Pharmacometabonomics Analysis Reveals Serum Formate and Acetate Potentially Associated with Varying Response to Gemcitabine-Carboplatin Chemotherapy in Metastatic Breast Cancer Patients

Gemcitabine-carboplatin (GC) chemotherapy was efficacious in metastatic breast cancer (MBC) patients probably resistant to anthracyclines and taxanes, but showed significant interindividual variation in treatment responses. Early prediction of response to treatment is clinically relevant to identify patients who will achieve clinical benefit. In this study, nuclear magnetic resonance (NMR) based pharmacometabonomics was used to noninvasively predict the response to GC chemotherapy of 29 MBC patients with prior exposure to both anthracyclines and taxanes from a phase II study. Formate and acetate levels in the baseline serum collected prior to GC chemotherapy were identified as potential predictive markers to select patients who will achieve clinical benefit and to identify those who should not be treated with the therapy to avoid futile treatment. The significantly lower baseline levels of serum formate and acetate in patients with resistant disease may reflect the higher demand of them as alternate/additional nutritional sources to fuel the accelerated proliferation of breast cancer cells that are biologically more aggressive or resistant to therapy. The results suggest that pharmacometabonomics can be a potential useful tool for predicting chemotherapy response in the context of precision medicine. Prospective studies with larger patient cohorts are required for validation of the findings

Metabonomic Analysis Reveals the CCl₄-Induced Systems Alterations for Multiple Rat Organs

CCl₄-induced metabonomic changes have been extensively studied for mammalian liver, and such changes have not been reported for other organs. To investigate the CCl₄ effects on other organs, we analyzed the CCl₄-induced metabonomic changes in rat kidney, lung, and spleen using ¹H NMR-based metabonomics approaches with complementary information on serum clinical chemistry and histopathology. We found that acute CCl₄ exposure caused significant level elevation for creatine and decline for glucose, taurine, trimethylamine, uridine, and adenosine in rat kidney. CCl₄-treatment also induced elevation of amino acids (isoleucine, leucine, valine, threonine, alanine, lysine, ornithine, methionine, tyrosine, phenylalanine, and histidine), creatine, and betaine in rat lung together with depletion of glycogen, glucose, taurine, glycine, and hypoxanthine. Furthermore, CCl₄ caused elevation of lactate, alanine, betaine, and uracil in rat spleen accompanied with decline for glucose, choline, and hypoxanthine. These observations indicated that CCl₄ caused oxidative stresses to multiple rat organs and alterations of their functions including renal osmotic regulations, accelerated glycolysis, and protein and nucleotide catabolism. These findings provide essential information on CCl₄ toxicity to multiple rat organs and suggest that systems toxicological views are required for metabonomic studies of toxins by taking many other organs into consideration apart from so-called targeted ones

Comprehensive Solid-State NMR Analysis Reveals the Effects of N-Methylation on the Molecular Dynamics of Glycine

Molecular dynamics of metabolites are important for their interactions and functions. To understand the structural dependence of molecular dynamics for N-methylated glycines, we comprehensively measured the ¹³C and ¹H spin–lattice relaxation times for sarcosine, <i>N</i>,<i>N</i>-dimethylglycine, betaine, and betaine hydrochloride over a temperature range of 178–460 K. We found that the reorientations of methyl groups were observed for all these molecules, whereas reorientations of whole trimethylamine groups were detected in betaines. While similar rotational properties were observed for methyl groups in <i>N</i>,<i>N</i>-dimethylglycine and those in betaine, three methyl groups in betaine hydrochloride had different motional properties (<i>E</i>_a ≈ 20.5 kJ/mol, τ₀ ≈ 1.85 × 10^–13 s; <i>E</i>_a ≈ 13.9 kJ/mol, τ₀ ≈ 2.1 × 10^–12 s; <i>E</i>_a ≈ 15.8 kJ/mol, τ₀ ≈ 1.1 × 10^–12 s). <i>N</i>,<i>N</i>-Dimethylglycine showed a phase transition at 348.5 K with changed relaxation behavior for methyl groups showing distinct <i>E</i>_a and τ₀ values. The DIPSHIFT experiments showed that CH₃ and CH₂ moieties in these molecules had dipolar-dephasing curves similar to these moieties in alanine and glycine. The activation energies for CH₃ rotations positively correlated with the number of substituted methyl groups. These findings provided useful information for the structural dependence of molecular dynamics for N-methylated glycines and demonstrated solid-state NMR as a useful tool for probing the structure–dynamics relationships