Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activating mutations within the various RAS protooncogenes have been detected in many human and murine hematopoietic neoplasms. Their causal significance has been difficult to assess, partly due to the lack of an animal model directly linking these mutations to hematopoietic neoplasms. A high-titer, helper-free recombinant retrovirus was used to introduce an activated Harvey RAS gene under the transcriptional control of the Moloney leukemia virus LTR into murine bone marrow cells. Eleven of fifteen mice reconstituted with these bone marrow cells developed fatal thymic lymphomas 10-12 week post-transplant. Analysis of DNA and RNA from tumor cells revealed the integrated proviral genome and provirally encoded RAS mRNA respectively. Immunophenotyping and T-cell receptor rearrangement analysis of fresh tumor cells and of cell lines derived from these tumors showed them to be T-cells arrested midway through thymic development. Despite evidence of proviral integration in marrow cells of mice with thymic tumors, no other hematologic abnormalities were detected. The short latency and reproducibility of thymic lymphoma development in mice transplanted with marrow transduced with this retrovirus suggests a direct causal effect of expression of an activated RAS gene in the transformation of a bone-marrow-derived lymphoid progenitor.
 ...
PMID:Introduction of an activated RAS oncogene into murine bone marrow lymphoid progenitors via retroviral gene transfer results in thymic lymphomas. 170 19

The preference of bleomycin, a DNA strand scission antitumor agent, to damage extrachromosomal (episomal) DNA was investigated. These episomes contain transcriptional promoters, replication origins, and oncogenes from MMTV, BPV, and v-Ha-ras and confer a neoplastic phenotype to a mouse fibroblast cell line. We found that bleomycin induces dose-dependent single- and double-stranded cleavage of intracellular episomes as measured by topological forms conversion. Bleomycin scission of episomes occurs within 1 min, and upon drug removal, damaged episomes are as rapidly repaired. By expressing the episomal and genomic damage as breaks per nucleotide, bleomycin has a 30-50-fold cleavage preference for episomal chromatin compared to genomic DNA. The episomes have preferred regions of the bleomycin-induced damage, particularly within the MMTV LTR and BPV origin of replication. Also, it is possible to assess bleomycin action on episomes in solid tumors in mice. Single intravenous injections of BLM into tumor-bearing mice result in single- and double-stranded cleavage of episomes that are dose related and occur within 1 min. Specific double-stranded breaks occur in the same regulatory regions of episomes in solid tumors and in cultured cells. Finally, we observe that damage to the episomal drug target occurs at therapeutic doses in mice.
 ...
PMID:Extrachromosomal chromatin: novel target for bleomycin cleavage in cells and solid tumors. 170 27

Intracisternal A particles (IAPs) are retrovirus-like structures consistently observable in a variety of mouse tumor cells such as myeloma and hybridoma and in early embryonic cells derived from rodents but nothing is known of their infectivity. Mouse IAPs contain a gag-like protein, a reverse transcriptase and a polyadenylated RNA molecule (IAP RNA). DNA sequences complementary to IAP RNA (IAP genome) are interspersedly present in rodent such as mice, rats, Chinese hamsters and Syrian hamsters at several hundred to a thousand copies per haploid genome. Molecularly cloned IAP genomes from two species Mus and Syrian hamster were 6 to 8 kb in length with LTRs of about 0.4 kb long. The nucleotide sequence of the Syrian hamster IAP genome, H18, predicted a typical LTR-gag-prt-pol-env-LTR structure, although many stop codons were present in the region corresponding to env. The comparison of the deduced amino acid sequences of the pol region showed IAP (type A), mouse mammary tumor virus (MMTV) (type B), and squirrel monkey retrovirus (SMRV) (type D) genomes to be closely related. By using a DNA fragment encoding the pol region of the Syrian hamster IAP genome, human endogenous retroviruses termed HERV-K, were cloned from a fetal human liver gene library. Typical HERV-K genome was 9.5 kb in length having LTRs of about 1.0 kb. The HERV-K provirus could encode gag (666 codons), prt (334 codons), pol (937 codons), and env (618 codons) genes. HERV-K was shown to be closely related to types A, B and D retroviruses. The HERV-K genomes are present at about 50 copies per haploid human genome. In several human tumor cell lines, the HERV-K genome was expressed as 8.8 kb poly(A)+ RNA which appeared to be a full-size transcript of this genome. In the human breast cancer cell line T47D, stimulation of HERV-K genome expression was observed following female steroids treatment. In a detailed investigation on the organization of HERV-K proviruses in human genome, we found repetitive sequences homologous to the LTR region of the HERV-K genome. They were about 630 bp in length with an A rich tail at 3' end and found to be a SINE type nonviral retroposon. These elements were present at 4,000 to 5,000 copies per haploid human genome.
 ...
PMID:Molecular biology of type A endogenous retrovirus. 171 Jun 82

