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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An important source of endogenous oxygen radicals are phagocytic cells such as neutrophils and macrophages. The human leukemia cell line HL-60 can be induced to differentiate into a neutrophil-like cell population. Among the properties of these differentiated cells is the ability to produce reactive oxygen species when stimulated by tumor promoters. Mutagenesis induced by HL-60-generated free radicals was assessed using the M13mp2 forward mutation assay. Single-stranded M13mp2 DNA was coincubated with phorbol ester-stimulated HL-60 cells, after which mutations were scored by transfecting the DNA into SOS-induced Escherichia coli. The mutation frequency was increased 6-fold above background in DNA incubated with HL-60 cells. The majority of the mutations were single-base substitutions. However, approximately 6% of the mutations were tandem double substitutions that occurred in runs of adjacent cytidines. Overall, the mutations were clustered at apparent "hot spots," many of which were similar to sites seen using iron to generate oxygen radicals. These results suggest that human cells able to produce oxygen radicals in response to tumor promoters might play a significant role in the generation of tumors.
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PMID:Mutagenic specificity of oxygen radicals produced by human leukemia cells. 131 Jun 39

Neuroblastoma is among the most common malignancies of childhood. Despite greatly improved therapy for some pediatric tumors, the prognosis for children with metastatic neuroblastoma has not changed significantly in the past 10 years. With conventional chemotherapy, radiation therapy, and surgery, children with metastatic neuroblastoma have a 20% long-term survival rate. We have pursued novel chemotherapeutic approaches to neuroblastoma that target the neurotransmitter receptors on the surface of these cells. Specificity for these neural crest tumor cells is effected by (1) selective protection of normal neuronal elements from toxicity, or (2) selective potentiation of toxicity for neural tumor cells. In the first instance, the oxygen radical-generating neurotransmitter analogue 6-hydroxydopamine is used as a neural crest-specific toxin. Normal neural crest cells are protected from this toxicity by oxygen radical-scavenging analogues of the compound WR2721, which is specifically taken up by nonneoplastic cells. In the second instance, neocarzinostatin, an antineoplastic natural product that must be activated by thiol groups to be toxic, is used in conjunction with 6-mercaptodopamine, a thiol-containing compound that gains specific entry into neural crest cells by virtue of its neurotransmitter-like structure. We have found that neocarzinostatin induces morphologic differentiation of neuroblastoma cells, and we are also currently characterizing the biochemical accompaniments of this morphologic change.
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PMID:A neurologist's approach to neuroblastoma. 131 58

Exposure of certain photoactive dyes to light prior to their use in biological systems (preactivation) has been shown to result in formation of long-lived cytotoxic photoproducts. The cytotoxic species responsible for the biological activity of preactivated merocyanine 540 (pMC540) appears to be a hydroperoxide generated by oxidation of ground-state dye by singlet molecular oxygen, formed via energy transfer from triplet excited-state dye to oxygen. A positive correlation (r = .93) exists between the levels of hydroperoxides and percent of tumor cells killed upon exposure to pMC540. Exposure of bovine serum albumin (BSA) (0.5 mg/mL) to pMC540 (0.2 mg/mL-1 mg/mL) results in loss of tryptophan fluorescence and 345 nm emission, suggesting a probable role of either hydroxyl (.OH) or .OH + superoxide (O2-). Polyacrylamide gel electrophoresis indicates fragmentation of treated BSA. Aggregation of pMC540-treated BSA is not detected. Bityrosine production is not observed. A dose-dependent decrease in BSA solubility is observed in treated samples, suggesting an increase in hydrophobicity. Amino acid analysis of BSA treated with pMC540 shows loss of some amino acids residues. The data presented here suggest that photoproducts of MC540 derived via the process of preactivation may mediate their effect (at least in part) by reactive oxygen species.
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PMID:Protein damage by photoproducts of merocyanine 540. 131 27

Bovine papillomavirus (BPV) DNA-transfected C3H/10T1/2 cells respond to tumor promoters by enhanced production of transformed foci. Vanadate, a suspected carcinogen, is a mitogen, generates active oxygen species and alters phosphorylation of proteins. We investigated whether vanadate would enhance transformation of BPV DNA-transfected C3H/10T1/2 cells. Transformed foci in BPV DNA transfected C3H/10T1/2 cells exposed continuously to vanadate for 21 days increased in a dose-dependent manner to 50-fold at 4 microM vanadate. This increase was not due to enhanced uptake of BPV DNA post transfection. Neither catalase nor superoxide dismutase inhibited the vanadate-mediated increase in transformed foci but this does not necessarily rule out the involvement of intracellular active oxygen species. At vanadate concentrations greater than 6 microM, cells lost adherence to the Petri plates. We conclude that vanadate is capable of enhancing BPV DNA-mediated cell transformation. Possible mechanisms may involve active oxygen species or altered patterns of protein phosphorylation.
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PMID:Vanadate enhances transformation of bovine papillomavirus DNA-transfected C3H/10T1/2 cells. 131 48

