Polymorphisms of ERBB2 and breast cancer risk: a meta-analysis of 26 studies involving 35,088 subjects.

BACKGROUND AND OBJECTIVES: Several epidemiologic studies have investigated the relationship between the polymorphisms of ERBB2 gene and breast cancer risk. However, the results are inconclusive. This meta-analysis aimed to assess the association between ERBB2 Ile655Val and Ala1170Pro polymorphisms and the susceptibility to breast cancer. METHODS: Twenty-six studies including 15,940 cases and 19,148 controls were analyzed in this meta-analysis. RESULTS: Overall, allele contrast (Val vs. Ile) of ERBB2 655 polymorphism produced significant results in worldwide populations (OR = 1.123, 95%CI = 1.01-1.249) and in Caucasian populations (OR = 1.149, 95%CI = 1.002-1.318). In addition, the Val/Val genotype of ERBB2 655 polymorphism was associated with an increase risk of breast cancer in African (Val/Val vs. Ile/Ile OR = 16.031 95%CI = 2.019-127.267; Val/Val vs. Ile/Val + Ile/Ile OR = 16.445 95%CI = 2.059-131.351), but not in Caucasian or Asian individuals. CONCLUSIONS: ERBB2 655 Val allele would be a risk factor for breast cancer, especially in Caucasian populations. In addition, the Val/Val genotype was a risk factor for breast cancer in African individuals. ERBB2 Ala1170Pro was not associated with breast cancer susceptibility.

Identification of less lipophilic riminophenazine derivatives for the treatment of drug-resistant tuberculosis.

Clofazimine (CFZ), a member of the riminophenazine class, has been studied in clinical trials for the treatment of multidrug-resistant tuberculosis (MDR-TB). CFZ has several side effects which can be attributed to its extremely high lipophilicity. A series of novel riminophenazine analogues bearing a C-2 pyridyl substituent was designed and synthesized with the goal of maintaining potent activity against Mycobacterium tuberculosis (M. tuberculosis) while improving upon its safety profile by lowering the lipophilicity. All compounds were evaluated for their in vitro activity and cytotoxicity. The results demonstrated that many new compounds had potent activity against M. tuberculosis with MICs of less than 0.03 µg/mL and low cytotoxicity with IC(50) values greater than 64 µg/mL. Some compounds were tested for in vivo efficacy against MDR-TB in an experimental mouse infection model. Two compounds demonstrated equivalent or better efficacy than CFZ in this model with significantly reduced skin discoloration potential.

Systematic evaluation of structure-activity relationships of the riminophenazine class and discovery of a C2 pyridylamino series for the treatment of multidrug-resistant tuberculosis.

Clofazimine, a member of the riminophenazine class of drugs, is the cornerstone agent for the treatment of leprosy. This agent is currently being studied in clinical trials for the treatment of multidrug-resistant tuberculosis to address the urgent need for new drugs that can overcome existing and emerging drug resistance. However, the use of clofazimine in tuberculosis treatment is hampered by its high lipophilicity and skin pigmentation side effects. To identify a new generation of riminophenazines that is less lipophilic and skin staining, while maintaining efficacy, we have performed a systematic structure-activity relationship (SAR) investigation by synthesizing a variety of analogs of clofazimine and evaluating their anti-tuberculosis activity. The study reveals that the central tricyclic phenazine system and the pendant aromatic rings are important for anti-tuberculosis activity. However, the phenyl groups attached to the C2 and N5 position of clofazimine can be replaced by a pyridyl group to provide analogs with improved physicochemical properties and pharmacokinetic characteristics. Replacement of the phenyl group attached to the C2 position by a pyridyl group has led to a promising new series of compounds with improved physicochemical properties, improved anti-tuberculosis potency, and reduced pigmentation potential.