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 have been studying the resistance mechanisms of various antitumor drugs and screening substances from natural and synthetic products which overcome resistance. In this paper, we described compounds mainly obtained from our screening systems. I. Circumvention of multidrug resistance (MDR). Lactoquinomycin was discovered from the culture broth of a strain of Streptomyces sp. and it showed preferential growth inhibition against multidrug-resistant L5178 Y cells. The mechanism of action of lactoquinomycin was studied. Another novel antibiotic, resorthiomycin, exhibited not only preferential inhibition against MDR tumor cells but also augmentation of cytotoxicity of several antitumor drugs. As synthetic potentiators, dipyridamole, cepharanthine, AHC-52 and analogs of dihydropyridines were described; all of them were thought to interact with a P-glycoprotein and inhibit active efflux of drugs from tumor cells. SDB-ethylenediamine was unique because it overcame MDR and also potentiates a wide range of antitumor drugs including 5-FU and bleomycin. II. E-64 was found to inhibit the activity of a bleomycin-inactivating enzyme. It potentiated the activity of peplomycin in vitro and in vivo. III. Cadeguomycin was discovered from the culture filtrate of a Streptomyces sp. and it potentiated Ara-C by inhibition of the activity of dCMP deaminase, an Ara-C-inactivating enzyme.
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PMID:[Antitumor drugs and potentiators aiming circumvention of drug resistance]. 168 86

P-glycoprotein (Pgp) has emerged as the central mediator in classic multidrug resistance in model systems in vitro. High levels of Pgp also have been detected in many normal human tissues and tumors; and its role in clinical drug resistance is currently under investigation. Recently significant levels of Pgp were localized to gravid and secretory endometrium; and it was demonstrated that the combination of estrogen and progesterone is sufficient to induce high levels of both Pgp mRNA and Pgp in uterine secretory epithelium. These findings suggest that increased Pgp expression also may be present in hormone-responsive malignancies such as endometrial adenocarcinoma. To determine whether Pgp is expressed in endometrial adenocarcinoma, 36 endometrial adenocarcinomas (grade I [n = 17]; grade II [n = 6]; grade III [n = 13]) were investigated retrospectively by the avidin-biotin-complex immunohistochemical procedure using three murine monoclonal antibodies (MAb) MAb C219, MAb C494, and MAb JSB-1, which recognize spatially distinct cytoplasmic epitopes of Pgp. Seventy-two percent of the tumors showed positive immunostaining with at least one MAb; 67% showed immunostaining with MAb C219, 50% with MAb C494, and 62% with MAb JSB-1. Forty-six percent of tumors were immunoreactive to two and 29% to all three antibodies. Membranous and Golgi/paranuclear type staining patterns were observed. Overall the intensity of immunostaining varied from one sample to another for a given tumor type, and considerable heterogeneity of expression was commonly seen within a given tumor. Strong to moderate immunoreactivity was seen in diffusely infiltrating, adenosquamous, and serous papillary carcinomas. In general, immunoreactivity to MAb C494 was weaker than MAb C219 or MAb JSB-1. Adenomatous and non-neoplastic endometrium adjacent to the tumors displayed strong membranous immunostaining with MAb JSB-1. Endometrial capillaries showed weak-to-moderate immunostaining to all three antibodies. It is concluded that Pgp is commonly expressed in endometrial adenocarcinoma and may be a significant factor responsible for their drug-resistant nature subject to modulation by progesterone.
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PMID:Immunohistochemical detection of P-glycoprotein in endometrial adenocarcinoma. 170 32

Drug resistance has been associated with resistance to NK- and LAK-cell-mediated cytotoxicity. We evaluated this issue in human cell lines, using multiple myeloma cells (8226) and 2 multi-drug-resistant (MDR) sublines selected using doxorubicin (8226/Dox40) and mitoxantrone (8226/MR40). In parallel, we studied the human breast carcinoma cell line series MCF7, MCF7/D40 and MCF7/Mitox. Unlike the sensitive parental cell lines, all 4 sublines display MDR-patterns of resistance, with the P-glycoprotein pump (P-170) detected only in the doxorubicin-selected sublines. Flow cytometric and immunocytochemical analyses showed expression of cellular adhesion molecules ICAM-I and LFA-3, and MHC-Class-I (MCF7/D40 only), to be decreased in the doxorubicin-selected MDR-sublines, whereas expression of CD56 (Leu 19) was strongly up-regulated in 8226/Dox40. Lysis of P-170-positive MDR tumor cells by NK or LAK cells was, however, unaffected by these alterations, suggesting redundancy in effector:target-cell adhesion pathways. Mitoxantrone-selected tumor cells did not display P-170, nor did they show altered expression of cellular adhesion molecules. Their susceptibility to NK or LAK cytolysis was also unimpaired as compared to the parental cell lines. Clinically, these results imply that immunotherapeutic modalities aiming at increased natural killer functions deserve full consideration even in patients who have become refractory to further cytostatic drug treatment.
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PMID:Altered expression of P-glycoprotein and cellular adhesion molecules on human multi-drug-resistant tumor cells does not affect their susceptibility to NK- and LAK-mediated cytotoxicity. 171 Jun 9

