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)

The development of tumor drug resistance is the major obstacle to successful systemic chemotherapy. Therefore, devising methods for reversing drug resistance is a high priority and could lead to significant improvements in cancer treatment. The mechanisms of tumor drug resistance are manifold and are not well understood. The phenomenon of multidrug resistance (MDR) represents the development of resistance to most drugs, regardless of their chemical structure. Several types of MDR are known, for example, the overexpression of a cell membrane glycoprotein (P-170), increased activity of glutathione S-transferase, elevated levels of glutathione (GSH), and alterations in topoisomerase action. A partial reversal of tumor drug resistance has been achieved by the use of competitive inhibitors for the function of glycoprotein P-170, or by the inhibition of GSH synthesis; however, this strategy has not been substantially successful for improving the response of human tumors to clinical therapy. We have recently used electroporation, in conjunction with the cytotoxic drug, cisplatin (cDDP), in an attempt to circumvent drug resistance in cDDP-resistant mouse tumor cells (RIF/Ptr1). Electroporation is the application of a high-voltage electric shock which is known to create transient pores in plasma membranes of cultured cells. Electroporation plus cDDP treatment increased intracellular cDDP concentration and reversed cellular resistance to cDDP-induced cell killing.
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PMID:New approaches to the study of tumor drug resistance. 136 47

Recombinant human tumor Necrosis Factor (rHuTNF) produced dose-dependent cytotoxicity against human ovarian cancer cells, OSC and OMC, obtained from fresh ascites. A combination of rHuTNF and the topoisomerase II inhibitor, Mitoxantrone, produced dose-dependent synergistic cytotoxicity on OSC and OMC cells. When OMC cells were incubated simultaneously for one hour with rHuTNF and Mitoxantrone, increased numbers of DNA single-strands breaks were produced. rHuTNF alone did not induce DNA single-strands breaks. These data are consistent with a role for topoisomerase-linked DNA lesions in the rHuTNF mediated potentiation of killing cells by Mitoxantrone.
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PMID:Augmentation of antineoplastic effects by the combination of recombinant human tumor necrosis factor and mitoxantrone on primary culture of human ovarian cancer cells. 144 98

In the concluding section of this review of cancer destruction by disruption of energy metabolism, the cellular mechanism for interfering with energy production is considered in terms of drug resistance arising independently of previous tumor injury. The occurrence of various degrees of damage to cancerous growths as a consequence of secondary shock is interpreted on the basis of elevated levels of stress hormones, including vasopressin, which have earlier been shown to interfere with energy metabolism in a murine sarcoma. Similarly, the indirect action of various antineoplastic procedures can be related to a role for the endocrine system, with particular reference to vasopressin and inappropriate anti-diuretic hormone secretion syndrome. Multiple drug resistance is also discussed, and the mode of action of the topoisomerase inhibitor doxorubicin is critically examined. The basis of selectivity of disruption of energy metabolism by substances such as hydralazine and L-isoproterenol is discussed from the viewpoint of altered activities of antioxidant enzymes in transformed cells, but these considerations alone are not thought to be sufficient to account for the highly specific nature of the antineoplastic action. Conversely, antioxidant enzymes, more especially those concerned with glutathione metabolism, probably play a major role in multiple drug resistance, although in this respect the case of autoxidative cellular injury awaits attention. Theoretical strategies for the intensification of tumor injury include the aim of prolonging the half-lives of lysophosphatides within damaged tissue. Whereas the clinical application of the principle of tumor destruction through selective disruption of energy metabolism is at present compromised for lack of information, the use of phenothiazines as antineoplastic agents is feasible, and awaits serious exploitation. The relative lack of incapacitating side-effects of phenothiazines should provide an attractive change for the clinical oncologist.
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PMID:Cancer destruction in vivo through disrupted energy metabolism. Part III. Spontaneous drug resistance, selectivity of antineoplastic action, and strategies for intensifying tumor injury. 146 33

Amplification of oncogenes in human tumors has been associated with a poor prognosis. Microscopically visible amplified oncogenes can be located either within chromosomes in homogeneously staining regions, or in an extrachromosomal compartment in double minutes (DMs). The DMs are composed of submicroscopic circular DNA (episomes), which have multimerized to form the microscopically visible DMs. When amplified oncogenes are located in an extrachromosomal location, they are vulnerable to loss from the cell. In this study we have found that the topoisomerase II inhibitor etoposide, in concentrations easily achievable clinically, causes a significant decrease in the number of DM-containing amplified oncogenes in three different human tumor cell lines. The elimination of amplified oncogenes from the cell could be accompanied by less aggressive tumor behavior.
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PMID:Preclinical leads for innovative uses for etoposide. 149 22

