phosphocreatine and Neoplasms

Anthracyclines are frequently used chemotherapeutic agents for childhood cancer that can cause cardiotoxicity during and after treatment. Although several medical interventions in adults with symptomatic or asymptomatic cardiac dysfunction due to other causes are beneficial, it is not known if the same treatments are effective for childhood cancer patients and survivors with anthracycline-induced cardiotoxicity. This review is an update of a previously published Cochrane review.. To compare the effect of medical interventions on anthracycline-induced cardiotoxicity in childhood cancer patients or survivors with the effect of placebo, other medical interventions, or no treatment.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2015, Issue 8), MEDLINE/PubMed (1949 to September 2015), and EMBASE/Ovid (1980 to September 2015) for potentially relevant articles. In addition, we searched reference lists of relevant articles, conference proceedings of the International Society for Paediatric Oncology (SIOP), the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), the International Conference on Long-Term Complications of Treatment of Children & Adolescents for Cancer, and the European Symposium on Late Complications from Childhood Cancer (from 2005 to 2015), and ongoing trial databases (the ISRCTN Register, the National Institutes of Health (NIH) Register, and the trials register of the World Health Organization (WHO); all searched in September 2015).. Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of medical interventions to treat anthracycline-induced cardiotoxicity with either placebo, other medical interventions, or no treatment.. Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessments, which another review author checked. We performed analyses according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions.. In the original version of the review we identified two RCTs; in this update we identified no additional studies. One trial (135 participants) compared enalapril with placebo in childhood cancer survivors with asymptomatic anthracycline-induced cardiac dysfunction. The other trial (68 participants) compared a two-week treatment of phosphocreatine with a control treatment (vitamin C, adenosine triphosphate, vitamin E, oral coenzyme Q10) in leukaemia patients with anthracycline-induced cardiotoxicity. Both studies had methodological limitations.The RCT on enalapril showed no statistically significant differences in overall survival, mortality due to heart failure, development of clinical heart failure, and quality of life between treatment and control groups. A post-hoc analysis showed a decrease (that is improvement) in one measure of cardiac function (left ventricular end-systolic wall stress (LVESWS): -8.62% change) compared with placebo (+1.66% change) in the first year of treatment (P = 0.036), but not afterwards. Participants treated with enalapril had a higher risk of dizziness or hypotension (risk ratio 7.17, 95% confidence interval 1.71 to 30.17) and fatigue (Fisher's exact test, P = 0.013).The RCT on phosphocreatine found no differences in overall survival, mortality due to heart failure, echocardiographic cardiac function, and adverse events between treatment and control groups.. Only one trial evaluated the effect of enalapril in childhood cancer survivors with asymptomatic cardiac dysfunction. Although there is some evidence that enalapril temporarily improves one parameter of cardiac function (LVESWS), it is unclear whether it improves clinical outcomes. Enalapril was associated with a higher risk of dizziness or hypotension and fatigue. Clinicians should weigh the possible benefits with the known side effects of enalapril in childhood cancer survivors with asymptomatic anthracycline-induced cardiotoxicity.Only one trial evaluated the effect of phosphocreatine in childhood cancer patients with anthracycline-induced cardiotoxicity. Limited data with a high risk of bias showed no significant difference between phosphocreatine and control treatments on echocardiographic function and clinical outcomes.We did not identify any RCTs or CCTs studying other medical interventions for symptomatic or asymptomatic cardiotoxicity in childhood cancer patients or survivors.High-quality studies should be performed.