Hematopoietic stem cells show reduced staining with a mitochondrial fluorescent dye, rhodamine 123 (Rh-123), which was supposed to indicate decreased mitochondrial activity in these cells. Rh123 and several other fluorescent dyes are substrates for transport mediated by P-glycoprotein (P-gp), an efflux pump responsible for multidrug resistance in tumor cells. We have found that staining of human bone marrow cells with fluorescent dyes is potentiated by P-gp inhibitors and inversely correlated with P-gp expression. P-gp is expressed in practically all hematopoietic progenitor cells, including long-term culture-initiating cells. The highest levels of P-gp among the progenitors are associated with cells displaying characteristics of pluripotent stem cells. These results have implications for stem cell purification and bone marrow resistance to cancer chemotherapy.
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PMID:Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. 171 73

To describe histologic changes associated with chemotherapy response, we reviewed biopsy and resection specimens from 52 patients with locally advanced esophageal or gastric adenocarcinoma who were treated with preoperative chemotherapy, followed by resection. P-Glycoprotein expression in the adenocarcinomas was also determined with the use of antibody C219. Significant changes in morphologic appearance of the tumor between prechemotherapy and postchemotherapy samples was noted in 17 tumors (32.7%). The most frequent changes observed in these 17 tumors were a decrease in tumor cellularity and an increase in dense fibrosis in comparison with the prechemotherapy specimen. In signet-ring cell carcinomas, the intracytoplasmic mucin vacuoles were often smaller after chemotherapy, making tumor cells more difficult to identify. Another finding observed in tumors that showed histologic alteration after chemotherapy was the formation of large mucin pools that contained lymphocytes and macrophages. The remaining 35 tumors showed similar histologic features in prechemotherapy and postchemotherapy specimens. P-Glycoprotein was identified in 15 (29.4%) of 51 specimens after chemotherapy. P-Glycoprotein content of the residual tumors did not correlate with stage, degree of differentiation, or clinically determined chemotherapy response. We concluded that chemotherapy-induced changes in morphology were frequent in patients with upper gastrointestinal tract adenocarcinomas treated with preoperative chemotherapy. These changes should be recognized as they may cause difficulties in both gross and histologic evaluation of the extent of tumor in postchemotherapy resection specimens. The response of adenocarcinomas to this chemotherapy protocol does not appear to be linked to P-glycoprotein expression.
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PMID:Histologic observations and P-glycoprotein expression in gastric and esophageal adenocarcinomas treated with preoperative chemotherapy. 171 59

A new combination of fluorescent dyes (rhodamine 123 and hydroethidine) was used to internally label hybridoma fusion partners. Murine hybridoma 520C9 (recognizing human c-erbB-2) was labeled with hydroethidine. Murine hybridoma 3G8 (recognizing human Fc gamma receptor III) was labeled with rhodamine 123, and verapamil was used to block rhodamine efflux via P-glycoprotein. Viability assays showed little cytotoxicity from these dyes at the concentrations used. The labeled cells were fused with polyethylene glycol, sorted for dual fluorescence on an Epics V cell sorter, and cloned. Hybrid hybridomas producing bispecific antibodies were selected for ability to promote lysis of SK-Br-3 breast cancer cells by human mononuclear cells. Several positive clones were obtained and shown to have a double content of DNA. Bispecific antibody produced by subclone 2B1 was purified by anion exchange chromatography and shown to bind both tumor cells and Fc gamma R III bearing cells. Using two parameter flow cytometric analysis, we were able to measure a 'bridging' effect of this bispecific antibody, which caused formation of complexes between PMNs and SK-Br-3 cells. Either parental antibody could compete with bispecific antibody to block such complexing. This fusion method provides several advantages over other techniques presently used (speed, convenience, low toxicity and automatic exclusion of dead cells) and can be applied to produce other hybrid hybridomas.
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PMID:Selection of hybrid hybridomas by flow cytometry using a new combination of fluorescent vital stains. 171 68