Studies of the biological chemistry of most anticancer drugs have revealed their cytotoxicity is expressed after the drugs have entered cells. It is thought that anthracycline antitumor drugs exert their cytotoxicity by entering cells, diffusing into nuclei, and inhibiting topoisomerase II and/or intercalating DNA base pairs. In order to deliver anthracyclines to transferrin (TRF) receptors on the plasma membranes of human tumor cells, we have prepared conjugates of adriamycin (ADR) with human TRF. These TRF-ADR conjugates were found to be stable at low pH and to exert more efficient cytotoxicity than free drug. By using spectrofluorometry, we found that the fluorescence of ADR within the conjugate was quenched by native DNA, demonstrating the presence of conformationally available drug to intercalate with nuclear DNA. However, fluorescence was not quenched when conjugate was reacted with viable cells, indicating that ADR did not reach the nucleus. Results of fluorescence microscopy experiments confirmed that free but not conjugated ADR reached the nuclei of viable cells, and TRF-ADR conjugates labeled with fluorescein isothiocyanate were found to initiate lateral diffusion as determined by patch and cap reactions. The involvement of TRF receptors was shown by flow cytometry experiments in which native TRF inhibited binding of fluorescein-labeled TRF-ADR conjugates. These data suggest that TRF-ADR conjugates mediate cytotoxicity by a mechanism other than intercalation with nuclear DNA. This mechanism, revealed by conjugating ADR to a TRF carrier, may not initiate complications such as cardiotoxicity and drug resistance.
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PMID:Transferrin conjugates of adriamycin are cytotoxic without intercalating nuclear DNA. 157 71

Resistance to 0.8 microM 4'-(9-acridinylamino)methanesulphon-m-anisidide (m-AMSA) was induced by stepwise increases of drug concentration in the human tumor cell line CALc18 originating from a breast adenocarcinoma. The resistant cell line CALc18/AMSA exhibited a resistance index of 10 and a cross-resistance to other topoisomerase II inhibitors. A 3-fold decrease in the levels of topoisomerase II decatenating activity was found in CALc18/AMSA cells. By contrast, topoisomerase I activity was increased by about 3-fold in resistant cells. Interestingly this line was hypersensitive to camptothecin, a specific inhibitor of topoisomerase I. Restriction endonuclease patterns of the topoisomerase I and topoisomerase II loci were found to be identical in CALc18/AMSA and CALc18 with no evidence of gene amplification and rearrangements. Alkaline elution of m-AMSA-treated cells showed that DNA single strand breaks and DNA-protein crosslinks were decreased in CALc18/AMSA. The DNA lesions also obtained in m-AMSA-treated nuclei indicated that no drug uptake modification occurred in both cells. Moreover, the in vitro m-AMSA-induced DNA cleavage per unit of decatenating activity and the inhibitory effects of antitumoral drugs on decatenation were not found to be different with topoisomerase II from sensitive or resistant cells. However the specific cleavage induced by m-AMSA/per mg of crude protein from resistant cells was 2 to 3 times decreased. Multidrug resistance gene transcripts were not detected while levels of acidic glutathione S transferase mRNA were found to be 8 to 10-fold greater in resistant than in sensitive cell line with no amplification of the gene. In conclusion, the diminution of topoisomerase II activity and the increase of both topoisomerase I and acidic glutathione S transferase transcripts could contribute to the resistant phenotype of these breast cancer cells.
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PMID:Study of molecular markers of resistance to m-AMSA in a human breast cancer cell line. Decrease of topoisomerase II and increase of both topoisomerase I and acidic glutathione S transferase. 164 55

DNA topoisomerases are essential nuclear enzymes that are involved in DNA replication. Clinically useful antitumor drugs such as doxorubicin, daunorubicin (anthracyclines), etoposide, teniposide (epipodophyllotoxins), and amsacrine (an aminoacridine) interfere with the function of topoisomerase II and camptothecin and its analogs inhibit topoisomerase I. Some mammalian tumor cells that express resistance to drugs that interfere with topoisomerase I or topoisomerase II have alterations in their respective topoisomerases. In this paper, we review the functions of the topoisomerases, discuss aspects of their cellular regulation, ask how interference with topoisomerase function can lead to tumor cell death, discuss the biochemical features of tumor cells that are resistant to these anti-topoisomerase drugs, and, in the context of drug resistance, we raise questions about how these drugs exert their cytotoxicity.
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PMID:Mechanisms of resistance to drugs that inhibit DNA topoisomerases. 165 18

