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)

Doxorubicin, cisplatin, and cyclophosphamide are the three drugs most commonly used in the treatment of ovarian cancer, but no effect greater than additivity was observed for any combination of these drugs in the present study. Only a few studies have been reported concerning the degree of their additivity or their best order of sequencing. In our in vitro studies, cisplatin in combination with doxorubicin or 4-hydroperoxycyclophosphamide (4HC) was tested against seven human gynecologic tumor-cell lines in different sequences, using a double-agar layer tissue-culture system. Drug interactions with respect to inhibition of tumor clonogenicity were evaluated by isobologram and fractional survival methods. Doxorubicin and 4HC were sequenced simultaneously and at 1, 6 and 24 h after cisplatin, and cisplatin was sequenced at 1, 6 and 24 h after 4HC. The isobolograms constructed for doxorubicin or 4HC plus cisplatin revealed strict additivity between these agents against ovarian cancer clonogenicity. Both doxorubicin and 4HC showed the greatest additivity when used simultaneously and at 1 h vs 6 or 24 h after cisplatin. Although the mechanisms by which these sequencing effects occur are unknown, these studies provide new leads for the design of clinical trials with combinations of these three agents.
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PMID:In vitro evaluation of cisplatin interaction with doxorubicin or 4-hydroperoxycyclophosphamide against human gynecologic cancer cell lines. 259 4

In this study we evaluated 77 patients with superficial bladder cancer who were treated with either intravesical bacillus Calmette-Guerin (BCG) (44 patients) or doxorubicin hydrochloride (Adriamycin, ADR) (33 patients) for prophylaxis of tumor recurrence after transurethral resection. The estimated actuarial probability of non-recurrence rate at three years for the BCG group was 73.0%, and the actuarial non-recurrence rate for the ADR group was 27.3%; a statistically significant difference (p = 0.0013). A comparison between the two groups was also made according to the patient's background, including whether the tumor was initial or recurrent, solitary or multiple, and the tumor grade. In all areas of the study, except for grade-1 tumors, the BCG group was significantly superior to the ADR group. The efficacy of BCG therapy as a result of different BCG treatment protocol was evaluated for six weekly instillations 1) without further maintenance instillation, 2) followed by 12 months of maintenance, and 3) followed by more than 18 months of maintenance. Long-term maintenance BCG instillation group (more than 18 months) showed the most favorable results, however, the differences were not statistically significant. These results indicate that intravesical BCG instillation was significantly superior to ADR in the prevention of bladder cancer recurrence and that six weekly intravesical BCG instillations may provide adequate prophylactic effects against recurrence of superficial bladder cancers.
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PMID:[Comparative study on prophylactic intravesical instillation of bacillus Calmette-Guerin (BCG) and adriamycin for superficial bladder cancers]. 260 Dec 18

Doxorubicin (DXR) conjugated to murine monoclonal antibodies (MoAb) raised against human breast tumor cells demonstrated a MoAb-specific, molar ratio-dependent in vitro cytotoxicity. These conjugates were prepared on a scale sufficient to allow for subsequent clinical trials (1 to 3 g of MoAb per conjugation reaction). The conjugation reaction proceeded via an N-hydroxysuccinimide (NHS) active ester intermediate of cis-aconityl-DXR (CA-DXR), resulting in a cis-aconitate acid-sensitive linker between the DXR and MoAb. Molar ratios of DXR to MoAb ranged from 40 to 45. The immunoreactivity of conjugated MoAb was only slightly decreased from naked MoAb. When immunoconjugates were incubated with MoAb-reactive tumor cells for 3 hours, specific cell-killing was observed. If the exposure time was lengthened to 18 hours, however, nonspecific killing resulted. Incubation of the immunoconjugate with the nonspecific adsorbant Amberlite XAD-2 caused an average 30% decrease in the DXR-to-MoAb molar ratio, suggesting a population of drug that is tightly but noncovalently associated with MoAb.
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PMID:Immunoconjugates of doxorubicin and murine antihuman breast carcinoma monoclonal antibodies prepared via an N-hydroxysuccinimide active ester intermediate of cis-aconityl-doxorubicin: preparation and in vitro cytotoxicity. 260 16

