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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We present a technique which allows the detection and chromosomal localization of DNA sequence copy number changes in solid tumor genomes from frozen sections and paraffin embedded, formalin fixed specimens. Based on comparative genomic hybridization and on universal DNA amplification procedures this technique is possible even if only a few tumor cells are available. We demonstrate the feasibility of this method to visualize complete and partial chromosome gains and losses and gene amplifications in archived solid tumor samples.
Hum Mol Genet 1993 Nov
PMID:Molecular cytogenetic analysis of formalin-fixed, paraffin-embedded solid tumors by comparative genomic hybridization after universal DNA-amplification. 828 Nov 55

S16020-2 (NSC-659687) is a new olivacine derivative that is highly cytotoxic in vitro and displays remarkable antitumor activity against various experimental tumors, especially some solid tumor models. Its antitumor activity is notably higher than that of 2-methyl-9-hydroxy-ellipticinium (NMHE) and comparable to that of doxorubicin HCl, although with a different tumor specificity. S16020-2 is being tested in phase I clinical trials. A study of the interaction of S16020-2 with DNA showed that it binds through intercalation between adjacent DNA base pairs, inducing an unwinding of 10 degrees of the double helix. Its DNA affinity is approximately equal to that of NMHE and decreases as a function of the salt concentration, indicating a significant electrostatic contribution to the overall binding free energy. S16020-2 did not interfere with the catalytic cycle of DNA topoisomerase I but stimulated DNA topoisomerase II-mediated DNA cleavage via a strictly ATP-dependent mechanism. The interactions of S16020-2 and NMHE with DNA topoisomerase II in vitro are very similar. Both drugs have the same DNA sequence specificity of cleavage and the same biphasic dose-effect response, and neither drug inhibited the rate of DNA religation. In contrast with these observations, in in vivo experiments, S16020-2 was able to induce topoisomerase II-mediated DNA strand breaks at concentrations 500-fold lower than NMHE. We conclude that DNA topoisomerase II most likely is the cellular target involved in the mechanism of cytotoxicity of S16020-2. Its higher biological activity and potency to induce cellular DNA cleavage suggest the involvement of as-yet-unidentified cellular factors.
Mol Pharmacol 1998 Feb
PMID:S16020-2, a new highly cytotoxic antitumor olivacine derivative: DNA interaction and DNA topoisomerase II inhibition. 946 78

A decrease in the intracellular concentrations of the transcripts for some tumor suppressor genes has been found during murine lung tumorigenesis; for p15INK4b and p16INK4a, this was due to homozygous deletions. We report here a decrease in the mRNA levels of the mutated in colorectal cancer (Mcc) and adenomatous polyposis coli (Apc) genes in mouse lung tumors and some neoplastic cell lines. This was assessed both by northern blotting and reverse transcriptase-polymerase chain reaction of RNA isolated from lung tumors that had been induced by urethane, N-nitrosodiethylamine, or 3-methylcholanthrene in (A/J x C57BL/6) F1 or A/J mice. A reduced amount of both Mcc and Apc messages was also seen when two neoplastic cell lines, a spontaneous transformant (E9) and a line derived from a chemically induced solid tumor (82-132), were compared with two independently derived nontumorigenic cell lines (E10 and C10); E9 was derived from E10, and all of these lines are probably of alveolar type 2 cell origin. A cell line derived from a chemically induced papillary lung tumor probably of bronchiolar Clara cell origin (LM2) had Mcc mRNA levels similar to those of C10 and E10 but reduced Apc mRNA levels. A line (p53-823) derived from a papillary tumor that arose in a mouse with a mutated p53 transgene had a reduced amount of the Mcc gene product only. These differential changes in the relative amounts of Apc and Mcc messages in LM2 and p53-823) cells may serve as useful models for studying the regulation of their expression. Both messages had half-lives of 6-9 h in normal E10 and neoplastic E9 cells, so decreased message stability does not account for these reductions. This is the first report of estimated degradation rates of these mRNAs. Apc and Mcc message content did not vary as a function of growth status of the cell lines. Single-strand conformation polymorphism analysis did not reveal mutations in Apc coding regions known to have a high mutation frequency in human colon tumors. Loss of heterozygosity of Apc and Mcc was not found in tumors that developed in the F1 mice, implying a lack of allelic deletions. These changes in tumor suppressor gene expression may contribute to the development and maintenance of neoplasia in lung epithelium.
Mol Carcinog 1998 Jan
PMID:Decreased expression of the adenomatous polyposis coli (Apc) and mutated in colorectal cancer (Mcc) genes in mouse lung neoplasia. 947 70