The effect of combinations of the anthracyclines aclarubicin and daunorubicin was investigated in a clonogenic assay using the human small cell lung cancer cell line OC-NYH and a multidrug-resistant (MDR) murine subline of Ehrlich ascites tumor (EHR2/DNR+). It was found that the cytotoxicity of daunorubicin in OC-NYH cells was antagonized by simultaneous exposure to nontoxic concentrations of aclarubicin. Coordinately, aclarubicin inhibited the formation of daunorubicin-induced protein-concealed DNA single-strand breaks and DNA-protein cross-links in OC-NYH cells when assayed by the alkaline elution technique. Aclarubicin had no influence on the accumulation of daunorubicin in these cells. In contrast, the accumulation of daunorubicin in EHR2/DNR+ cells was enhanced by more than 300% when the cells were simultaneously incubated with the MDR modulator verapamil, aclarubicin, or the two agents combined. Yet the cytotoxicity of daunorubicin was potentiated significantly only by verapamil. The increased cytotoxicity of daunorubicin in the presence of verapamil was completely antagonized when aclarubicin was used together with the MDR modulator. Finally, the effect of daunorubicin on the DNA cleavage activity of purified topoisomerase II in the presence and absence of aclarubicin was examined. It was found that daunorubicin stimulated DNA cleavage by topoisomerase II at specific DNA sites. The addition of aclarubicin completely inhibited the daunorubicin-induced stimulation of DNA cleavage. Taken together, these data indicate that aclarubicin-mediated inhibition of daunorubicin-induced cytotoxicity is due mainly to a drug interaction with the nuclear enzyme topoisomerase II. This antagonism at the nuclear level explains why aclarubicin is a poor modulator of daunorubicin resistance even though aclarubicin is able to increase the intracellular accumulation of daunorubicin in a MDR cell line.
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PMID:Antagonistic effect of aclarubicin on daunorubicin-induced cytotoxicity in human small cell lung cancer cells: relationship to DNA integrity and topoisomerase II. 165 44

Patients with metastatic testis tumors are generally curable using chemotherapy, whereas those with disseminated bladder carcinomas are not. We have compared levels of the nuclear enzyme topoisomerase II in three testis (SuSa, 833K, and GH) and three bladder (RT4, RT112, and HT1376) cancer cell lines which differ in their sensitivity to chemotherapeutic agents. The testis cell lines were more sensitive than the bladder lines to three drugs whose cytotoxicity is mediated in part by inhibiting topoisomerase II: amsacrine; Adriamycin; and etoposide (VP16). The frequency of DNA strand breaks induced by amsacrine was higher (1.5- to 13-fold) in the testis cells than in the bladder cells. The level of topoisomerase II-mediated DNA strand breakage in vitro, measured by filter trapping of amsacrine-induced protein:DNA cross-links, was similarly higher in nuclear extracts from the testis than the bladder cells. Western blot analysis showed a generally higher level of topoisomerase II protein in testis than in bladder cell nuclear extracts. Topoisomerase II protein expression broadly correlated with drug-induced strand breakage in both protein extracts and whole cells, but not with population doubling time. However, despite a 2- to 20-fold increased sensitivity to the different topoisomerase II inhibitors, the testis line 833K had a less than 2-fold higher level of topoisomerase II protein than that of the bladder line RT4. These results indicate that the level of expression of topoisomerase II is an important determinant of the relative chemosensitivity of testis and bladder tumor cell lines, but that additional factors must contribute to the extreme chemosensitivity of testis cells.
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PMID:Relationship between topoisomerase II level and chemosensitivity in human tumor cell lines. 166 Mar 43

The cellular levels of topoisomerase II expression were compared between 10 fresh human tumors and normal tissues to predict the selective anticancer effect of its inhibitors such as adriamycin and VP-16. Topoisomerase II expression was observed in 9 of the 10 tumor tissues (90.0 per cent), 3 of which showed extremely high levels, whereas only 5 of the normal tissues (50.0 per cent) expressed any cellular topoisomerase II and the levels were not higher than those seen in the cancer cells. Six of the 9 positive tumors showed a higher level of topoisomerase II expression than the normal tissues, while the other 3 showed the same level. It can be interpreted from these results that topoisomerase II inhibitors could be effective in cancer patients due to the greater level of this enzyme in tumor cells than in normal tissues. Thus, it is suggested that a comparative analysis of topoisomerase II expression between tumors and normal tissues may be useful for predicting the selective cytotoxicity of topoisomerase II inhibitors in clinical practice.
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PMID:mRNA expression of topoisomerase II in human tumors and normal tissues. 166 37


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