ABSTRACT
Carbamazepine (CBZ) blocks neuronal sodium channels in a voltage- and frequency-dependent manner, delaying the recovery of the channels from the inactivated state, reducing the number of action potentials within a burst, and decreasing burst duration. The α-subunit of the first neuronal sodium channel (SCN1A) is a major gene in different epilepsies. A synonymous polymorphism (SCN1A IVS5N + 5 G>A or rs3812718) is common in exon 5 of this gene. Mutations in the α-unit of this gene are associated with CBZ-resistant epilepsy and a higher maintenance dose of CBZ. We have investigated the association of this single nucleotide polymorphism (SNP) and epilepsy, efficacy and dose-dependence of CBZ therapy in 147 adult Macedonian patients and 137 non epileptic controls. No significant differences in allelic frequencies and genotype distribution were found between patients and controls (p = 0.94278), or between CBZ-responsive and unresponsive patients (p = 0.55449). An association between the A allele and a higher maintenance dose in CBZ-responsive patients was detected. No statistical difference was found between the plasma levels of CBZ and genotype of patients receiving the same dose, indicating that the variant exerts its effect at the level of receptor responsiveness. The predictive value of pretreatment testing showed a minor insignificant difference between patients with different genotypes, primarily due to a small number of patients.
ABSTRACT
The aim of the study was to determine the possible relationship between different clinical and EEG features and executive functions in patients with juvenile myoclonic epilepsy (JME), i.e. to determine if sex, age, duration, absences, clinical asymmetric seizures, asymmetry or focality in epileptiform activity in EEG, EEG slow activity and familiar occurrences are associated with frontal dysfunction in JME patients. 28 patients (17 females, 11 males), mean age--22 y. were enrolled in the study. Executive functions were evaluated with the Wisconsin Card Sorting Test (WCST). Crosstabulation of certain characteristics have been used. The mean age at the beginning of epilepsy for the whole group was 13.5 y. and duration 8.5 y. All patients had myoclonic jerks, 28.6% of patients described unilateral predominance. Absences were registered in 42.9% patients. Bilateral spike or polyspikes/wave complexes were registered in 89.2% of patients, asymmetry of generalized discharges or focality in at least one EEG in 53.6% of patients, with anterior slow activity in 25% of them. Familiar occurrence was found in 42.9%. Of 28 patients, 14 had normal findings on WCST, while the other half of the patients did very poorly, achieving only 1-3 categories. Statistical analysis showed that only the female sex had p-value of 0.05, while other clinical and EEG features were not significantly associated with the occurrence of frontal impairment. Aside from female sex, no other clinical or EEG parameters were associated with the occurrence of executive dysfunction. But considering the relatively small sample size, our study may have been underpowered to detect subtle association and in our opinion, the current results must be replicated with a larger group of subjects to confirm the findings.
Subject(s)
Electroencephalography , Executive Function/physiology , Myoclonic Epilepsy, Juvenile/physiopathology , Adult , Female , Humans , Male , Young AdultABSTRACT
OBJECTIVES/HYPOTHESIS: The p53 tumor suppressor gene plays an important role for cell cycle regulation and is the most frequent mutated gene in head and neck cancer. Controversy remains regarding the biological and clinical value of immunohistochemical identification of the proteins accumulated in association with inactivation of the p53 gene and increased tumor growth. Therefore, the objective of the present study was to perform a cell kinetic analysis of cases with untreated squamous cell carcinoma and to compare the result with immunostaining for p53-related proteins in the tumor cells. STUDY DESIGN: A prospective series of 32 patients presenting with various stages of untreated squamous cell carcinoma of the head and neck were included. Bromodeoxyuridine (BrdU) was injected as a tracer dose before tumor biopsy for cell kinetic analysis, and p53 protein accumulation was detected using two antibodies (DO7 and PAb 1801). RESULTS: Antibody DO7 showed the highest and the optimal immunoreactivity. Diploid tumors were found in 27 cases (84%), and the mean potential doubling time (Tpot) was 55 +/- 7 hours for these tumors. Positivity of DO7 (>1%) was demonstrated in 85% of the cases. However, a discrimination level exceeding 20% was required to obtain a significant negative relationship (Spearman's rank correlation coefficient test, P < or = .03) between Tpot and DO7 positivity. At that level, 33% of the tumors remained DO7-positive. The corresponding Tpot was not significantly different from the overall mean. The rates of metastatic disease and survival were not dependent on DO7 immunoreactivity or cancer cell kinetics. CONCLUSION: Accumulation of p53-related proteins is associated with an unrestrained growth of head and neck cancer.
