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)

Taxol and cisplatin are the two most effective agents discovered to date for treating advanced-stage cancer of the ovary. Learning how best to combine these agents is the focus of preclinical and clinical studies conducted at a number of institutions. Taxol's effect on cellular sensitivity to cisplatin was studied in paired cisplatin-sensitive A2780 and cisplatin-resistant A2780/CP70 human ovarian cancer cell lines. Cisplatin growth curves were generated under conditions of specific sequencing with Taxol, and IC50s (concentrations at which growth is inhibited to 50% of control) for cisplatin were obtained and compared. Taxol was used at an IC10 dose in all experiments. Taxol treatments were for 24 hours and cisplatin treatments were for 1 hour in all experiments. Dimethyl sulfoxide (DMSO) was the diluent for all Taxol stock solutions. Separately, the effects of Taxol and DMSO on cisplatin cellular accumulation were measured. End points reported include measures of cytotoxicity and Taxol effects on cisplatin cellular accumulation. Using a microculture tetrazolium assay, cisplatin growth curves were obtained under the influence of Taxol, at a Taxol dose of 3 nM for both cell lines. DMSO alone had no effect on tumor cell growth. In A2780 cells, the influence of Taxol on cisplatin cytotoxicity was modest, whereas cisplatin-induced cell kill was augmented 1.5-fold when cisplatin was given immediately after Taxol. In A2780/CP70 cells, Taxol augmented cisplatin-induced cell kill by 30-fold when cisplatin was given immediately after Taxol; 75-fold when cisplatin was given 24 hours after completion of Taxol; and 19-fold when cisplatin was given 48 hours after completion of Taxol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Taxol effect on cisplatin sensitivity and cisplatin cellular accumulation in human ovarian cancer cells. 791 34

The cytotoxic effects of Taxol and/or ionizing radiation were evaluated in four human tumor cell lines. The recognized antimicrotubular effects of the drug leading to transitory accumulations of cells in the G2/M phase of the cell cycle, the most radiosensitive phase of the cycle, prompted this assessment of the potential for Taxol to function as a cell-cycle, phase-specific radiosensitizer. Taxol alone was cytotoxic to all four cell lines at low (< 25 nM) concentrations. A Taxol concentration of 10 nM for 24 hours led to 48, 15, 8, and 4.4% of cells retaining clonogenic potential for melanoma, two cervical carcinomas, and astrocytoma, respectively. There were significant Taxol concentration-time-dependent differences in response between the cell lines. Cell lines also showed significant differences in their responses to ionizing radiation. Combined treatment resulted in a demonstration of radiation sensitization with the astrocytoma and melanoma cell lines but not with the cervical carcinoma cell lines. Sensitizer enhancement ratios at the 10% cell survival level were 1.8 for 10 nM Taxol for 24 hours with the astrocytoma cells and 1.2 for 40 nM Taxol for 24 hours with the melanoma cells. The cervical carcinoma cell lines showed an additive effect for radiation and Taxol at all drug concentrations; that is, combined treatments elicit an additive or supra-additive response with, however, no simple relationship between Taxol concentration, Taxol time of treatment, and radiation dose in optimizing cytotoxic effectiveness. Combined modality treatments using relatively low concentrations of Taxol and ionizing radiation can result in an enhanced response and, at the least, an additive response, which could be advantageous in a clinical setting.
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PMID:Taxol and radiation. 791 35

Taxol, a microtubule-stabilizing agent, has been shown to have antineoplastic activity against various tumors. In addition, it has been shown that taxol resembles bacterial lipopolysaccharide in its ability to activate macrophages. Recently we have shown that lipopolysaccharide induces the expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) in murine B-cell lines. In light of the similarity of taxol and lipopolysaccharide in their effects on macrophages, we tested whether taxol could also induce the expression of GM-CSF in B-cell lines. In the present study we used the murine B-lymphoma cell line M12.4.1. In unstimulated cells, no GM-CSF mRNA was detected, whereas in taxol-stimulated stimulated cells at a concentration of 30 microM, GM-CSF mRNA was induced 4-8 h after stimulation. This induction of GM-CSF mRNA was down-regulated by 10 ng/ml of interleukin 4. Actinomycin D chase experiments revealed that interleukin 4 did not affect the half-life of the taxol-induced GM-CSF cytoplasmic mRNA, nor did it alter GM-CSF gene transcription. Polymerase chain reaction analysis of nuclear RNA, utilizing probes specific for sequences in the first intron of GM-CSF, indicated that taxol enhances accumulation of nuclear precursor RNA and that interleukin 4 decreases this accumulation. The present study shows a novel activity of taxol in inducing the release of the hematopoietic growth factor GM-CSF from B-cells. Since GM-CSF is known to recruit macrophages and enhance their cytotoxicity against tumor cells, our observations suggest that part of the known antitumor activity of taxol may be due to synergistic effects of GM-CSF activity together with direct cytotoxic actions through microtubule stabilization.
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PMID:Taxol induces the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor in murine B-cells by stabilization of granulocyte-macrophage colony-stimulating factor nuclear RNA. 791 12

