Restoration of Taxol Sensitivity of Multidrug-Resistant Cells by the Cyclosporine SDZ PSC 833 and the Cyclopeptolide SDZ 280-446

Background: Taxol, a promising agent for the treatment of cancer, has entered phase II clinical trials. Nevertheless, it belongs to the class of compounds that show impaired retention in multidrug-resistant cells expressing P-glycoprotein (Pgp), a drug efflux pump. Chemosensitizers like verapamil modulate multidrug resistance by interfering with the efflux action of Pgp and thus can decrease drug resistance or can restore drug sensitivity by restoring normal drug accumulation and distribution within the multidrug-resistant tumor cell. The two strongest, nearly equipotent chemosensitizers identified to date are the cyclosporine derivative SDZ PSC 833 and the semisynthetic cyclopeptolide SDZ 280-446. Purpose: This study was designed to investigate the capacities of verapamil, SDZ PSC 833, and SDZ 280-446 to decrease resistance of two multidrug-resistant cell lines to taxol. Methods: We studied in vitro the growth of two multidrug-resistant tumor cell lines displaying high resistance to taxol: multidrug-resistant Chinese hamster ovary cells and murine monocytic leukemia P388 cells. We determined the taxol concentration that produced 50% inhibition of cell growth (IC50) in the two multidrug-resistant cell lines and in the parent cell lines, in the presence of a range of chemosensitizer concentrations (0-30 μM). IC50 values were determined in the presence and in the absence of verapamil, SDZ PSC 833, or SDZ 280-446. Results: At nontoxic concentrations (0.3-1 μM), SDZ PSC 833 and SDZ 280-446 produced an almost complete reversal of the high taxol resistance of the multidrug-resistant tumor cells, whereas only partial restoration of sensitivity to taxol was achieved with verapamil. Conclusion: SDZ PSC 833 and SDZ 280-446 can restore the normal taxol sensitivity of highly resistant multidrug-resistant tumor cells. Implications: The combination of taxol with SDZ PSC 833 or SDZ 280-446 may be recommended for treatment of multidrug-resistant cancers. [J Natl Cancer Inst 85: 478-483, 1993

Variants in the FFAR1 Gene Are Associated with Beta Cell Function

The FFAR1 receptor is expressed mainly in pancreatic beta cells and is activated by medium to long chain free fatty acids (FFAs), as well as by thiazolidinediones, resulting in elevated Ca(2+) concentrations and promotion of insulin secretion. These properties suggest that FFAR1 could be a mediator of lipotoxicity and a potential candidate gene for Type 2 diabetes (T2D). We therefore investigated whether variations at the FFAR1 locus are associated with T2D and beta cell function.We re-sequenced the FFAR1 region in 96 subjects (48 healthy and 48 T2D individuals) and found 13 single nucleotide polymorphisms (SNPs) 8 of which were not previously described. Two SNPs located in the upstream region of the FFAR1 gene (rs1978013 and rs1978014) were chosen and genotyped in 1929 patients with T2D and 1405 healthy control subjects. We observed an association of rs1978013 and rs1978014 with insulinogenic index in males (p = 0.024) and females (p = 0.032), respectively. After Bonferroni corrections, no association with T2D was found in the case-control material, however a haplotype consisting of the T-G alleles conferred protection against T2D (p = 0.0010).Variation in the FFAR1 gene may contribute to impaired beta cell function in T2D

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Novel CCR1 antagonists with oral activity in the mouse collagen induced arthritis.

Cinnamides as novel CCR1 antagonist chemotypes are described with high affinity to human and rodent receptors. A1B1 and A4B7 showed oral activity in the mouse collagen induced arthritis