Mechanistic details of the interaction of 1,10-phenanthroline and its copper complex with Ehrlich ascites tumor cells were examined, using inhibition of cell proliferation, DNA breakage, and increased membrane permeability as indices of cellular damage. The metal chelating agent, 1,10-phenanthroline (OP), the 1:0.5 complex of 1,10-phenanthroline and CuCl2 [(OP)2Cu], and CuCl2 inhibited growth of Ehrlich ascites tumor cell monolayers during 48-h treatments by 50% at about 3.5, 2, and 70 nmol/10(5) cells/mL, respectively. (OP)2Cu at 10 nmol/10(5) cells also enhanced uptake of trypan blue dye during 6 h of treatment, while dye uptake in OP- and CuCl2-treated cells remained similar to controls. DNA breakage, measured by DNA alkaline elution, was produced during 1-h treatments with (OP)2Cu at drug/cell ratios similar to those producing growth inhibition. Copper uptake was similar for both (OP)2Cu and CuCl2. Electron spin resonance (ESR) spectroscopy suggested that cellular ligands bind copper added as (OP)2Cu or CuCl2 and then undergo time-dependent reductions of Cu(II) to Cu(I) for both forms. Inhibition of (OP)2Cu-induced single-strand scission and trypan blue uptake by scavengers of activated oxygen is consistent with participation of superoxide and H2O2 in both processes. In contrast, superoxide dismutase (SOD) did not reduce the magnitude of the fraction of cellular DNA appearing in lysis fractions prior to alkaline elution of (OP)2Cu-treated cells. Dimethyl sulfoxide (DMSO) inhibited uptake of trypan blue dye but did not inhibit DNA strand scission produced by (OP)2Cu. Thus, multiple mechanisms for generation of oxidative damage occur in (OP)2Cu-treated cells. Growth inhibition produced by OP or (OP)2Cu, as well as the low levels of strand scission produced by OP, was not reversed by scavengers.
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PMID:Interactions of 1,10-phenanthroline and its copper complex with Ehrlich cells. 131 48

Between 1974 and 1989, 49 patients with histologically confirmed malignant fibrous histiocytoma received postoperative radiotherapy at the Mallinckrodt Institute of Radiology for primary (41) or recurrent (8) disease. Median age of the patients was 63 years, and the median follow-up period was 41 months. Patients were grouped according to the 1988 AJC staging classification: stage IA (one patient), stage IIA (4 patients), stage IIB (9 patients), stage IIIA (15 patients), stage IIIB (18 patients), and stage IVA (2 patients). Eight tumors (16%) were in the pelvis, 8 (16%) in the trunk, 4 (8%) in the head and neck, and 29 (60%) in the extremities. Primary surgical procedures included incisional biopsy (4 patients), excisional biopsy (19), narrow margin excision (14), wide local excision (9), and removal of the entire compartment (3). Based on pathology reports, the margins of resection were classified as positive in 23 (5 gross, 18 microscopic), 5 close, 11 negative, and 10 unknown. Patients were irradiated with shrinking field technique; the median radiation dose was 6000 cGy, with more than 95% of patients receiving at least 4500 cGy. In addition, seven patients received postoperative chemotherapy. The 5-year overall survival rate was 62%, disease-free survival 64%, local control 68%, and freedom-from-distant metastasis 85%. Thirteen patients had local recurrences, with greater than 75% recurring within 3 years. Sites of local recurrence were as follows: trunk (3), pelvis (3), lower extremities (4), and head and neck (3). There appears to be a correlation of local failure with positive surgical margin: of 23 patients with positive margins, 9 (39%) had local recurrences, whereas 1 of 11 patients (9%) with negative margins had local recurrence. Three of 13 patients with persistent or recurrent disease were salvaged by additional treatment, rendering ultimate local control in 80% (39/49). Thirty-four of 36 patients with local control obtained good to excellent function. Two patients were found to have grade 3 complications: 1 patient had edema of the extremity, and the other developed necrotic skin ulcer that was successfully treated with hyperbaric oxygen. Five patients developed distant metastases, with 80% occurring within 2 years. In summary, adequate but conservative surgery with postoperative radiotherapy for malignant fibrous histiocytoma can achieve local tumor control as well as preservation of functional limbs with acceptable morbidity in a large proportion of patients.
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PMID:Postoperative radiotherapy for malignant fibrous histiocytoma. 131 28