In the continuous presence of Colcemid, the mitotic index in cultures of nine human tumor cell lines began to increase immediately upon addition of the drug. For 12 human normal (nontumorigenic) cell lines, the mitotic index did not begin to increase for some 2 to 3 h after the addition of Colcemid. The effect was independent of whether the cells were of fibroblast or epithelial origin and occurred over a 1000-fold range of Colcemid concentrations. No such differential effect was seen with single concentrations of either Taxol or nocodazole, but a similar delayed effect was seen for two concentrations of vinblastine. These observations suggest a fundamental difference between human normal and human tumor cells involving a cell cycle checkpoint in G2, about 1 to 2 h before mitosis.
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PMID:Cell cycle arrest by Colcemid differs in human normal and tumor cells. 791 97

The incidence of ovarian cancer has been increasing gradually over the last 25 years. The presenting symptoms are non-specific and, in many cases, there is extensive intraabdominal spread at the time of diagnosis. Diagnosis is based on abdominal ultrasonography followed by laparotomy for tumor classification and extensive excision. Assay of CA125 can be a useful diagnostic tool for post-menopausal women, and for determining the response to treatment. Routine screening for ovarian cancer is not feasible. The most important prognostic factor is tumor extension. In early stages, chemotherapy does not improve the prognosis in "low-risk" patients, and its value in high-risk patients remains to be determined. In patients with advanced-stage ovarian carcinoma, platinum derivatives are the reference drugs. The high toxicity of cisplatin has led to the development of carboplatin, which has similar activity but virtually no nephrotoxicity, neurotoxicity or ototoxicity. Carboplatin is currently considered as the cytostatic drug of choice, as it can be given at higher doses which may improve the survival time. The possible indications for intraperitoneal chemotherapy remain to be determined. Secondary laparotomy should not be used, except in clinical trials. Taxol (paclitaxel), a new cytostatic agent that prevents mitosis through an original mode of action, is currently undergoing evaluation.
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PMID:[Epithelial cancer of the ovary: current data]. 791 18

Tumour cells are more heat sensitive than corresponding normal cells but the reasons for this are poorly understood. Here we report that induction of heat shock proteins was associated with a down-regulation of the metastasis associated mts1 gene in BL6-B16 murine melanoma cells, and the heat-resistant HTG variant of the BL6 line. Melanocyte stimulating hormone, which does not affect B16 cell proliferation but upregulates mts1 expression, only marginally enhanced heat shock protein expression in F1 cells as determined by immunohistochemical methods. Retinoic acid, which inhibits cell proliferation and down-regulates the mts1 gene, reduced heat shock protein expression in the ML8-B16 variant line. This suggests that the changes in the heat shock protein expression reported here may be cell proliferation related. Heat shock proteins are known to stabilize microtubules, whereas mts1 has been implicated in their depolymerization. Taxol, which stabilizes microtubules and arrests cells at the G1 phase of the cell cycle, down-regulated mts1 gene expression in both F1 and ML8 lines. Taxol also reduced heat shock protein expression in ML8 cells. These data suggest opposing functions of heat shock proteins and the mts1 gene in microtubule polymerization, and may provide a rationale for the use of hyperthermia as a treatment for tumours.
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PMID:Metastasis-associated mts1 gene expression is down-regulated by heat shock in variant cell lines of the B16 murine melanoma. 791 58

