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

We recently demonstrated a correlation between the expression levels of the PKC eta isozyme and the MDR1 or MRP genes in blasts from AML patients, and in primary breast cancers. In order to extend these findings we analysed ovarian cancer cells from 14 ascites aspirates from 8 patients using a cDNA-PCR approach. 5 patients were examined in follow up studies. 4 out of these 5 patients received continuous chemotherapy. The relative increases in MDR1, MRP, LRP or PKC eta mRNA expression levels were monitored. In one of these patients combined significant increase in MDR1, MRP, LRP and PKC was seen. One follow up sample was obtained after chemotherapy was discontinued. In this case significant relative decreases of MDR1, LRP and PKC eta mRNA expression levels were found. Furthermore, a significant positive correlation was determined for the relative mRNA expression levels of MRP and PKC eta. These results point to a multifactorial emergence of MDR in this type of tumor with a possible involvement of the PKC eta isozyme.
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PMID:Expression analysis of protein kinase C isozymes and multidrug resistance associated genes in ovarian cancer cells. 961 8

We investigated the effects of MCNU (methyl-6)3-(2-chloroethyl)-3-nitrosoureido)-6-deoxy- alpha-D-glucopyranoside), a nitrosourea anti-tumor agent developed in Japan, on cell growth and differentiation in five human myeloma cell lines and compared it with relative expression levels of MDR-1 gene. Although 10 microg/ml of MCNU inhibited cell growth in KMM-1 and KMS-5 lines, other three cell lines required 20-40 microg/ml of MCNU to obtain similar growth inhibition. Accumulation up to the G2 phase of the cell cycle was observed in KMM-1 and KMS-5 lines and the cloning efficiency of KMS-5 cells was reduced by MCNU. On the other hand, expression of surface markers on these lines was not altered remarkably except for increased expression of CD38 on KMS-5 cells. However, the effect of MCNU on these cell lines did not correlate to relative expression levels of MDR-1 gene analyzed by RT-PCR. MCNU may inhibit the growth of myeloma cells by the accumulation of these cells up to the G2 phase, but may not affect their differentiation.
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PMID:Effect of the nitrosourea anti-tumor chemotherapeutical agent MCNU on five human myeloma cell lines. 962 26

Tumor-derived p53 mutants can transcriptionally activate a number of promoters of genes involved in cellular proliferation. For this transactivation, mutant p53 does not use the wild-type p53 DNA-binding site, suggesting a mechanism of transactivation that is independent of direct DNA binding. Here we describe our analysis of the domain requirements for mutant p53 to transactivate promoters of the human epidermal growth factor receptor (EGFR), human multiple drug resistance 1 (MDR-1) and human proliferating cell nuclear antigen (PCNA) genes. We also report the identification of a structural domain required for the 'gain of function' property of mutant p53-281G. 'Gain of function' is measured as the tumorigenicity (in nude mice) of 10(3) murine cells expressing mutant p53 constitutively. We have generated internal deletion mutants of p53-281G deleting conserved domains I, II, III, IV and V, individually. We have also generated one deletion mutant eliminating amino acids 100 through 300 that removes four of the five conserved domains (II - V); another mutant, p53-281G del 393-327, deletes the oligomerization and nonsequence-specific nucleic acid-binding domains of p53. For the EGFR and MDR-1 promoters, all these mutants have significantly lower transactivation ability than intact p53-281G. These deletion mutants, however, significantly activated the pCNA promoter, suggesting that the mechanism of transactivation of the PCNA promoter is different from that of the EGFR and MDR-1 promoters. When expressed constitutively in 10(3) cells, p53-281G del 393-327 was found to be defective in inducing tumor formation in nude mice although intact p53-281G was very efficient. Thus, our results suggest that structural domains near the C-terminus are needed for 'gain of function'.
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PMID:'Gain of function' phenotype of tumor-derived mutant p53 requires the oligomerization/nonsequence-specific nucleic acid-binding domain. 967 96

Chemotherapy resistance is a major problem in the management of patients with breast cancer. Clinical resistance of solid tumors such as breast cancer is likely to be multifactorial and heterogeneous. Usually, patients refractory to chemotherapy exhibit resistance to multiple cytotoxic agents of different structure (and often function). A comparable experimental phenomenon has been termed multidnug resistance or MDR. MDR can be caused by various molecular mechanisms. One of these mechanisms is overexpression of MDR1/P-glycoprotein, which cna be expected in around 30-40% of primary and 50% of metastatic breast cancers. Preliminary evidence suggests that P-glycoprotein-positivity is associated with poor treatment outcome in both primary and advanced breast cancer. Studies of MDR reversal in metastatic breast cancer have generally yielded negative results. Recently, however, we found dexverapamil to be able to induce partial remissions to epirubicin in 4/23 patients (17%) with metastatic breast cancer refractory to the same dose and schedule of epirubicin alone. Dexverapamil did not increase the toxicity or the area under the plasma concentration-time curve of epirubicin. More carefully designed and conducted studies are needed to conclusively determine the clinical relevance of various resistance mechanisms in breast cancer and whether chemosensitizers such as dexverapamil or cyclosporins are able to enhance chemotherapy efficacy in this tumor.
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PMID:Chemotherapy resistance in breast cancer. 970 89