Several studies have indicated a correlation between the presence of inflammation and the development of cancer. The aim of our study was to determine if pulmonary neutrophils could transform the proximate respiratory carcinogen (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-diol), to an ultimate carcinogenic metabolite via myeloperoxidase (MPO). To test this hypothesis, virus-free male DBA/2 mice were exposed by inhalation to the Gram-negative bacteria Proteus mirabilis for 1 h. For various time points post-exposure, bronchoalveolar lavage (BAL) was performed to determine total and differential cell counts, cellular MPO activity and production of superoxide. Twelve hours after the exposure, cellular activity of MPO as well as percentage and total number of polymorphonuclear leukocytes peaked and declined thereafter. At this same time point, cells from BAL exhibited increased release of superoxide, as measured by reduction of cytochrome c, after addition of soluble or particulate stimuli, 12-O-tetradecanoylphorbol-13-acetate (TPA) or opsonized zymosan respectively. These cells also elicited biotransformation of B[a]P-7,8-diol as evidenced by enhanced B[a]P-7,8-diol-derived chemiluminescence, tetraol formation and covalently bound adduct formation to exogenous DNA upon addition of TPA or opsonized zymosan. Moreover, the cell-free BAL fluid of infected mice contained substantial MPO activity in comparison to that of uninfected animals. Also, MPO enhanced the binding of B[a]P-7,8-diol to lung DNA in vitro. Unlike previous work emphasizing the potential roles of oxygen free radicals in tumor promotion, our results indicate a role of neutrophilic MPO in the initiation of carcinogenesis.
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PMID:Myeloperoxidase-enhanced formation of (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene-DNA adducts in lung tissue in vitro: a role of pulmonary inflammation in the bioactivation of a procarcinogen. 132 50

The effect of the oxygen concentration on the rate of oxygen consumption by 786 and TA3 ascites tumor cell lines has been determined under steady-flow conditions with a membraneless fast-responding O2 electrode and using ascorbate and N,N,N',N'-tetramethyl-p-phenylenediamine as electron donors. The reaction was initiated by rapid injection of O2 into anaerobically incubated test system. The time-dependence of the intact cell respiration showed three distinct phases; an early very fast but short duration phase, a subsequent slow phase that prevailed for most of the reaction period and a third phase which preceded the reestablishment of anaerobiosis. Kinetic analysis of the reaction indicated a linkage between the catalytic efficiency and the transmembrane electrochemical potential. The rates of O2 uptake, obtained in the presence of both protonophores and ionophores, were monotonic and pseudo-first order over 90% of the course of O2 consumption. Extrapolation of the observed rates to zero time, at which zero delta mu H+ and thus constant flow prevails, was used to calculate the oxygen concentration for the half-maximal respiratory rate, which was found to be in the range 1.55-2.10 microM O2. No noticeable variation in the value of this kinetic parameter was found between the two cell lines used. Possible reasons for discrepancies in published reports on the oxygen dependence of the cytochrome c oxidase activity in various mitochondrial and reconstituted systems are discussed.
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PMID:The oxygen dependence of the mitochondrial respiration rate in ascites tumor cells. 132 61

Evidence is presented that the nitroxide free radical, TEMPO, at concentrations commonly used to prevent oxidative damage, increases the intracellular hydrogen peroxide concentration. To investigate the origin of this increased hydrogen peroxide concentration, we have incubated various human tumor cell lines with compounds interfering with the generation of active oxygen metabolites. Sodium azide, inhibitor of the respiratory chain, the iron-chelating agent desferrioxamine, superoxide dismutase and catalase had no effect on the hydrogen peroxide concentration. Metyrapone, inhibitor of the cytochrome P450 system, was demonstrated to decrease, but not completely prevent, the hydrogen peroxide production. N-ethylmaleimide, a sulphydryl-bond alkylating agent, was able to completely prevent the increased hydrogen peroxide production. We conclude that, by increasing the cellular hydrogen peroxide concentration, TEMPO exerts a pro-oxidant effect. This increase in hydrogen peroxide production seems to be mediated by the induction of oxidase activity in the cytochrome P450 system, but other cellular systems involved in electron transport may also play a role.
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PMID:Increased hydrogen peroxide concentration in human tumor cells due to a nitroxide free radical. 132 9

Several clinical trials have been reported using Fluosol and oxygen breathing as an adjunct to radiation. Theoretical considerations and animal experiments, however, indicate that a combination of perfluorochemicals and hyperbaric oxygen (HBO) increases tumor oxygenation and radiation response to a greater extent than is seen either with a perfluorochemical and normobaric oxygen or with HBO alone. This is the first report of a pilot study of the use of Fluosol and HBO with radiation in humans. Twenty patients with anaplastic astrocytoma or glioblastoma multiforme were treated in a phase I trial of radiation with Fluosol and HBO at three atmospheres. Total Fluosol dose was escalated from 42 ml/kg in six courses to 80 ml/kg in four courses. Patients were irradiated in an HBO chamber with 600 cGy weekly fractions following Fluosol administration. Sixteen patients completed treatment; no interruption was necessitated by treatment toxicity. The addition of Fluosol/HBO did not increase the incidence of HBO related toxicities. No significant chronic toxicities were seen. This pilot study demonstrates that Fluosol and HBO can safely be used as an adjunct to radiation in the treatment of human tumors.
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PMID:Fluosol and hyperbaric oxygen as an adjunct to radiation therapy in the treatment of malignant gliomas: a pilot study. 132 43


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