Topics: Adult; Adult Survivors of Child Adverse Events; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antibiotics, Antineoplastic; Cardiotonic Agents; Child; Enalapril; Heart Failure; Humans; Neoplasms; Phosphocreatine; Randomized Controlled Trials as Topic

Topics: Antineoplastic Agents; Cardiotonic Agents; Cardiovascular Diseases; Humans; Neoplasms; Phosphocreatine

Magnetic resonance spectroscopy (MRS) has been used for more than two decades to interrogate metabolite distributions in living cells and tissues. Techniques have been developed that allow multiple spectra to be obtained simultaneously with individual volume elements as small as 1 uL of tissue (i.e., 1 x 1 x 1 mm(3)). The most common modern applications of in vivo MRS use endogenous signals from (1)H, (31)P, or (23)Na. Important contributions have also been made using exogenous compounds containing (19)F, (13)C, or (17)O. MRS has been used to investigate cardiac and skeletal muscle energetics, neurobiology, and cancer. This review focuses on the latter applications, with specific reference to the measurement of tissue choline, which has proven to be a tumor biomarker that is significantly affected by anticancer therapies.

Topics: Animals; Biopsy; Brain; Choline; Citric Acid; Esters; Female; Humans; Hydrogen; Isotopes; Lipids; Magnetic Resonance Spectroscopy; Male; Muscle, Skeletal; Neoplasm Transplantation; Neoplasms; Nucleosides; Phosphates; Phosphocreatine; Polyamines; Propylamines

Nuclear magnetic resonance spectroscopy has progressed far since the original description of the phenomenon (30,31) and now permits noninvasive and harmless measurements to be repeatedly made of tissue biochemistry. Currently, there is a paucity of NMR data on normal human metabolism and the interpretation of spectra recorded from diseased tissues must be circumspect. This is further complicated by the inability of NMR spectroscopy to render accurate quantitative measurements and all observations must be considered to be compatible with, rather than diagnostic of, specific diseases. Nevertheless, NMR is an important addition to the clinician's armamentarium and these relatively expensive instruments should be situated in regional referral centres. Undoubtedly the most significant advances in NMR will only occur following the successful combination of the imaging and spectroscopic techniques, since that will enable anatomical and metabolic data to be obtained from a single site without the need for biopsy. Nuclear magnetic resonance spectroscopy has much to offer and the practical hazards appear to be few. In the next few years we will undoubtedly see an improvement in the quality of the data obtainable an a growing diversity of clinical applications.

Topics: Humans; Hypoxia, Brain; Magnetic Resonance Spectroscopy; Muscles; Muscular Atrophy; Muscular Diseases; Neoplasms; Phosphates; Phosphocreatine; Phosphofructokinase-1

Topics: Adenosine Triphosphate; Adrenal Glands; Animals; Diphosphoglyceric Acids; Female; Humans; In Vitro Techniques; Kidney; Magnetic Resonance Spectroscopy; Male; Mitochondria, Liver; Muscles; Muscular Dystrophies; Myocardium; Neoplasms; Ovum; Phosphates; Phosphocreatine; Semen; Sugar Phosphates

In vivo magnetic resonance spectroscopy (MRS) studies of glial brain tumours reported that higher grade of astrocytoma is associated with increased level of choline-containing compounds (Cho) and decreased levels of N-acetylaspartate (NAA) and creatine and phosphocreatine (Cr). In this work, we studied the metabolism of glioma tumours by in vitro proton magnetic resonance spectroscopy (1H-MRS). 1H-MR spectra were recorded in vitro from perchloric acid extracts of astrocytoma (WHO II) and glioblastoma multiforme (WHO IV) samples. We observed differences between astrocytoma and glioblastoma multiforme in the levels of Cho, alanine, lactate, NAA, and glutamate/glutamine. In astrocytoma samples, we found higher MR signal of NAA and lower signal of Cho and alanine. MR spectra of glioblastoma samples reported significantly higher levels of lactate and glutamate/glutamine. In contrast, levels of Cr were the same in both tumour types. We also determined NAA/Cr and Cho/Cr ratios in the tumour samples. The NAA/Cr ratio was higher in astrocytomas than in glioblastomas multiforme. Conversely, the Cho/Cr ratio was higher in glioblastoma multiforme. The results indicate that MRS is a promising method for distinguishing pathologies in human brain and for pre-surgical grading of brain tumours.