P-glycoprotein (P-gp) actively pumps out a number of anticancer drugs, such as epirubicin, from tumor cells. P-gp is also expressed in the small intestine under normal physiological conditions. Inhibition of intestinal P-gp function using MDR reversing agents may enhance the oral bioavailability of some chemotherapeutic agents. Human colon adenocarcinoma (Caco-2) cell line expresses many characteristics of differentiated cells of the normal small intestine. Using Caco-2 as an in vitro intestinal model, the overall goal of the present study was to evaluate the MDR-reversing effects of some commonly used nonabsorptive pharmaceutical surfactants, such as Tween 20, Tween 80 and acacia on the intracellular accumulation of epirubicin by flow cytometry. Tween 20, Tween 80 or acacia all significantly increased intracellular accumulation of epirubicin with the highest enhancing effect for acacia and the lowest for Tween 20. Apart from progesterone, the enhancing effects of surfactants were better than those of non-surfactant MDR reversing agents such as verapamil, trifluoperazine and reserpine. In conclusion, our results demonstrate that progesterone, acacia, Tween 20 and Tween 80 are potent MDR modifiers of epirubicin in Caco-2 at concentrations that could be achieved in vivo. Use of surfactants in excipients may increase the intestinal absorption of some drugs through P-gp inhibition and thus improve drug bioavailability for P-gp substrate.
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PMID:Comparison of effects of surfactants with other MDR reversing agents on intracellular uptake of epirubicin in Caco-2 cell line. 971

Drug resistance, especially in its multiple forms (multidrug resistance, MDR), is a major and difficult problem to resolve in cancer therapy. Certain cytokines might be capable of bypassing this process and here we report on the in vitro effects of Tumor Necrosis Factor alpha, (TNF) on a MDR variant (FLC/DOX) of Friend leukemia. Drug resistance of FLC/DOX is associated with at least two mechanisms, i.e. overexpression of P-glycoprotein and increase in glutathione-related detoxifying activities. Nevertheless, TNF exerts more cytotoxicity in FLC/DOX than in its parental, drug-sensitive, counterpart and this effect is related to the induction of apoptosis. In contrast, Doxorubicin (DOX) never induces apoptosis in FLC/DOX, even when applied at high, fully cytotoxic, concentrations. We have tried to elucidate TNF signaling in FLC/DOX. The results have indicated that in this cell line TNF-triggered apoptosis exhibits some distinct features. It occurs mostly through type I (p55) TNF receptors, probably involves a calphostin-C sensitive protein kinase C activity and requires synthesis of proteins (it is inhibited by actinomycin D or cycloheximide) and of inducible nitric oxide (NO) synthase (it is inhibited by NG-methyl-L-arginine or aminoguanidine). Further, it is not influenced by agents which increase or decrease cell sulfhydryl groups, such as N-acetylcysteine or buthionine sulfoximine, respectively. These steps appeared to be either not or dissimilarly involved in the resistance to DOX of the same cells. In particular, DOX activity was stimulated by calphostin C and buthionine sulfoximine, and reduced by N-acetyl-cysteine. These findings illustrate that TNF may activate fresh cytotoxic pathways in tumor cells which are multidrug resistant, also owing to multifactorial causes.
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PMID:The apoptotic signaling of TNF-alpha in multidrug resistant Friend leukemia cells. 971 11

In tumor specimens such as those from neuroblastoma, ovarian, and lung carcinoma patients, the prevalence of extrachromosomal circular DNA molecules harboring amplified genes has been well established. In some cases, the amplified genes have been identified as oncogenes, and their increased expression appears to contribute to the maintenance and progression of the malignancy. The aim of this study was to investigate the effect of fractionated radiation treatment, given in daily doses similar to those administered clinically, on the stability of extrachromosomal circular DNA molecules in cancer cells. Our studies were conducted with multidrug-resistant KB cells, which harbor extrachromosomal copies of the multidrug resistance gene (MDR1) almost exclusively on circular DNA molecules of approximately 750 and 1500 kb pairs. This size range is representative of extrachromosomal circular DNA molecules that have been shown to harbor amplified oncogenes in vivo. Exponentially growing MDR KB cells were exposed to 1400 and 2800 cGy ionizing radiation administered in 7 and 14 fractions, respectively, at 200 cGy per fraction/day. A statistically significant decrease in MDR1 extrachromosomal gene copy number was reproducibly detected in the irradiated cells compared with unirradiated cells passaged for the duration of the experiment in the absence of radiation treatment. This decrease was accompanied by a reduction in multidrug resistance and in P-glycoprotein levels, as determined by clonogenic dose-response assays and Western analyses, respectively. P-glycoprotein is a multidrug transporter encoded by the MDR1 gene. Fluorescence in situ hybridization studies further determined that extrachromosomal circular DNA loss correlated to the entrapment of these DNA molecules in radiation-induced micronuclei. These results indicate that radiation-induced loss of extrachromosomally amplified genes from tumor cells via their entrapment in micronuclei contributes to the improved therapeutic response observed for some cancers.
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PMID:Fractionated ionizing radiation accelerates loss of amplified MDR1 genes harbored by extrachromosomal DNA in tumor cells. 973 94