Reduced intracellular drug retention has been recognized as a major characteristic of multidrug resistance (MDR) phenotype in a number of cell line models and has been associated to overexpression of a P-170 membrane glycoprotein. Although many studies have been performed on MDR cell lines, so far only few data have been presented utilizing fresh human tumor cells, leaving open the question of the relevance of reduction of intracellular drug exposure to clinical drug resistance. We chose to utilize blast cell samples obtained from patients with childhood acute lymphoblastic leukemia (ALL) to study their interaction with Doxorubicin (DX) and Daunorubicin (DN) as representative drugs, evaluating cellular drug uptake by flow cytometry. Aim of the work was to check possible difference of anthracycline fluorescence levels in clinically "potentially sensitive" (15 cases) and "potentially resistant" (11 cases) human leukemic blast cells. For this purpose, leukemic cells derived from peripheral blood of patients were exposed in vitro to DX and DN according to different schedules and analyses by flow cytometry. The calculated fluorescence levels associated with the different anthracycline treatment shows a wide interpatient spreading of values. The mean values in the potentially resistant group did not differ significantly from the mean values of the potentially sensitive group at any considered concentration, suggesting that biochemical mechanisms different from that involved in drug transport are responsible for the outcome of clinical drug resistance in childhood ALL.
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PMID:[Anthracycline resistance: cytofluorometric study on infantile lymphoblastic leukemia]. 263 27

Activation of lymphocytes for proliferation is associated with the appearance of an intracellular factor (ADR) that can induce DNA synthesis in isolated quiescent nuclei. ADR plays a role in the sequence of intracellular events leading to activation for IL-2-mediated proliferation. Because of the nature of the defining assay, the locus of ADR action appears to be near the terminal end of the transduction pathway. Interestingly, although lymphocytes from aged individuals respond poorly to proliferative stimuli, they appear to produce normal to above-normal levels of ADR. In contrast, their nuclei are only poorly responsive to stimulation by ADR. Preparations rich in ADR activity have proteolytic activity as well. In addition, aprotinin, as well as a variety of other protease inhibitors, suppresses ADR-induced DNA synthesis in a dose-dependent manner. ADR activity can be removed from active extracts by absorption with aprotinin-conjugated agarose beads, and can be removed from the beads by elution at pH 5.0. This latter suggests that ADR itself is a protease. However, its endogenous substrate is not yet known. We have also detected an inhibitor of ADR activity in the cytoplasm of resting lymphocytes. This is a heat-stable protein of approximately 60,000 Da. In addition to suppressing the interaction of ADR with quiescent nuclei, the inhibitor can suppress DNA synthetic activity of replicative nuclei isolated from mitogen-activated lymphocytes. Interestingly, these preparations had little or no activity on replicative nuclei derived from several neoplastic cell lines. The resistance of tumor cell nuclei to spontaneously occurring cytoplasmic inhibitory factors such as the one described here may provide one explanation for the loss of growth control in neoplastic cells.
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PMID:Intracellular mechanisms of lymphoid cell activation. 264 67

Doxorubicin toxicity is generally accepted to be free radical-mediated. N-Substituted dehydroalanines (indexed as AD compounds) are capto-dative olefins which react and scavenge free radicals, especially the superoxide anion (O2-) and hydroxyl radical (HO). AD-20, an orthomethoxyphenylacetyl dehydroalanine derivative, decreases the mortality of mice when administered before an acute single dose or multiple non-toxic doses of doxorubicin. Doxorubicin administered to mice induces elevated serum transaminase levels, and the pretreatment of mice with AD-20 decreases significantly these serum enzymatic activities. Preliminary histological examinations suggest that these serum transaminase elevations reflect most likely liver injury. In addition to its cardiotoxicity, doxorubicin induces a severe bone marrow depletion. Although this initial decrease in the peripheral leukocytes induced by doxorubicin is not prevented by the administration of AD-20, it produces a fast recuperation in the white blood cells levels after 1 week, supporting a protective effect at this level. Moreover, the antitumor effect of doxorubicin in L1210 tumor-bearing mice was enhanced when AD-20 was injected before doxorubicin. We postulate that these effects may be related to the free radical scavenging ability of AD-20.
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PMID:Increasing therapeutic effect and reducing toxicity of doxorubicin by N-acyl dehydroalanines. 271 44

To see whether a tumor cell population may contain cells resistant to lymphokine-activated killer (LAK) lymphocytes, cells from a LAK-sensitive melanoma line (Me 665/2) were co-cultured with LAKs. Three sublines were obtained after 1, 2 or 3 immunoselection cycles. Immunoselected (IS) sublines show reduced proliferation, decreased reactivity to the monoclonal antibody (MAb) R24 and appeared morphologically more differentiated in comparison with the parental Me 665/2 line. A progressively reduced sensitivity to LAKs was observed in IS sublines with a more than 8-fold reduction in LAK susceptibility. A reduced complement (C)-mediated lysis was also observed in IS sublines. Since we have previously shown that LAK sensitivity of melanoma cells may be associated with Doxorubicin (Dx) resistance, the sensitivity to Dx was tested in these lines. An augmented sensitivity to Dx was noted in IS sublines as compared with Me 665/2. The differences in LAK susceptibility between the IS sublines and the parental Me 665/2 line remained stable for 2 weeks but declined and disappeared thereafter. These results indicate that (1) a LAK-sensitive tumor line may contain a subpopulation of cells which are significantly less lysed by LAKs; (2) a correlation between LAK sensitivity and susceptibility to C-mediated lysis is also present; and (3) increased sensitivity to Dx is evident in the IS sublines.
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PMID:Generation and partial characterization of melanoma sublines resistant to lymphokine activated killer (LAK) cells. Relevance to doxorubicin resistance. 271 94