Taxol is a promising anticancer agent under investigation for therapy of ovarian, breast, colon, and head and neck cancer. One problem associated with the administration of taxol is its low solubility in most pharmaceutically-acceptable solvents; the formulation used clinically contains Cremophor EL (polyethoxylated castor oil) and ethanol as excipients, which cause serious adverse effects. To eliminate this vehicle and possibly improve the antitumor efficacy of taxol, we have formulated taxol in liposomes of various compositions. Liposome formulations containing taxol and phospholipid in the molar ratio 1:33 were prepared from phosphatidylglycerol (PG) and phosphatidylcholine (PC) (1:9 molar ratio), and were physically and chemically stable for more than 2 months at 4 degrees C, or for 1 month at 20 degrees C. A method of producing taxol-liposomes by lyophilization has been developed, by which large batches can be prepared reproducibly in a 'pharmaceutically rational' manner. Taxol-liposomes retained the growth-inhibitory activity of the free drug in vitro against a variety of tumor cell lines. In mice, taxol-liposomes were well-tolerated when given in bolus doses by both iv and ip routes. The Maximum Tolerated Dose (MTD) was > 200 mg/kg; it exceeded that of free taxol, which had a MTD of 30 mg/kg by iv or 50 mg/kg by ip administration. Free taxol administered in the Cremophor vehicle was toxic at doses > 30 mg/kg, as was the equivalent volume of vehicle without drug.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Novel taxol formulations: preparation and characterization of taxol-containing liposomes. 793 31

This phase I/II study was done to evaluate the safety and feasibility of two schedules of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) administered by 1-hour infusion in the outpatient setting. Fifty-six patients with advanced, refractory malignancies received one of two paclitaxel schedules by random assignment: 135 mg/m2 given as a single dose over 1 hour or 135 mg/m2 given in divided hourly daily doses for 3 days. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. No serious acute hypersensitivity reactions were seen with either schedule of paclitaxel. Other adverse effects were usually mild and easily tolerated. Other than alopecia, which was universal, myelosuppression was the most common severe toxicity. However, grades 3 and 4 leukopenia occurred in only 19% and 2% of treatment courses, respectively. Nine patients required hospitalization for treatment of fever associated with neutropenia. There were no significant differences in toxicity observed when comparing the two paclitaxel regimens. It is too early to adequately assess tumor response, but thus far 11 of 56 patients (20%) had partial or complete response to therapy. Responses were observed in patients with breast, ovarian, and lung cancers. Paclitaxel can be safely given by 1-hour infusion in the outpatient setting, both as a single dose and in divided doses for 3 days. Severe acute hypersensitivity reactions did not occur in 162 courses. Neutropenia was mild in most patients and severe thrombocytopenia was rare. The use of this dose and these schedules of paclitaxel as a component of combination chemotherapy regimens should be possible. Investigation of paclitaxel at 200 mg/m2 given by 1-hour infusion is currently in progress.
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PMID:Paclitaxel (Taxol): phase I/II trial comparing 1-hour infusion schedules. 793 60

The mainstay of treatment for head and neck cancer patients with recurrent disease has been chemotherapy with cisplatin/5-fluorouracil or methotrexate. Clearly, new drugs are needed to improve response rates and prolong survival. One new chemotherapeutic agent that has shown activity in head and neck cancer, as well as other tumor types, is paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). In a recently completed phase II trial in patients with recurrent head and neck cancer, the complete and partial response rate to high-dose paclitaxel (250 mg/m2) given as a 24-hour infusion with granulocyte colony-stimulating factor support was 40% (12 of 30 patients). The principal toxicities were similar to those reported in other trials: neutropenia, peripheral neuropathy, and arthralgias/myalgias. Other single-agent trials with paclitaxel currently are in progress, as are trials of paclitaxel--containing combination therapy using cisplatin, carboplatin, ifosfamide, and/or methotrexate. Also under evaluation are paclitaxel combined with radiotherapy and given in lower doses and alternative infusion schedules. Findings, to date suggest that paclitaxel may be the most active single chemotherapeutic agent for the treatment of head and neck cancer.
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PMID:Paclitaxel (Taxol) for the treatment of head and neck cancer. 793 63

Taxol is an antineoplastic agent with significant activity against ovarian as well as breast cancer. To investigate mechanisms by which taxol exerts its cytotoxic action, taxol-induced apoptosis, characterized by morphologic changes and internucleosomal DNA fragmentation, was examined in a human ovarian tumor cell line. Time-dependent morphologic changes, characteristic of apoptosis, were observed over the same time as the appearance of internucleosomal DNA fragmentation. The specific protein tyrosine kinase inhibitors genistein and herbimycin A, and the ATP depletion agent sodium azide, interfered with taxol-induced DNA fragmentation and clonal cell death. Based on a quantitative reverse transcription-polymerase chain reaction technique, bcl-2 alpha oncogene expression was decreased in conjunction with taxol-induced DNA fragmentation, and this decrease could be blocked by genistein. These results strongly implicate protein tyrosine phosphorylation as an event that mediates apoptosis and, thus, the antitumor activity of taxol in ovarian cancer.
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PMID:Evidence for involvement of tyrosine phosphorylation in taxol-induced apoptosis in a human ovarian tumor cell line. 794 20


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