Repeated exposures to high doses of chemotherapy are often required to eradicate solid tumors. The success of such high-dose therapy is often limited by the myelosuppressive and toxic effects of these drugs on bone marrow cells and by the intrinsic resistance of the cancer cells to chemotherapy. To test ways of using genetic modification of somatic cells to circumvent both of these problems, we first genetically modified normal bone marrow cells with multidrug resistance-1 (MDR-1) cDNA retroviral vectors to render these cells more resistant to p-glycoprotein-transported agents. Experiments conducted previously in a mouse model in our laboratory (E. G. Hanania et al., Cancer Gene Ther., 2: 251-261, 1995; E. G. Hanania and A. B. Deisseroth, Cancer Gene Ther., 1: 21-25, 1994), which involve transplantation of mouse marrow cells modified with the human MDR-1 cDNA, showed that the majority of the marrow cells of these animals were resistant to repetitive administration of myelotoxic doses of Taxol, a MDR-1-transported drug. Next, to test the effects of genetically modifying marrow cells to make them resistant to chemotherapy, and genetically modifying tumor cells to make them more sensitive to chemotherapy, a mouse breast cancer cell line was transfected with a plasmid expression vector that contained a wild-type p53 chemosensitization transcription unit. Others have shown that restoration of the p53 gene can lead to decreased proliferation, reduced tumorigenicity, and increased sensitivity to chemotherapy-induced apoptosis. In this animal model, the simultaneous use of both chemoprotection and chemosensitization vectors, which provided protection of the normal cells to the chemotherapy and at the same time sensitized the tumor cells to the toxic effects of the chemotherapy, resulted in levels of in vivo tumor reduction that were not possible when either genetic chemoprotection of marrow cells or chemosensitization of tumor cells was used alone. These data should be of interest to those who are studying ways of using genetic modification to improve the outcome of established chemotherapy treatment programs for solid tumors.
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PMID:Simultaneous genetic chemoprotection of normal marrow cells and genetic chemosensitization of breast cancer cells in a mouse cancer gene therapy model. 981 84

The human multidrug resistance protein (MRP1) causes drug resistance by extruding drugs from tumor cells. In addition to an MDR-like core, MRP1 contains an N-terminal membrane-bound region (TMD0) connected to the core by a cytoplasmic linker (L0). We have studied truncated MRP1 versions containing either the MDR-like core alone or the core plus linker L0, produced in the baculovirus-insect (Sf9) cell system. Their function was examined in isolated membrane vesicles. Full-length MRP1 showed ATP-dependent, vanadate-sensitive accumulation of leukotriene C4 and N-ethylmaleimide glutathione. In addition, leukotriene C4-stimulated, vanadate-dependent nucleotide occlusion was detected. The MDR-like core was virtually inactive. Co-expression of the core with the N-terminal region including L0 fully restored MRP1 function. Unexpectedly, a truncated MRP1 mutant lacking the entire TMD0 region but still containing L0 behaved like wild-type MRP1 in vesicle uptake and nucleotide trapping experiments. We also expressed the MRP1 constructs in polarized canine kidney derived MDCKII cells. Like wild-type MRP1, the MRP1 protein without the TMD0 region was routed to the lateral plasma membrane and transported dinitrophenyl glutathione and daunorubicin. The TMD0L0 and the MRP1 minus TMD0L0 remained in an intracellular compartment. Taken together, these experiments strongly suggest that the TMD0 region is neither required for the transport function of MRP1 nor for its proper routing to the plasma membrane.
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PMID:Functional multidrug resistance protein (MRP1) lacking the N-terminal transmembrane domain. 982 94

The C-aromatic taxoids were synthesized to develop effective inhibitors against drug efflux mediated by p-glycoproteins. Among those tested using multi-drug resistant tumor cells (2780AD), the benzoate 11 exhibited significant activity as potent as verapamil, a well-established MDR reversing agent.
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PMID:Synthesis of C-ring aromatic taxoids and evaluation of their multi-drug resistance reversing activity. 987 57


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