors in the three groups was similar. The cumulative incidence of microscopic lesions in various organs showed that malignant lymphoma was the major cause of death in aging female B(6)C(3)F(1) mice, the incidence of which was unaffected by intravaginal treatment. We conclude that long-term intravaginal administration of WHI-07 is not associated with systemic toxicity or increased carcinogenicity in mice. WHI-07 has clinical potential as an active ingredient of a safe vaginal/rectal microbicide. 相似文献
156.
Effect of pretreatment of semen with pokeweed antiviral protein on pregnancy outcome in the rabbit model 总被引:4,自引:0,他引:4
OBJECTIVE: To determine whether artificial insemination of semen pretreated with pokeweed antiviral protein, a 29-kD antihuman immunodeficiency virus (HIV) protein purified from the leaves of Phytolacca americana, has any adverse effects on pregnancy outcome in the rabbit model. DESIGN: Prospective, controlled study. SETTING: Center for Advanced Preclinical Sciences at the Parker Hughes Institute. ANIMAL(S): Forty-eight female and 12 male New Zealand White rabbits. INTERVENTION(S): Fresh pooled semen obtained from 12 bucks was treated for 1 hour with and without 100 microg/mL or 1000 microg/mL pokeweed antiviral protein. Ovulated does in groups of 16 were artificially inseminated with control and pokeweed antiviral protein-treated semen and allowed to complete term pregnancy. MAIN OUTCOME MEASURE(S): Proportion of does that became pregnant and delivered newborn rabbits; the litter size, weight, growth, and viability of pups until lactation day 5. RESULT(S): Pokeweed antiviral protein treatment of semen had no adverse effect on gestation length, pregnancy rate, perinatal outcome, growth, and development of the offspring. CONCLUSION(S): Pokeweed antiviral protein shows clinical potential as a safe, prophylactic antiviral agent in assisted reproduction in HIV-1 discordant couples. 相似文献
157.
High-performance liquid chromatographic methods for the determination of topoisomerase II inhibitors
Chen CL Thoen KK Uckun FM 《Journal of chromatography. B, Biomedical sciences and applications》2001,764(1-2):81-119
Various methods for separating eleven different types of topoisomerase II (TOPO-2) inhibitors, including epipodophyllotoxins, anthracyclines, anthracenediones, anthrapyrazoles, anthracenebishydrazones, indole derivatives, aminoacridines, benzisoquinolinediones, isoflavones, bisdioxopiperazines and thiobarbituric acids, are summarized. Proper sample preparation and storage is critical to the successful analysis of some TOPO-2 inhibitors due to difficulties associated with adsorption, instability and complex biological components. Solid-phase and liquid-liquid extractions are widely used to separate TOPO-2 inhibitors from biological samples, although simple deproteinization followed by direct analysis of the supernatant is preferable to extraction based on its speed and simplicity. High-performance liquid chromatography (HPLC) is the favored method for the bioanalysis of TOPO-2 inhibitors. UV or diode array detection is generally employed for early pharmacokinetic studies, while fluorescence or electrochemical detection is used more frequently for analytes with fluorescent or oxidative-reductive properties. For analyses requiring highly sensitive and/or specific detection, electrospray mass spectrometry (ESI-MS or ESI-MS-MS) provides a suitable alternative. A comprehensive compilation of the HPLC techniques currently used to separate TOPO-2 inhibitors will aid the future development of analytical methods for new TOPO-2 inhibitors. 相似文献
158.
Tyrosine kinases as new molecular targets in treatment of inflammatory disorders and leukemia 总被引:1,自引:0,他引:1
Many protein tyrosine kinases (PTK), including Janus kinase 3 (JAK3) and Bruton's tyrosine kinase (BTK), have been recently identified as potential drug targets to treat diverse diseases including inflammation and cancer. The wealth of structural information currently available for protein kinase-inhibitor complexes facilitates the structure-based design of novel kinase inhibitors. In this report, we discuss the structural basis of protein kinase inhibitor design and the common binding features of small molecule kinase inhibitors including pyridinyl imidazoles, purines, oxindoles, anilinoquinazolines and isoquinalines. The structural features of targeted kinase proteins and their inhibitor complexes are discussed with respect to their structure-and-activity relationships (SAR). We present a structural comparison of kinase inhibitors with a special emphasis on inhibitors of JAK3 and BTK. 相似文献
159.
BTK (Bruton's tyrosine kinase) is a member of the TEC family of tyrosine kinases that plays a central but diverse modulatory role in various cellular processes. The unique role of BTK in a multitude of signaling pathways, its function as a dual regulator of apoptosis and its involvement in a number of developmental processes makes BTK a desirable target for potential anti-cancer, anti-inflammatory and anti-viral agents as well as other treatments. The biochemistry and signaling networks of BTK were well described in numerous detailed reviews written by members of our team and others before us. Therefore in this particular review we are going to concentrate on the possible practical application of previously obtained knowledge to specific diseases and disorders. 相似文献
160.
Pre-clinical safety evaluation of novel nucleoside analogue-based dual-function microbicides (WHI-05 and WHI-07) 总被引:4,自引:0,他引:4
Compounds WHI-05 [5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl)-methoxyalaninyl phosphate] and WHI-07 [5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)-methoxyalaninyl phosphate] are aryl phosphate derivatives of zidovudine (ZDV) with anti-HIV and contraceptive activity. WHI-05 and WHI-07 differ fundamentally from currently used surfactant microbicides that are cytotoxic to genital tract epithelial cells at spermicidal concentrations. These drugs were rationally designed to bypass the thymidine kinase dependency of ZDV activation in genital tract secretions, as well as to achieve spermicidal activity. WHI-05 and WHI-07 were formulated via a non-toxic gel-microemulsion for intravaginal use as potential anti-HIV spermicides. Pre-clinical safety studies of intravaginally administered WHI-05 and WHI-07 gel-microemulsions were performed in mice and rabbits to mimic closely the intravaginal application of a microbicidal preparation in women. In addition, systemic toxicity studies were performed in mice and non-human primates. The LD10 doses for WHI-05 and WHI-07 when administered intravenously or intraperitoneally were >500 mg/kg for mice. Female cynomolgus monkeys treated with 20 mg/kg WHI-05 and WHI-07 intravenously developed no grade 2-4 systemic toxicities. Repetitive intravaginal administration of 2% WHI-05 and WHI-07 via a gel-microemulsion to achieve concentrations as high as 6.1 x 10(4) and 5.7 x 10(6) times their respective in vitro anti-HIV IC50 values, and 1200 and 5700 times their spermicidal EC50 values, for up to 13 weeks, was not associated with mucosal, systemic or reproductive toxicity. Furthermore, long-term (2 years) intravaginal administration of 2% WHI-07 gel-microemulsion was not associated with systemic toxicity or increased carcinogenicity in mice. The improved potency, as well as the lack of mucosal, systemic and reproductive toxicity of WHI-05 and WHI-07, means that these compounds have clinical potential as safe, prophylactic contraceptives in addition to their microbicide activity to curb the sexual transmission of HIV. 相似文献