Subject(s)
Carcinoma, Squamous Cell/pathology , Gene Expression Regulation, Neoplastic/genetics , Head and Neck Neoplasms/pathology , Tumor Suppressor Protein p53/genetics , Adult , Aged , Aged, 80 and over , Aneuploidy , Antibodies, Monoclonal , Antimetabolites , Bromodeoxyuridine , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/secondary , Cell Count , Cell Cycle/genetics , Cell Differentiation , Chromogenic Compounds , Coloring Agents , Diploidy , Female , Flow Cytometry , Forecasting , Genes, p53/genetics , Head and Neck Neoplasms/genetics , Humans , Immunoenzyme Techniques , Male , Middle Aged , Neoplasm Staging , Prospective Studies , Statistics, Nonparametric , Survival Rate , Tumor Suppressor Protein p53/immunologyABSTRACT
This study was undertaken to determine whether NK-cells constitute a necessary mediator for the suppression of tumor growth by indomethacin. C57Bl mice with a methylcholantrene (MCG 101) tumor were studied. Indomethacin treatment was provided by daily subcutaneous injections (1 microgram/g body weight). NK-cells were depleted by treatment with a monoclonal antibody to NK1.1. Consecutive indomethacin injections prolonged survival in tumor bearing animals. Indomethacin was equally effective in animals with intact NK-cells as in NK-cell-depleted animals. Further, the MCG cells were apparently insensitive to the lytic activity of NK-cells in vivo. Thus, the clearance of intravenously injected MCG cells from lungs was not affected by depletion of NK-cells in vivo; in contrast, the corresponding clearance of NK-cell-sensitive YAC-1 lymphoma cells was strikingly reduced by the depletion of NK-cells. Our data suggest that NK cells are not a necessary mediator for the suppression of tumor growth by indomethacin.
Subject(s)
Antineoplastic Agents/pharmacology , Indomethacin/pharmacology , Killer Cells, Natural/physiology , Sarcoma, Experimental/drug therapy , Animals , Cytotoxicity, Immunologic , Female , Lymphocyte Depletion , Lymphoma/drug therapy , Mice , Mice, Inbred C57BL , Sarcoma, Experimental/immunologyABSTRACT
Tumor cell kinetics were studied in C57 Bl/J mice with a transplantable sarcoma, MCG 101, exposed to hyperbaric oxygen (HBO2), 2.8 atm abs, 2 hours daily for 9 days or until spontaneous death. The isoenzymatic pattern of lactate dehydrogenase (LDH) confirmed that there was a significant shift toward aerobic metabolism in tumor tissue as well as in the liver and skeletal muscle. Recruitment of cells from the G0G1 state into DNA synthesis was associated with an increased mobilization of substrates for polyamine synthesis in terms of an elevated ornithine decarboxylase (ODC) activity. However, cell cycle turnover in terms of bivariate flow cytometric analysis after bromodeoxyuridine (BrdUrd) injection, final tumor weight, and survival time were not changed compared with the controls. Tumor cell metabolism demonstrated evidence of an unchanged net energy utilization, in that activities (V(max) of phosphofructokinase (PFK) and LDH were not significantly changed. When the tumor-bearing animals were exposed to advanced HBO2 pressure (3.7 atm abs) for 3 h as a single dose, the DNA distribution and growth rate were not changed immediately. However, 3.5 h later we observed a DNA pattern similar to that after repeated HBO2 treatments, 2.8 atm abs, concomitant with a preponderance of cells in the late S-phase, which is consistent with a block at the entry of G2M. We conclude that MCG 101 sarcoma recovers from HBO2 exposure by an accumulation of cells in the S-phase without significant changes of net tumor growth. This may have relevance to clinical radiocurability.
