Correlation of polymorphism C3435T of the MDR-1 gene and the response of primary chemotherapy in women with locally advanced breast cancer

Primary chemotherapy is a useful strategy for the treatment of locally advanced breast cancer and therefore allows in vivo evaluation of the action of cytotoxic drugs and the possibility of accomplishing conservative breast surgeries, as well as the early treatment of metastasis. Mechanisms of resistance to the drugs include the action of protein associated with the efflux of drugs from the intracellular environment hindering their activity; one of the most studied proteins is P-glycoprotein codified by the MDR-1 gene. The presence of polymorphisms can determine different physiological actions of these proteins, intervening with the response of the drug’s action. We evaluated the presence of single nucleotide polymorphism (SNP) C3435T of the MDR-1 gene and its correlation with the response to primary chemotherapy using the RECIST criteria. Forty-one Brazilian women with stages II and III breast cancer using the PCR-RFLP analysis were evaluated. Thirty-three patients with the SNP genotype (TT and CT) and eight patients with the wild genotype (CC) were found; there was no statistically significant correlation between the diverse genotypes and the clinical and pathological responses according to the Cramer correlation coefficient (V = 0.14). The parameters: nuclear and histological degree, and estrogens, progesterone and c-erb B2 receptors did not demonstrate a statistical correlation with the SNP C3435T. Patients with complete pathological response (12.5%) showed only the polymorphic genotype and not the wild genotype. The characteristics of miscegenation in our population could explain the absence of the characterization of a sub-group of individuals where the presence of the polymorphic genotype influenced the response to the primary chemotherapy.

Fuel oxidation by insulin-dependent diabetics during late pregnancy in response to an oral glucose load

To determine the oxidative response to a 50-g oral glucose challenge by diabetic women during late pregnancy under a more i9ntensive therapeutic regimen than is conventionally employed, six normal pregnant women and ten insulin-dependent pregnant diabetic women were studied during the third trimester. Fuel (carbohydrate and lipid) oxidation rates were determined by indirect calorimetry, blood levels of substrates and C-peptide were measured directly, and glucose metabolism data (oxidation and nonoxidative metabolism) were estimated for both groups at the postabsorptive state and for the 2-h period following glucose ingestion. The increases in the non-protein respiratory quotient (npRQ) and carbohydrate oxidation ratesw in response to glucose ingestion in the diabetic pregnant group were significantly smaller than in the normal pregnant individuals. The total amount of glucose oxidized by the diabetic pregnant group during the 2-h tests (6.1 ñ 0.6 g/m2) was significantly smaller than that oxidized by the pregnant group (8.3 ñ 0.4 g/m2), whereas there was more but not statistically signioficant lipid oxidation in the diabetic group (3.0 ñ 0.3 vs 2.6 ñ 0.1 g/m2).The diabetic pregnant group not only oxidized less glucose (10.9 ñ 1.1 vs 14.1 ñ 0.8g, P<0.05) but more of this hexose remained in their glucose space (9.1 ñ 1.6 vs 3.2 ñ 1.1, P<0.05) and they excreted 2.8 ñ 1.0 g into the urine. The diabetic pregnant subjects had significantly lower blood levels of lactate, pyruvate and C-peptide than the normal pregnant subjects, but significantly higher blood levels of glucose, beta-hydroxybutyrate and acetoacetate. The present data show that an intensive conventional therapeutic regimen during late pregnancy was not sufficient to completely normalize the glucose-processing capability of insulin-dependent diabetic patients

Effects of glucose loads of 50 and 100g on carbohydrate and lipid oxidation in normal human subjects

The effects of 50 - and 100-g glucose loads on carbohydrate and lipid oxidation and substrate metabolism of seven normal subjects were studied in the postabsorptive state and for 3 h following glucose ingestion. 2. The increases in the non-protein respiratory quotient (npRQ) and carbohydrate oxidation rate were larger after the ingestion of 100 g glucose than after the 50-g glucose load. The total amount of glucose oxidized during the test with 100 g of glucose ingested orally (100-g OGT) (13.4 ñ 0.8 g/m2) was significantly greater than oxidized during the 50-g OGT (9.5 ñ 0.6 g/m2), whereas lipid oxidation predominated in the tests with the smaller dose of glucose. The difference between the amounts of glucose oxidized during the two tests was greater when the increments above the basal values of glucose oxidation were compared (100-g OGT = 8.0 ñ 0.5 g/m2 vs 50-g OGT = 3.8 ñ 0.5 g/m2; P < 0.001). 3. The glucose disposal data revealed that the subjects not only oxidized more of the hexose after the ingestion of 100 g of glucose but they also stored more after the 50-g glucose meal. 4. The changes in the concentrations of glucose, lactate, pyruvate, alanine and insulin in the blood were also related to the amount of the glucose load. 5. It is suggested that the modulation of this oxidative response to glucose ingestion occurs in the insulin-dependent tissues