Topics: Aspartic Acid; Astrocytes; Astrocytoma; Brain; Brain Neoplasms; Choline; Chromium; Creatine; Glioblastoma; Glioma; Humans; In Vitro Techniques; Magnetic Resonance Spectroscopy; Neoplasms; Phosphocreatine; Spectrophotometry

We aimed to investigate whether changes in high-energy phosphate metabolism after treatment of children and young adults with anthracycline can be demonstrated non-invasively by 31P magnetic resonance spectroscopy.. Abnormal myocardial energy metabolism has been suggested as a mechanism for anthracycline-induced cardiotoxicity. Deterioration in such has been shown in animal studies by resonance spectroscopy.. We studied 62 patients, with a mean age of 13.5+/-5 years, 3.7+/-4.3 years after a cumulative anthracycline dose of 270+/-137 mg/m2. Normal echocardiographic findings had been elicited in 54 patients. The control group consisted of 28 healthy subjects aged 20+/-7 years. Resonance spectrums of the anterior left ventricular myocardium were obtained at 1.5 Tesla using an image-selected in vivo spectroscopy localization technique.. The ratio of phosphocreatine to adenosine triphosphate after blood correction was 1.09+/-0.43 for the patients, and 1.36+/-0.36 (mean+/-SD) for controls (p=0.005), with a significantly reduced mean ratio even in the subgroup of patients with normal echocardiographic results (1.11+/-0.44 versus 1.36+/-0.36, p=0.01). The ratio did not correlate with the cumulative dose of anthracycline. The ratio of phosphodiester to adenosine triphosphate was similar in patients and controls (0.90+/-0.56 versus 0.88+/-0.62).. In patients treated with anthracyclines in childhood, myocardial high-energy phosphate metabolism may be impaired even in the absence of cardiomyopathy. Our data support the concept that anthracycline-induced cardiotoxicity is not clearly dose dependent.

Topics: Adenosine Triphosphate; Adolescent; Adult; Anthracyclines; Child; Child, Preschool; Energy Metabolism; Female; Humans; Magnetic Resonance Spectroscopy; Male; Myocardium; Neoplasms; Phosphates; Phosphocreatine

Under full nutrient in vitro conditions, the cellular adenylate energy charge of six different rodent and human tumor cell types was identical, i.e., 0.94 +/- 0.01, suggesting the potential utility of this parameter as a cell (and tissue) independent marker of nutrient deprivation and hypoxia, across tumor types. The adenylate energy charge values of tumors, arising from these cells, was reduced and variable ranging from 0.72 to 0.91 for the various tumor types. However, neither the tumor adenylate energy charge, NTP/Pi, nor PCr/Pi ratios correlated with the radiobiologic hypoxic cell fractions across tumor types. The reduced adenylate energy charge in vivo suggests varying degrees of nutrient deprivation in the different tumor types, however, factors other than or in addition to hypoxia likely contribute to tumor energy status.

Topics: Adenine Nucleotides; Animals; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Line; Cell Survival; Energy Metabolism; Female; Glioma; Humans; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Mice, Nude; Neoplasms; Neoplasms, Experimental; Pharyngeal Neoplasms; Phosphates; Phosphocreatine; Ribonucleotides; Sarcoma, Experimental; Transplantation, Heterologous; Tumor Cells, Cultured; Whole-Body Irradiation

In an effort to investigate the role of creatine kinase and its substrates in malignancy we have tested the effect of cyclocreatine [1-carboxymethyl-2-iminoimidazolidine (CCr)] on the growth of tumor cells in vitro and in vivo. CCr is phosphorylated by creatine kinase to yield a synthetic phosphagen [(N-phosphorylcyclocreatine (CCr approximately P)] with thermodynamic and kinetic properties distinct from those of creatine phosphate. We show that CCr accumulates as CCr approximately P in tumor cells expressing a high level of creatine kinase, and that the accumulation of this phosphagen is detrimental to tumor cell growth. Tumor cell lines expressing a low level of creatine kinase accumulate much less CCr approximately P, and consequently are growth inhibited only at higher concentrations of CCr. When these resistant cells are transfected with a creatine kinase B expression vector, they express creatine kinase, accumulate CCr approximately P, and are growth inhibited. In vivo, in nude mouse xenografts, the rate of growth of a high creatine kinase expressing tumor cell line is inhibited in animals fed 1% CCr. Our results indicate that CCr inhibits the growth of tumor cells in vitro and in vivo.