Malignant mesothelioma (MM) is a fatal solid tumor of the mesothelium for which there is currently no ameliorating treatment. Using our murine model of this malignancy, which closely resembles the human disease, we have shown that immunotherapy may be of value in the treatment of MM. Because recombinant interleukin-12 (rIL-12) has strong immunomodulatory effects in vivo, we studied the effects of rIL-12 on murine antitumor immune responses, using a nonimmunogenic murine MM tumor cell line (AB1) in vivo. Systemic administration of rIL-12 at the time of tumor inoculation prevented AB1 tumor growth in up to 70% of treated mice, 50% of which were still resistant to AB1 upon rechallenge, indicating that long-term immunologic antitumor effects had been established. This rIL-12-induced effect was dependent on the involvement of both CD4(+) and CD8(+) but not natural killer (NK) cells. Importantly, treatment of established tumors with intralesional injections of rIL-12 resulted in temporary tumor regression or growth inhibition. This effect was dependent on the continuous presence of rIL-12 and correlated with increased numbers of CD4(+) and CD8(+) cells infiltrating the remaining tumor mass. Effective inhibition of tumor growth also occurred when IL-12 was released within MM tumors by coadministration of MM cells that had been stably transfected with the gene for IL-12. These data indicate that IL-12 has potential in the immunotherapy of MM, through gene transfer or local cytokine administration, provided that significant intratumor levels of IL-12 can be achieved for prolonged periods.
Am J Respir Cell Mol Biol 1998 Nov
PMID:Interleukin-12 induces an effective antitumor response in malignant mesothelioma. 980 38

Neovascularisation plays a crucial role in solid tumor growth and metastasis formation. Our previous studies showed that theophylline and theobromine suppressed cutaneous neovascular reaction induced in mice by human blood leukocytes, and lung as well as ovarian cancer cells. Here, we investigated the in vivo effect of theobromine on angiogenic activity of human urothelial cell line HCV-29, v-raf transfected (mouse cutaneous assay), and the in vitro effect of this drug on VEGF, tPA, uPA and PAI mRNA expression in these cells (RT-PCR method). Theobromine suppressed angiogenesis induced in mice by HCV-29-v-raf cells, inhibited VEGF mRNA expression, and had no effect on transcription of uPA and tPA in these cells. HCV-29-v-raf transfectants do not display transcripts of PAI, in the presence or the absence of theobromine.
Int J Mol Med 1998 Dec
PMID:Inhibitory effect of theobromine on induction of angiogenesis and VEGF mRNA expression in v-raf transfectants of human urothelial cells HCV-29. 985 Jul 31

Cyclooxygenases (COXs) are key enzymes in the conversion of arachidonic acid to prostaglandins (PGs) and other eicosanoids. Nitric oxide synthase (NOS) is the enzyme that catalyzes the formation of nitric oxide (NO), a regulator of vascular permeability, from the guanidino nitrogen atom of L-arginine. Two isoforms of both enzymes occur: a constitutive one, Cox-1 and the inducible counterpart Cox-2; also NOS has a constitutive counterparts (cNOS) and an inducible form, called iNOS. The inducible isoforms of both enzymes are of maximum interest. It has been recently shown that cyclooxygenase-2 (Cox-2) is inducible by a variety of stimuli and that eicosanoids, mainly of the PGE2 species, are inducers of basic regulator of angiogenesis, including VEGF/VPF, bFGF, TGF-beta, PDGF, and endothelin-1. In addition, iNOS is inducible by Cox-2. p53 down-regulates the angiogenic process at various levels: it induces thrombospondin-1, a powerful antiangiogenic factor, down-regulates VEGF and NOS and, in addition, down-regulates hypoxia-induced angiogenesis, either inducing apoptosis or enhancing antiangiogenetic factors. It is noteworthy how important the p53 oncosuppressor is in the angiogenesis of solid tumor growth. Cox-2, iNOS and p53 are thus fundamental play-makers of the angiogenic process: they are discussed in detail and a tentative hierarchical cascade is proposed.
Int J Mol Med 1998 Dec
PMID:Cox-2, iNOS and p53 as play-makers of tumor angiogenesis (review). 985 Jul 41

p53 is the most commonly altered tumor-suppressor gene in humans, involved in the development and progression of many diverse forms of human cancer. Although much remains to be learned about the biology of this important growth regulatory gene, sufficient experience has been accumulated with respect to the occurrence and pattern of p53 mutational change to justify molecular diagnostic testing for specific objectives. The authors outline specific concepts for testing with particular emphasis for solid tumor molecular diagnostics. This article focuses on microdissection-based fixed tissue molecular analysis, introducing new considerations related to quality control appropriate for this type of methodology. Given the rapidly evolving nature of molecular genetics, the suggestions provided here should be viewed as flexible. Nevertheless, the concepts are intended to serve as a model for other oncogene/tumor suppressor-gene assays to be developed with the overall purpose of establishing informative integrated histopathologic/genetic molecular diagnostic testing to complement standard microscopic analysis.
Mol Diagn 1998 Sep
PMID:Microdissection-Based p53 Genotyping: Concepts for Molecular Testing. 1008 78

