New insights into antimetastatic signaling pathways of melatonin in skeletomuscular sarcoma of childhood and adolescence.

Melatonin is an indole produced by the pineal gland at night under normal light or dark conditions, and its levels, which are higher in children than in adults, begin to decrease prior to the onset of puberty and continue to decline thereafter. Apart from circadian regulatory actions, melatonin has significant apoptotic, angiogenic, oncostatic, and antiproliferative effects on various cancer cells. Particularly, the ability of melatonin to inhibit skeletomuscular sarcoma, which most commonly affects children, teenagers, and young adults, is substantial. In the past few decades, the vast majority of references have focused on the concept of epithelial-mesenchymal transition involvement in invasion and migration to allow carcinoma cells to dissociate from each other and to degrade the extracellular matrix. Recently, researchers have applied this idea to sarcoma cells of mesenchymal origin, e.g., osteosarcoma and Ewing sarcoma, with their ability to initiate the invasion-metastasis cascade. Similarly, interest of the effects of melatonin has shifted from carcinomas to sarcomas. Herein, in this state-of-the-art review, we compiled the knowledge related to the molecular mechanism of antimetastatic actions of melatonin on skeletomuscular sarcoma as in childhood and during adolescence. Utilization of melatonin as an adjuvant with chemotherapeutic drugs for synergy and fortification of the antimetastatic effects for the reinforcement of therapeutic actions are considered.

A short review on creatine-creatine kinase system in relation to cancer and some experimental results on creatine as adjuvant in cancer therapy.

The creatine/creatine kinase (CK) system plays a key role in cellular energy buffering and transport. In vertebrates, CK has four isoforms expressed in a tissue-specific manner. In the process of creatine biosynthesis several other important metabolites are formed. The anticancer effect of creatine had been reported in the past, and recent literature has reported low creatine content in several types of malignant cells. Furthermore, creatine can protect cardiac mitochondria from the deleterious effects of some anticancer compounds. Previous work from our laboratory showed progressive decrease of phosphocreatine, creatine and CK upon transformation of skeletal muscle into sarcoma. It was convincingly demonstrated that prominent expression of creatine-synthesizing enzymes L-arginine: glycine amidinotransferase and N-guanidinoacetate methyltransferase occurs in sarcoma, Ehrlich ascites carcinoma and sarcoma 180 cells; whereas, both these enzymes are virtually undetectable in skeletal muscle. Creatine transporter also remained unaltered in malignant cells. The anticancer effect of methylglyoxal had been known for a long time. The present work shows that this anticancer effect of methylglyoxal is significantly augmented in presence of creatine. On creatine supplementation the effect of methylglyoxal plus ascorbic acid was further augmented and there was no visible sign of tumor. Moreover, creatine and CK, which were very low in sarcoma tissue, were significantly elevated with the concomitant regression of tumor.

Quantification of phosphorus metabolites in human calf muscle and soft-tissue tumours from localized MR spectra acquired using surface coils.

Metabolite concentrations determined from MR spectra provide more specific information than peak area ratios. This paper presents a method of quantification that allows metabolite concentrations to be determined from in vivo 31P MR spectra acquired using a surface coil and ISIS localization. Corrections for the effects of B1 field inhomogeneity produced by surface coils are based on a measured and calibrated spatial sensitivity field map for the coil. Account is taken of imperfections in pulse performance, coil loading effects and relaxation effects, the latter making use of published metabolite relaxation times. The technique is demonstrated on model solutions. The concentrations of the main 31P metabolites in normal human calf muscle measured using this method are [PCr] = 26.9 +/- 4.1 mM; [Pi] = 3.6 +/- 1.2 mM; [NTP] = 6.8 +/- 1.8 mM. Quantification of spectra acquired from soft-tissue tumours in patients both pre- and post-treatment showed that changes in metabolite concentrations are more sensitive to metabolic changes than changes in peak area ratios.

MR spectroscopy of musculoskeletal soft-tissue tumors.

Published studies of sarcomas using 31P MRS suffer from technical limitations that include absence of localization to regions of interest, resulting in heavy contamination with signals from muscle, and poor resolution. This review has shown that, in spite of their limitations, many of these studies provide important leads to indicate the directions that need to be taken to further develop clinical and biologic uses of MRS. The uniqueness of the metabolic information available in vivo in a noninvasive manner using MRS provides a major stimulus to pursue these directions. In particular, the potential of 31P MRS to predict treatment sensitivity and resistance in individual cases could lead to a very cost-beneficial clinical use of this procedure. 1H-decoupling and NOE-enhancement, implemented in conjunction with dual-tuned surface coils and accurate localization of 31P MR spectra to regions of interest in three dimensions using CSI, have enabled us to overcome the major technical limitations mentioned earlier, broaden the scope of 31P MRS investigations, and obtain more information about the in vivo metabolic characteristics of soft-tissue sarcomas than has heretofore been available. Our approach, which has been fully implemented in a clinical imager, provides a good technical basis from which to examine potential clinical uses of 31P MRS. In particular, we can now rigorously test the hypotheses, derived from preliminary studies in the literature, that initial metabolic features or early treatment-induced changes in PME predict sensitivity of a sarcoma to that particular treatment. To this end, we at Fox Chase Cancer Center, along with investigators at Duke University, the Institute of Cancer Research/Royal Marsden Hospital, Johns Hopkins University, Memorial Sloan-Kettering Cancer Center, St. Georges Hospital Medical School, the University of California at San Francisco, and Wayne State University have initiated an NCI-sponsored cooperative trial to examine the role of 31P MRS in the clinical management of soft-tissue sarcomas and other selected cancers.