Subject(s)
Hyperbaric Oxygenation , Sarcoma, Experimental/pathology , Animals , Body Weight , Carcinogens , Cell Cycle , Cell Division/genetics , DNA, Neoplasm/metabolism , Female , L-Lactate Dehydrogenase/metabolism , Male , Methylcholanthrene , Mice , Mice, Inbred C57BL , Sarcoma, Experimental/chemically induced , Sarcoma, Experimental/genetics , Sarcoma, Experimental/metabolismABSTRACT
We studied the tumor host response to excessive doses of an anabolic steroid (nandrolone propionate, 2.5 mg 20 g intraperitoneally every second day for 11 days) with respect to body composition and tumor cell kinetics in MCG 101 sarcoma-bearing mice (C57BL/6J) with progressive cachexia. Although survival and food intake were not affected, a significant weight gain was observed that was essentially attributed to water retention. Net protein content was increased only to a minor extent (15%), of which only the liver accounted for a significant part of the body compartments. Hepatic protein accumulation was obviously caused by decreased protein degradation, since hepatic RNA content was unchanged. After anabolic steroid administration, reduced histochemical staining of succinate dehydrogenase was observed in skeletal muscles rich in oxidative type 1 fibers, but it was not different from that of tumor-bearing control animals, which was also confirmed by measurements of citrate synthase and cytochrome c oxidase activities in skeletal muscle and liver tissue. The anabolic steroid had no significant effect on tumor growth in terms of weight progression, energy state, polyamine synthesis rate, cell division rate, and cell cycle cytocompartments. We conclude that anabolic steroid supplementation is not therapeutically beneficial in counteracting progressive weight loss in experimental cancer.
Subject(s)
Cachexia/physiopathology , Nandrolone/analogs & derivatives , Sarcoma, Experimental/pathology , Anabolic Agents/pharmacology , Animals , Body Composition , Cachexia/etiology , Female , Mice , Mice, Inbred C57BL , Nandrolone/pharmacology , Neoplasm Transplantation , Sarcoma, Experimental/complications , Sarcoma, Experimental/metabolismABSTRACT
Tumor-bearing mice with two different locally growing malignant tumors (epithelial like, MCG 101; malignant melanoma, K1735-M2) were used to evaluate the putative role of prostaglandins for survival and local tumor growth in experimental cancer. Daily systemic injections of indomethacin (1 mu g/g bw) were used to block prostaglandin production in normal and T-cell deficient tumor-bearing nude mice. Tumor progression was determined by measurements of tumor weight, DNA-synthesis, cell cycle kinetics in vivo and in vitro (flow cytometry), tumor tissue concentrations of polyamines (putrescine, spermidine, spermine) and tumor tissue gene expression of growth regulating factors (IL-1 alpha, IL-6, TNF alpha, A,B-PDGF, EGF, VEGF, bFGF, TGF beta(3), angiogenin and transferrin receptor). Tumor tissue content of von Willebrandt factor VIII was estimated by immunohistochemistry. Indomethacin had no effect on survival, host nutritional state or local tumor growth in mice bearing the malignant melanoma with low PGE(2) production. In contrast, indomethacin prolonged survival, improved cachexia and decreased tumor growth in mice bearing the MCG 101 tumor with hundredfold higher prostaglandin tumor production, leading to elevated liver and muscle tissue as well as plasma concentrations of PGE(2). Indomethacin inhibited almost completely the high tumor PGE(2) production in MCG tumors, leading to prolonged potential doubling time for tumor growth in vivo, and a trend to decreased tumor tissue concentration of polyamines (spermidine). Indomethacin had no inhibitory effect on tumor cell proliferation in vitro, although PGE(2) production was decreased by 75%. The effect of indomethacin in vivo was independent of T-cells and was observed with similar magnitude irrespective of the number of MCG cells (10(4)-10(6)) implanted or the site of implantation (s.c., i.p., liver, lung, skeletal muscles). Tumor growth inhibition by indomethacin was not intrinsically transferable by tumor cells from indomethacin treated tumor-animals. Tumor expression of mRNA for several growth regulating factors were either increased (IL-6, TNF alpha, GM-CSF, TGF beta(3)) unchanged (EGF, VEGF, PDGF A,B, IL-1 alpha, transferrin receptor) or decreased (b-FGF and angiogenin) (p<0.05) by indomethacin treatment of MCG mice. Decreased tumor content of von Willebrandt factor VIII in combination with an attenuated tumor vasculature were associated with decreased tumor growth (p<0.05). Our results confirm that high tumor production of prostaglandins was related to reduced survival. Tumor prostaglandins probably promote local tumor growth by stimulation of tumor surrounding cells to produce growth factor(s) for tumor angiogenesis including tumor and matrix cell proliferation unrelated to immune cells.