Background: Topographic genotyping is a system of solid tissue molecular analysis designed to correlate microscopic alterations with specific forms of gene damage. In this system, microscopic targets are selected on the basis of cellular and immunohistochemical features. Minute tissue samples corresponding to these targets are precisely removed and analyzed for the presence and specific type of oncogene/tumor suppressor gene damage by means of polymerase chain reaction (PCR) followed by DNA sequencing. In this study, topographic genotyping was used to investigate the prognostic value of p53 and K-ras-2 mutational damage in 204 patients with colorectal cancer from two tertiary care centers. Methods and Results: The intensity and distribution of p53 immunohistochemical staining were correlated with the presence and specific type of mutational change, which resulted in a better understanding of the highly variable nature of p53 immunostaining patterns. Molecular genotype was correlated with the depth and extent of colorectal cancer spread (Dukes B and C) and with survival for follow-up periods of up to 10 years. An algorithm for p53/K-ras-2 genotyping was formulated to include p53 immunohistochemistry and DNA sequencing both of p53 exons 5-8 and of K-ras-2 exons 1 and 2. By using this algorithm, survival was shown to be significantly better in those patients whose tumors manifested normal p53 and K-ras-2 genes (P >.01). Patients with p53-mutated tumors composed a poor prognostic group, characterized by a high rate of intra-abdominal recurrence in the form of peritoneal seeding. Patients with K-ras-2-mutated tumors also composed a poor prognostic group, marked by a tendency for distant hematogenous metastasis involving lung, bone, and brain. Conclusions: Topographic genotyping's molecular diagnostic approach to colorectal cancer combines immunohistochemistry, PCR, and DNA sequencing. It is informative, cost-effective, timely, and yet fully integrated with standard histopathology. The use of this approach by pathologists as a model system for molecular diagnosis of colorectal cancer and other forms of solid tumor malignancy is recommended. As new prognostic molecular lesions are documented for tumor progression and metastasis, topographic genotyping will be well suited to facilitate their clinical application.
Mol Diagn 1996 Jun
PMID:Prediction of Biologic Aggressiveness in Colorectal Cancer by p53/K-ras-2 Topographic Genotyping. 1033 Jan 94

Efforts in metastasis research have centered on the phenotypic and genetic differences between primary site and metastatic site tumors. However, genes that may be used as molecular markers of metastasis in circulating tumor cells remain unidentified. Genes regulating the dissemination and survival of solid tumor cells in the blood, as well as their adaptation to new environments, could be candidates for unique metastatic tumor markers. Differential display (DD) was conducted to compare the blood of tumor-free individuals with the blood of patients with lung, breast, and colon cancers. Twenty-one up-expressed genes in the tumor patient blood samples but none in the tumor-free donor blood samples were identified. Nine of these samples were isolated, amplified, and directly sequenced. A gene AB-1 homologous to a Bcl-2 family member, which might function as an apoptosis inhibitor, was identified. The overexpression of an apoptosis inhibitor in blood from patients with metastatic tumors might be correlated with the capability of solid tumor cells to survive in peripheral blood. This is the first demonstration of the usefulness of comparing control and patient blood samples by DD to find novel potential genetic markers identifying metastasis in the blood. http://link.springer-ny. com/link/service/journals/00020/bibs/5n5p313.html
Mol Med 1999 May
PMID:A strategy to identify genes associated with circulating solid tumor cell survival in peripheral blood. 1039 May 47

Malignant mesothelioma (MM) is a solid tumor of the mesothelium for which there is no curative treatment. MM appears to be sensitive to immunotherapeutic approaches, and one of the most powerful immunomodulatory cytokines with antitumor effects is interleukin (IL)-12. We have previously shown in a murine model of MM that systemic administration of recombinant IL-12 induces a potent anti-MM immune response. The nature and accessibility of MM tumors means that they are suitable candidates for direct cytokine and gene-transfer therapeutic approaches. Therefore, we undertook a study to assess the antitumor effects induced by the local production of IL-12 within MM tumors by transfecting a murine MM line with the genes for IL-12. The IL-12 transfectant (AB1-IL-12) did not produce tumors in normal mice, but did so in athymic nude mice, implicating T cells in the prevention of MM tumor growth. In mixing experiments, paracrine IL-12 production inhibited growth of untransfected MM cells provided that cells producing IL-12 represented more than 50-80% of the inoculum. Furthermore, BALB/c mice previously challenged with AB1-IL-12 were protected against rechallenge with parental AB1 tumor, indicating that the transfectant induced long-term immunity. AB1-IL-12 induced systemic immunity that was effective at reducing the incidence of parental AB1 tumor at a distal site, but its effects were dose-dependent. Though both CD4(+) and CD8(+) cells infiltrated the rejecting tumor, CD8(+) effector cells were essential for protection against development of parental AB1 tumor. This study shows that paracrine secretion of IL-12, generated by gene transfer, can induce immunity against MM that can act locally and also at a distant site. In addition, there was no evidence of toxicity, which has been associated with the systemic administration of IL-12, indicating that this cytokine is a good candidate for experimental gene therapy in MM.
Am J Respir Cell Mol Biol 1999 Sep
PMID:Cytokine gene therapy of mesothelioma. Immune and antitumor effects of transfected interleukin-12. 1046 Jul 52


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