The effect of a selective estrogen receptor modulator on the progression of spontaneous autoimmune disease in MRL lpr/lpr mice.

The MRL lpr/lpr mouse strain is an animal model for the autoimmune disorder systemic lupus erythematosus (SLE). Pathologic changes in the mice include a severe proliferative glomerulonephritis, lymph node and spleen enlargement, increase in autoantibody titers, and shortened life spans. In the present investigation, female MRL lpr/lpr mice have been dosed po daily for 7 months with the selective estrogen receptor modulator (SERM) LY139478 (4 mg/kg) or 17alpha-ethinylestradiol (EE2, 1 mg/kg) and compared to vehicle control animals.

Synthesis and biological evaluation of a new series of sterols as potential hypocholesterolemic agents.

A new series of sterols was synthesized and tested in a CHO cell-based LDL receptor/luciferase (LDLR/Luc) assay to investigate the capability of derepressing the transcription of LDL receptor promoter in the presence of 25-hydroxycholesterol. The effect of various substitutions on antagonizing the repressing effect mediated by 25-hydroxycholesterol was also studied in terms of regio- and stereochemistry, lipophilicity, steric bulk, and pi-electron density. Except 12, compounds active in the primary LDLR/Luc assay were not active in the secondary simian virus 40/luciferase (SV40/Luc) assay, demonstrating the specificity of their in vitro activity.

Inhibition of cholesteryl ester transfer protein in normocholesterolemic and hypercholesterolemic hamsters: effects on HDL subspecies, quantity, and apolipoprotein distribution.

The effects of cholesteryl ester transfer protein (CETP) inhibition on the serum lipoprotein profile in both normocholesterolemic and hypercholesterolemic hamsters has been determined following subcutaneous injection of 12.5 mg/kg of the CETP neutralizing monoclonal antibody, TP2. Inhibition of CETP activity was greater than 60% and resulted in a 30-40% increase in high density lipoprotein (HDL) in both normal and hypercholesterolemic animals.

Chemoimmunoconjugate development for ovarian carcinoma therapy: preclinical studies with vinca alkaloid-monoclonal antibody constructs.

Preclinical efficacy studies are presented in a human ovarian carcinoma model utilizing several novel conjugation strategies with the KS1/4 monoclonal antibody and derivatives of the vinca alkaloid desacetylvinblastine hydrazide. The chemoimmunoconjugates KS1/4-beta-alanine-methylenemalonic acid ethyl ester-4-decacetylvinblastine 23-hydrazide (KS1/4-BAMME-DAVLB-HY), KS1/4-beta-alanine-5-formylpyrrole-2-carboxylic acid-4-desacetylvinblastine 23-hydrazide (KS1/4-BAP-DAVLB-HY), and KS1/4-4-desacetylvinblastine 23-hydrazide were explored in the OVCAR-3 human ovarian carcinoma xenograft model. These conjugates, constructed with variable linker stability between the vinca alkaloid and the antibody, were studied by comparing the route of administration and the treatment schedule.

Long-term growth suppression of human glioma xenografts by chemoimmunoconjugates of 4-desacetylvinblastine-3-carboxyhydrazide and monoclonal antibody 9.2.27.

A conjugate of 4-desacetylvinblastine-3-carboxyhydrazide (DAVLBHY) and the glioma-reactive monoclonal antibody (mAb) 9.2.27 induced long-term suppression of tumor growth in athymic nude mice engrafted with U87MG human glioma cells.