The most consistantly reported alteration of multidrug-resistant carcinoma cells is the overexpression of a membrane glycoprotein, termed P-glycoprotein. In this study we examined whether the strong intrinsic chemotherapy resistance of glial tumors might be related to the expression of the MDR1 gene which codes for P-glycoprotein. Fourteen glial tumors were examined immunohistochemically using the monoclonal antibody C219. In addition, RNA samples of 11 of these tumors were analysed using a sensitive Northern blot assay. P-glycoprotein is expressed in all 14 glial tumors; the number of stained tumor cells, however, varied considerably ranging from 0.3% to 15%. There was no correlation between the number of MDR1-positive cells and the histological malignancy. Varying amounts of MDR1 mRNA were detectable in 7 from 11 examined tumors. The results of our study show that the MDR1 gene is expressed in human glial tumors and suggest that the multidrug transporter may contribute to the clinical non-responsiveness of these tumors to chemotherapy.
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PMID:The multidrug-resistance gene MDR1 is expressed in human glial tumors. 172 31

Previously, we identified P-glycoprotein in primary gastroesophageal adenocarcinomas and in adjacent mucosa. This study is a further investigation of P-glycoprotein expression in adenocarcinomas and benign mucosa. Sixteen resection specimens were studied (seven for gastric adenocarcinoma, seven for esophageal adenocarcinoma, one for adenocarcinoma at the gastroesophageal junction, and one for severe dysplasia in Barrett's esophagus). Multiple samples of tumor and mucosa were submitted according to a specimen diagram. Lymph node and distant metastases were studied when available. P-glycoprotein expression was identified in paraffin-embedded tissues by immunohistochemistry using monoclonal antibody C219 and was scored as the percentage of cells stained. P-glycoprotein was identified in six of 16 resection specimens. Intratumoral variability of C219 score was noted in three resections. No increase in expression was identified in lymph node or distant metastases as compared with primary tumors or in the invasive margin of the tumor as compared to the center. For every case in which tumors expressed P-glycoprotein, it was also diffusely present in all types of benign gastric and Barrett's mucosa, both adjacent to and distant from (up to 8 cm) the tumor. We also studied biopsies from 10 patients with Barrett's esophagus who did not have carcinoma. P-glycoprotein was only focally present in one of the 10 biopsies. Mucosa expressing P-glycoproteins may be the substrate from which a P-glycoprotein positive tumor arises.
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PMID:P-glycoprotein expression in gastroesophageal adenocarcinomas, their metastases, and surrounding mucosa: a mapping study. 172 84

Cyclosporin A (CsA) and FK-506 have similar immunosuppressive activity profiles and cyclophilin-like intracellular targets. Since CsA can reverse the multidrug resistance of tumor cells showing P-glycoprotein-mediated drug efflux, the possible resistance-modulating activity of FK-506 was evaluated in vitro with multidrug-resistant P388 cells and their sensitive parental controls. Higher concentrations of FK-506 than CsA were needed to achieve a similar degree of chemosensitization, suggesting that FK-506 might interact less efficiently than CsA with the P-glycoprotein expressed in multidrug-resistant tumor cells. However, FK-506 was active on a broader range of concentrations than CsA, particularly because of direct cytostatic effects of CsA which appeared at concentrations only slightly higher than those required to show a significant resistance-modulating activity.
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PMID:FK-506 (fujimycin) reverses the multidrug resistance of tumor cells in vitro. 172 25

Several mechanisms of drug resistance have been defined using cell lines selected for resistance in vitro. However, the relevance of these to tumor cell resistance in vivo remains unclear. We established tumor cell lines from biopsies of human sarcomas before and after doxorubicin therapy. One pretreatment sarcoma line, STSAR90, was 6-fold less sensitive to doxorubicin than was a normal fibroblast line, AG1522. The sensitivities of six other sarcoma lines were similar to that of AG1522. STSAR90 cells did not overexpress P-glycoprotein mRNA, by Northern analysis with the pCHP1 complementary DNA fragment. Photoaffinity labeling with the vinblastine analogue N-(p-azido-3-125I-salicyl)-N'-beta-aminoethylvindesine did not show increased P-glycoprotein concentrations. Accumulation of [3H]daunomycin was not decreased in STSAR90 compared with a less resistant sarcoma line, STSAR11, nor was the doxorubicin sensitivity of STSAR90 increased by coincubation with verapamil. Glutathione levels were twice as high in STSAR90 as in STSAR11, and glutathione peroxidase activity was 3.5- to 6-fold higher. This was due mostly to an increase in selenium-dependent peroxidase activity. After exposure to doxorubicin, STSAR90 cells formed only half as much measurable hydroxyl radical as STSAR11, as detected by electron spin resonance spectrometry. Doxorubicin sensitivity was increased in STSAR90 cells when intracellular glutathione levels were reduced by buthionine sulfoximine. These results indicate that multidrug resistance due to P-glycoprotein-mediated drug efflux is not the only mechanism of doxorubicin resistance that occurs in sarcomas and that glutathione peroxidase-dependent detoxification of doxorubicin-induced oxygen radicals may contribute to clinical doxorubicin resistance.
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PMID:Increased glutathione peroxidase activity in a human sarcoma cell line with inherent doxorubicin resistance. 184 55


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