Melphalan, a nitrogen mustard derivative of the neutral amino acid L-phenylalanine, was transported across the rat blood-brain barrier by the large (L-system) neutral amino acid transporter in tumor-bearing brain, but no evidence for blood-brain barrier transport by the alanine-serine-cysteine system carrier was obtained in the present study. The ability of melphalan to inhibit phenylalanine uptake was compared in rats implanted with two experimental CNS tumors: the C-6 glioma (a model of primary brain tumors) and Walker carcinoma (a model of metastatic brain tumors). The melphalan concentration which caused 50% inhibition of blood-brain barrier (BBB) phenylalanine uptake (Ki) was 0.49 +/- 0.18 mM in the Walker tumor, compared with 0.46 +/- 0.19 mM in the contralateral control brain. In the ipsilateral hemisphere (Ki = 0.59 +/- 0.25 mM) and contralateral hemisphere (Ki = 0.45 +/- 0.19 mM), drug entry was also via the neutral amino acid transporter. In C-6 gliomas (Ki = 0.77 +/- 0.20 mM) and contralateral control brain (Ki = 0.84 +/- 0.29 mM), melphalan also inhibited BBB phenylalanine transport. A major finding was that, at melphalan concentrations greater than 1.0 mM, BBB permeability of radiolabeled indium (chelated to EDTA) increased in proportion to melphalan concentration. In the contralateral hemisphere of rats implanted with C-6 gliomas, brain extractions of indium-EDTA measured 3 to 4% in the absence of drug, 5 to 6% at 2.5 mM melphalan, and 9 to 10% at 5 mM melphalan. A similar phenomenon was observed in the nontumoral brain regions of rats implanted with Walker carcinoma cells. In normal (nonimplanted) rats, melphalan's inhibition (Ki = 0.29 mM) of phenylalanine and tryptophan (Ki = 0.20 mM) uptake was confirmed, and brain extraction of sucrose (a nonspecific marker which does not penetrate the intact BBB) was observed to increase in proportion to melphalan concentration. We conclude that melphalan not only enters the brain via the neutral amino acid transporter, but at higher concentrations (greater than 1 mM) may open the blood-brain barrier in a nonspecific manner.
 ...
PMID:Melphalan penetration of the blood-brain barrier via the neutral amino acid transporter in tumor-bearing brain. 172 74