Topics: Animals; Antineoplastic Agents; Cell Division; Cell Line; Cell Transformation, Neoplastic; Creatine Kinase; Creatinine; Female; Humans; Imidazolidines; Isoenzymes; Male; Mice; Mice, Nude; Neoplasms; Neoplasms, Experimental; Phosphocreatine; Transplantation, Heterologous; Tumor Cells, Cultured; Uterine Cervical Neoplasms

This study investigates the potential of in vivo 31P magnetic resonance spectroscopy (MRS) to characterize musculoskeletal tumors and to determine preoperative levels of histological necrosis, which is an important clinical indicator of patient response. Pretherapy MRS was performed on 28 patients with large musculoskeletal tumors: 13 with osteosarcoma, 3 with chondrosarcoma, 5 with malignant fibrous histiocytoma, 1 with desmoid tumor, 1 with Ewing's, 2 with hemangioendothelioma, 1 with myxoid liposarcoma, 1 with synovial cell sarcoma, and 1 with rhabdomyosarcoma. Fifteen patients had follow-up MRS examinations after commencement of chemotherapy (mean of five/patient), eight of whom have now had surgery. Elevated levels of PMEs (P < 0.01), P(i) (P < 0.01), and PDEs (P < 0.02) as well as elevated tumor pH (P < 0.05) were observed in all patients. The synovial cell sarcoma was characterized by high levels of PMEs (> 20%) and low pH (pH 6.76). This contrasted with the spectra obtained from the malignant fibrous histiocytomas which had high levels of PDEs (17 +/- 5%). Reductions in PDE levels postchemotherapy were associated with a high degree of necrosis (> 90%) at surgery, while an increase in PDE levels was associated with a low level of histological necrosis. Likewise, reductions in the ratios PDE/NTP and PDE/PCr and an increase in P(i)/PDE were also associated with a high level of necrosis.

Topics: Adult; Aged; Bone Neoplasms; Chemotherapy, Adjuvant; Ethanolamines; Female; Glycerylphosphorylcholine; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscular Diseases; Necrosis; Neoplasm Staging; Neoplasms; Osteosarcoma; Phosphatidylethanolamines; Phosphocreatine; Phosphorus; Phosphorylcholine; Preoperative Care

pH measurements require a suitable pH reference within the 31P NMR spectrum with respect to which the chemical shift of Pi, and hence pH, may be calculated. In muscle spectra PCr is prominent and provides a reference frequency. However, recent localized tumor studies have reported the absence of PCr, for example, in breast tumors. The use of the alpha-, beta-, and gamma-ATP peaks as suitable references has been suggested, but the position of the beta- and gamma-ATP peaks is dependent upon the intracellular Mg2+ concentration. The alpha-ATP is not affected by ionic concentrations; however, it contains UDPG and NAD+, the presence of which can lead to peak-shape distortion. This paper considers the use of the H2O resonance from the proton spectrum used for shimming as a suitable pH reference, provided this is also localized to the same region of interest, using a sequence giving rise to eddy current effects comparable to those of the 31P NMR sequence. Localized in vivo measurements in the muscle and brain of volunteers indicate good agreement between the proton and phosphorus chemical shifts, allowing the PCr position to be predicted to within 0.01 ppm in all cases.

