phosphocreatine and Carcinoma

The brain isoform of creatine kinase has been implicated in cellular transformation processes. Cyclocreatine, a creatine kinase substrate analog, was previously shown to be cytotoxic to a broad spectrum of solid tumors. We have synthesized, enzymatically characterized, and evaluated the antitumor activity of a series of substrate analogs of creatine kinase. Using in vitro assays, we demonstrate that several of these analogs are cytotoxic to the human ME-180 cervical carcinoma, the MCF-7 breast adenocarcinoma and the HT-29 colon adenocarcinoma cell lines at low mM concentrations. Analogs that were active in vitro delayed the growth of a subcutaneously implanted rat 13,762 mammary adenocarcinoma. Tumor growth delays of 6-8 days were achieved, which is comparable to effects seen with standard regimens of currently used anticancer drugs. These studies further establish the creatine kinase system as a promising and novel target for anticancer chemotherapy drug design.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Cell Death; Colonic Neoplasms; Creatine; Creatine Kinase; Creatinine; Female; Humans; Neoplasms, Experimental; Phosphocreatine; Rats; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Metabolic consequences of hypothyroidism in adult human brain, despite neuropsychological symptoms, have not been reported. We used 31P nuclear magnetic-resonance spectroscopy of the frontal lobe to examine the effect of acute hypothyroidism on cerebral metabolism. Paired analysis showed that the phosphocreatine/inorganic-phosphate (PCr/Pi) ratio increased from a median of 2.04 (interquartile range 0.15) to 2.22 (0.25) after treatment with levothyroxine (p = 0.01). These reversible alterations in adult cerebral phosphate metabolism during acute hypothyroidism parallel PCr/Pi ratio changes described in skeletal muscle. This is the first direct evidence of cerebral metabolic effects of hypothyroidism on adult brain.

Topics: Acute Disease; Adult; Brain; Carcinoma; Energy Metabolism; Humans; Hypothyroidism; Magnetic Resonance Spectroscopy; Middle Aged; Phosphates; Phosphocreatine; Thyroid Neoplasms; Thyroidectomy; Thyroxine

In vivo and in vitro 31P-NMR spectroscopy was used to study the high energy phosphate metabolism of VX-2 tumors implanted into rabbit liver, kidney, and hind-limb muscle. Tumors, at various stages of growth, were first examined by in vivo 31P-NMR spectroscopy, then they were excised and underwent histologic examination and biochemical analysis; both in vitro 31P-NMR and standard enzymatic techniques were used. There was good correlation among the in vivo NMR spectra, the in vitro NMR data, and the biochemical analyses. Although the tumor spectra showed characteristics similar to those reported in the other tumor models, there was a striking variability in the spectra obtained from tumors implanted in the same site and from different sites. There was poor correlation between the degree of necrosis in the tumor and the tumor pH and between the Pi:ATP ratio and necrosis. This variability has important implications for the potential value of using 31P-NMR spectroscopy to monitor tumor growth and therapy in vivo.

Topics: Adenosine Triphosphate; Animals; Carcinoma; In Vitro Techniques; Kidney Neoplasms; Liver Neoplasms; Magnetic Resonance Spectroscopy; Muscular Diseases; Neoplasms, Experimental; Phosphocreatine; Phosphorus; Rabbits

Topics: Adenine Nucleotides; Adenosine; Adenosine Triphosphate; Adenoviridae; Base Sequence; Carcinoma; Cell Nucleus; Cells, Cultured; Creatine Kinase; Cytosine Nucleotides; Electrophoresis, Polyacrylamide Gel; Humans; Micropore Filters; Molecular Weight; Mouth Neoplasms; Phosphocreatine; Polynucleotides; Ribonucleases; RNA, Messenger; RNA, Ribosomal; RNA, Viral; Tritium; Virus Cultivation

Nuclei isolated from cultured human cells (KB) infected with adenovirus type-2 were used to study events occurring during the adenosine triphosphate-dependent release of viral RNA. When cells were labeled with [(3)H]uridine for 50 min beginning 18 hr after infection, most nuclear viral messenger RNA was in the form of high molecular weight precursors with sedimentation coefficients greater than 28 S. When nuclei were incubated in the presence of ATP and an ATP-generating system, labeled RNA the size of viral mRNA (10-29 S) was released. Cleavage of viral RNA precursor molecules of high molecular weight occurred during incubation of nuclei. The change in size of viral RNA did not require exogenous ATP and occurred before release of RNA from nuclei. This RNA cleavage seems comparable to processing of mRNA in vivo, for discrete viral species were produced. Cleavage was completed after 10 min of incubation but was not the rate-limiting step in the release reaction, which required about 20 min for completion.

Topics: Adenosine Triphosphate; Adenoviridae; Carbon Isotopes; Carcinoma; Cell Fractionation; Cell Line; Cell Nucleus; Creatine Kinase; Electrophoresis, Polyacrylamide Gel; Humans; Kinetics; Molecular Weight; Mouth Neoplasms; Nucleic Acid Hybridization; Phosphocreatine; RNA; RNA, Viral; Tritium; Uridine