We have investigated the action of recombinant human gamma-interferon (rHuIFN-gamma) against human ovarian cancer xenografts growing as ascites or as bulky solid i.p. tumors in nude mice. Both forms of the disease responded to i.p. rHuIFN-gamma with significant increases in mouse survival time, and in 2 of 3 ascitic models the mice were cured of peritoneal disease. The activity of rHuIFN-gamma was dose and schedule dependent, and xenografts derived from 3 different patients showed a heterogeneity of response. Peak i.p. levels of rHuIFN-gamma in nude mice bearing multiple i.p. solid tumors were similar to those found in ovarian cancer patients receiving i.p. rHuIFN-gamma, but clearance was more rapid in the mice. Rat gamma-interferon had no antitumor activity at the same doses and schedules although it had some biological activity in the nude mice. Histological examination of treated tumors revealed increased necrosis and loss of cellular organization with large areas of hypocellular epithelial mucin. These changes were preceded by a fall in tumor tryptophan and a rise in tumor kynurenine. We conclude that rHuIFN-gamma has a direct dose related antitumor effect on ovarian cancer xenografts that is preceded by increased metabolism of tryptophan.
 ...
PMID:Antitumor activity of gamma-interferon in ascitic and solid tumor models of human ovarian cancer. 174 38

Tryptophan depletion observed during induction of indoleamine 2,3-dioxygenase (IDO) in cultured cells has been suggested to involve a mechanism identical to that employed in self-defense against inhaled microorganisms and tumor growth. We recently reported that a dramatic induction of IDO occurred in i.p. transplanted tumor (Meth-A) cells undergoing rejection from allogeneic mice (C57BL/6), and that soluble factor(s) released from infiltrated host cells was responsible for the IDO induction. Here we report on the characterization of the soluble factor. To assay the factor, we used a 35 mm special culture dish (Transwell), which consisted of two wells divided vertically with a membrane (0.4 micron pore). Host cells (mainly lymphocytes) that infiltrated into the transplantation loci were cultured in the upper well, and untreated Meth-A cells in the lower well. With this in vitro system, the membrane-permeable factor, released by the host cells (upper well), induced IDO in the tumor cells (lower well). The culture superna tants, obtained by centrifuging the culture media from the upper and lower wells, contained the IDO inducer. The inducer activity was completely neutralized by the addition of antibody against interferon-gamma (IFN-gamma) but not by antibody against IFN-alpha/beta. The concentration of IFN-gamma in the medium after 1-day culture with a Transwell culture dish was found to be 2-3 U/ml based on the neutralization curve with the antibody. At this concentration, recombinant IFN-gamma induced IDO in Meth-A cells to the same extent as the inducer in the culture medium. These observations indicate that the in vivo factor for IDO induction in the allografted tumor cells is IFN-gamma.
 ...
PMID:Induction of indoleamine 2,3-dioxygenase in tumor cells transplanted into allogeneic mouse: interferon-gamma is the inducer. 177 76

In this paper we describe the use of polymerase chain reaction (PCR) to amplify DNA sequences suitable for studies on the activity of DNA-binding drugs of possible interest in anti-tumor as well as anti-viral therapy. To this aim (a) we amplified by PCR two regions of the HIV-1 genome (one localized within the LTR, the other within the env gene), known to bind nuclear factors and (b) we determined whether different aromatic polyamidines are able to differentially affect the electrophoretic mobility of these HIV-1 PCR fragments. We found that aromatic polyamidines differentially affect the electrophoretic migration of PCR-amplified HIV-1 genomic regions. This differential effect, related to a differential DNA-binding activity, could lead to a differential inhibition of protein-DNA interactions.
 ...
PMID:Effects of aromatic polyamidines on the electrophoretic mobility of HIV-1 genomic regions amplified by polymerase-chain reaction. 181 18