Topics: Body Water; Brain; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Muscles; Neoplasms; Phosphocreatine; Phosphorus; Protons

Studies were performed to characterize phosphorus-31 magnetic resonance (MR) spectra obtained from 10 superficial human tumors outside the brain and to determine whether P-31 MR spectroscopy could allow detection of a response to therapy before a change in tumor size was measured. The ratio of phosphomonoester to adenosine triphosphate peak intensities (PME/ATP) was unusually large in all tumors studied. The average PME/ATP in lymphomas (1.8 +/- 0.5) was greater than in nonlymphoma cancers (1.1 +/- 0.15). The average PME/ATP for all tumors studied (1.4 +/- 0.5) was much greater than that of underlying skeletal muscle (0.23 +/- .09). Eight of the tumors were studied before and after therapy. Responders were distinguished from nonresponders on the basis of changes in tumor size. PME/ATP decreased during therapy in three lymphomas that responded to therapy. In an adenocarcinoma and Ewing sarcoma that did not respond to therapy, PME/ATP increased. PME/ATP remained constant in two squamous cell carcinomas that responded to therapy and decreased in one squamous cell carcinoma that decreased in size by 40% but was classified as a nonresponder. Changes in PME/ATP did not always parallel changes in tumor size during therapy. In two patients, a decrease in PME/ATP preceded a decrease in tumor size. In four patients, PME/ATP increased transiently during periods when tumor size remained constant.

Topics: Adenosine Triphosphate; Axilla; Carcinoma, Squamous Cell; Groin; Head and Neck Neoplasms; Humans; Lymphoma; Magnetic Resonance Spectroscopy; Neoplasms; Phosphocreatine

In 31P-(1H) MR experiments of humans in a 1.5-T whole-body system, signal intensity enhancements of 31P resonances of up to 68 +/- 4% (for phosphocreatine of the calf muscle) have been observed upon irradiation at proton frequency. This observation is explained as a nuclear Overhauser effect due to the dipolar coupling between 1H and 31P spins.

Topics: Humans; Magnetic Resonance Spectroscopy; Models, Structural; Muscles; Neoplasms; Phosphocreatine; Protons

Topics: Acid-Base Equilibrium; Energy Metabolism; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Neoplasms; Phosphates; Phosphocreatine

The effects of hydralazine on tumor energy metabolism and on some cardiovascular parameters were measured. Tumor energy metabolism was studied in C3Hf/Sed mice with isotransplants of a spontaneous murine fibrosarcoma (FSaII, congruent to 100 mm3 in volume) and 31P-NMR. Cardiovascular parameters were measured in anesthetized C3Hf/Sed mice via intracarotid catheter. Hydralazine doses of 0.25 mg/kg given ip caused an increase of the phosphocreatine to inorganic phosphate ratio (PCr: Pi) in 5 of 6 animals. These doses had minimal effects on mean arterial blood pressure, though there may have been an increased cardiac output due to a decreased afterload. Hydralazine doses greater than or equal to 2.0 mg/kg given ip were associated with a decrease in PCr, nucleotide triphosphate, and pH, and an increase in Pi (P less than .01 for control vs. 10 mg hydralazine/kg). This substantial decrease in high-energy phosphates was associated with a pronounced decrement in mean arterial blood pressure. These findings provide a rational basis for the study in experimental systems of hydralazine-induced enhancement of cell killing by hyperthermia and by agents toxic to hypoxic cells. Further, these results can be taken as a sign that hydralazine should be used with care in patients undergoing radiation treatment.

Topics: Animals; Blood Pressure; Cardiac Output; Dose-Response Relationship, Drug; Energy Metabolism; Female; Hydralazine; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C3H; Neoplasms; Phosphates; Phosphocreatine; Vasodilation

High-resolution 31P NMR spectra of normal and malignant muscle tissue from mice were obtained at 100 MHz. The spectrum of normal muscle was found to resemble that obtained by Hoult et al. for normal rat skeletal muscle. But the spectrum of malignant muscle tumor (rhabdomyosarcoma) was found to comprise only the inorganic phosphate and sugar phosphate peaks, which indicates potential usefulness of this NMR method for diagnosis. Moreover, the inorganic phosphate peak was observed to be shifted downfield 70 Hz from the location seen in normal muscle. This identification of an NMR absorption frequency different in cancer tissue than in normal, singles out what may be the first of many absorption frequencies that could be utilized as target frequencies for delivery of cancer-destructive radiation.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred CBA; Muscular Diseases; Neoplasms; Phosphocreatine; Rhabdomyosarcoma