We have used monochlorobimane as a quantitative marker by which cells of naturally high or low GSH contents were purified by fluorescence-activated cell sorting (FACS). The cell line chosen for this purpose, MLS, was a human ovarian tumor cell line established from a patient who had received extensive chemotherapy and showed evidence of 'multidrug' resistance. Cells of a specified volume were sorted into subpopulations containing the 1% most dim (low GSH) and 1% most bright (high GSH) cells. With an increasing number of sortings, cell subpopulations emerged with progressively lower (dim) and higher (bright) GSH content as compared to the parent population. After 4 sortings, GSH contents were 10.6 +/- 0.8, 5.1 +/- 0.4, and 7.2 +/- 0.7 X 10(-18) moles/micron3 for MLS/bright, MLS/dim and MLS/parent respectively. The high and low GSH phenotypes were of limited stability reverting to the parent phenotype by the sixth week following the last FACS. Cells with high GSH content were more resistant to adriamycin than cells with low GSH content, for example, at 1 log cell kill MLS/bright was 1.6 fold more resistant than MLS/dim. An ADR resistant variant of the MLS line, designated MLS/ADRR/2, established by twice treating MLS cells with 1 microgram/ml ADR for 2 hr, also showed increased GSH content (1.3-fold) and ADR resistance as compared with the parent line. These results illustrate the possible importance of tumor cell GSH status in determining the response to chemotherapy of a heterogenous population of tumor cells with diverse GSH contents.
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PMID:Isolation by flow cytometry of a human ovarian tumor cell subpopulation exhibiting a high glutathione content phenotype and increased resistance to adriamycin. 271 85

From 1975 to 1986, 26 patients with soft tissue tumors of the extremities underwent a total of 29 perfusions. The cytostatics used were doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH) (19 perfusions), melphalan (two perfusions), and a combination of these agents (eight perfusions). Before perfusion most patients had been treated by surgical excision(s), radiotherapy, or systemic chemotherapy. Of 17 patients perfused because of local inoperable tumor, four showed prolonged complete remission of the tumor mass, stable disease was seen in three, and ten showed progression. The complete remissions observed in three patients with aggressive fibromatosis and in one with lymphangiosarcoma occurred after perfusion with doxorubicin combined with melphalan. Doxorubicin added to the perfusate as the sole cytostatic was not effective. Local recurrence was observed in five of nine patients treated by adjuvant perfusion, always after dubiously radical tumor excision. Toxicity was high, especially in the first few years. Tissue necrosis necessitated amputation in three cases (in two after perfusion with doxorubicin and melphalan and in one after repeated perfusion with doxorubicin only). This complication was no longer seen after adjustment of the dosage and dose distribution of doxorubicin, but the morbidity after perfusion with doxorubicin remained considerable.
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PMID:Results of regional isolation perfusion with cytostatics in patients with soft tissue tumors of the extremities. 274 57

A series of 2-aminoalkyl-5-nitropyrazolo [3,4,5-kl]acridines (pyrazoloacridines) were tested in vitro against a panel of multidrug-resistant cell lines comprising Adriamycin-resistant P388 leukemia, B16 melanoma, and mammary adenocarcinoma 16c. This new class of anticancer agents, particularly the 9-substituted methoxy derivatives, exhibited significant activity against all of the lines tested. The degree of cross-resistance to these compounds ranged from zero to 8-fold in the 138-fold Adriamycin-resistant P388/ADR line and was greatly diminished in the B16/ADR and 16c/ADR lines. Selected pyrazoloacridines were subsequently tested in vivo against B16 and B16/ADR cells established as solid tumors from the tissue culture line and shown to retain a significant degree of Adriamycin resistance. Whereas the B16/ADR line exhibited 2 logs less net tumor-cell kill than the B16 parent in response to Adriamycin treatment, the resistant tumor was completely sensitive to the pyrazoloacridines tested and proved in some experiments to be collaterally sensitive. The favorable activity of the pyrazoloacridines against these Adriamycin-resistant tumor lines points to the potential efficacy of these compounds against multidrug-resistant tumors encountered clinically.
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PMID:Activity of the pyrazoloacridines against multidrug-resistant tumor cells. 275 1


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