A total of 45 chemicals, including two aromatic hydrocarbons, five aromatic amines, three azo dyes, ten nitroso compounds, three steroids, four tryptophan metabolites and their related compounds, four naturally occurring substances, four pyrolysates of amino acids and ten miscellaneous compounds, were tested for newborn mouse tumorigenesis assay (NMTA). The results of the NMTA were compared with data from 'Survey of Compounds Which Have Been Tested for Carcinogenic Activity', NIH, NCI, USA (SCWHBTCA), and also with data from the IARC Monographs (Vols 1-41), Lyon, France (IARC). Of the 45 chemicals tested by the NMTA, 28 chemicals showed positive results in the NMTA, and the remaining 17 chemicals were found to be negative for tumor development. The correlation of the results between the NMTA and the mouse and/or rat carcinogenesis test starting at young adult age reported in the SCWHBTCA and in the IARC were compared with 37 chemicals tested; the remaining eight chemicals were found only in our NMTA results. It can be concluded that 31 out of 37 chemicals (83.8%) tested by the NMTA showed similar carcinogenic or non-carcinogenic results obtained in either adult mouse and/or rat carcinogenesis tests. The remaining six chemicals showed contradictory results between the NMTA and either adult mouse and/or rat carcinogenesis tests. Those six chemicals were N-hydroxy-4-acetylaminobiphenyl, estradiol, 3-hydroxyanthranilic acid, 3-hydroxy-L-kynurenine, isonicotinic acid hydrazide and phenobarbital. Among the 37 chemicals, 34 were comparable with the results of the adult mouse carcinogenesis test and those of the NMTA. Twenty-nine out of 34 chemicals (85.3%) showed similar results to the adult mouse carcinogenesis test. Contradictory results were obtained with the following five chemicals: N-hydroxy-acetylaminobiphenyl, 3-hydroxy-anthranilic acid, 3-hydroxy-L-kynurenine, isonicotinic acid hydrazide and phenobarbital. There were 35 chemicals which were comparable with the results of the adult rat carcinogenesis test, and 32 chemicals showed the same results as the NMTA (91.4%). Dissimilar results were obtained with the following three chemicals: estradiol, 3-hydroxy-anthranilic acid and phenobarbital. Based on the results presented in this report, it is reasonable to conclude that the NMTA is one of the most useful and reliable methods for detecting tumorigenic or non-tumorigenic chemicals, when a small amount of chemical is available for rodent carcinogenesis test and the duration of the study is limited to 1 year.
 ...
PMID:Evaluation of the newborn mouse model for chemical tumorigenesis. 186 Jan 62

High free tryptophan (F-TRP) plasma levels are found in cancer patients (CP). F-TRP plasma concentrations are affected by the levels of its carrier, albumin (ALB), and free fatty acids (FFA) competing with TRP for ALB binding sites. The lack of correlation between F-TRP, ALB and FFA in CP suggests a tumor-dependent effect on the rise in F-TRP. To verify this hypothesis, F-TRP, ALB and FFA levels were assayed in 12 lung and 16 breast CP susceptible to radical surgery, before and 15 days after surgical removal of the tumor. F-TRP levels significantly decreased after tumor ablation. Since no correlation was found between F-TRP, ALB and FFA variations, it is conceivable that the tumor itself may be responsible for the high F-TRP levels in CP.
 ...
PMID:Increased plasma free tryptophan levels in human cancer: a tumor related effect? 188 65

A derivative of ascorbic acid, 2-O-octadecylascorbic acid (CV-3611), is a strong scavenger of active oxygen species. We examined the effect of CV-3611 on a short-term test of bladder carcinogenesis, using concanavalin A (Con A)-dependent agglutination of isolated bladder epithelial cells. Rats were given 0.01% N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN) for 1 week, and then 5% sodium saccharin or 2% DL-tryptophan or 0.01% BHBN alone or with 0.002, 0.006 or 0.02% CV-3611 for 3 weeks. Treatment with CV-3611 reduced the effects of the bladder tumor promoters sodium saccharin and DL-tryptophan by 48-86 and 65-87%, respectively. CV-3611 also reduced the number of aggregates of bladder epithelial cells from rats treated with BHBN for 4 weeks. These results suggest that CV-3611 has a suppressive effect on rat bladder carcinogenesis.
 ...
PMID:Inhibitory effect of 2-O-octadecylascorbic acid in agglutination assay with concanavalin A; short-term examination of rat urinary bladder carcinogenesis. 190 18


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>