Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Very low concentrations of paclitaxel, a clinically active anticancer agent isolated from the bark of the Pacific yew tree, were found to produce micronuclei in human colon carcinoma cells, suggesting inhibition of mitotic spindle assembly or function. The possibility that paclitaxel acts at the level of the mitotic spindle was investigated by evaluating its ability to inhibit the progression of mitotic cells to G1 phase. Paclitaxel inhibited mitotic progression with a median inhibitory concentration of 4 nM, a concentration equivalent to the median cytotoxic concentration, without arresting cells in mitosis. A direct correlation was shown to exist between the cytotoxic potency and ability to inhibit mitotic progression for analogues of paclitaxel and antimicrotubule agents but not for the topoisomerase II-active agents etoposide and teniposide. After release from the nocodazole block, cells synchronized in mitosis remained sensitive to very low concentrations of paclitaxel for < 30 min, the time required for spindle formation, yet remained sensitive to vinblastine for > 90 min. This result indicates that very low concentrations of paclitaxel inhibit formation of mitotic spindles in cells without affecting function of preformed spindles and without arresting cells in mitosis. Continuous exposure to low nanomolar concentrations of paclitaxel for more than one cell cycle resulted in cells with DNA contents > 4C and as much as 8C. These results support a hypothesis, that, by not being capable of segregating sister chromatids, paclitaxel-treated cells eventually reform nuclear membranes around individual or clusters of chromosomes, revert to G1 phase cells containing 4C DNA, and enter S phase, resulting in cells with as much as 8C DNA content. It is proposed that this is the primary cytotoxic mechanism of paclitaxel.
 ...
PMID:Paclitaxel inhibits progression of mitotic cells to G1 phase by interference with spindle formation without affecting other microtubule functions during anaphase and telephase. 791 75

Five promising new drugs for gynecological cancer were reviewed. Taxans (Paclitaxel: Taxol and Docetaxel: Taxotere) diterpenoid plant products enhance the polymerization of tublin. Taxol showed significant activity for platinum refractory ovarian cancer in a phase 1 clinical trial in the United States. The combination with cisplatin (CDDP) showed superior results to CDDP plus Cyclophosphamide and has been recognized as a new standard in adjuvant chemotherapy for advanced ovarian cancer. The major toxicities are myelosuppression, alopecia, and hypersensitivity reactions (HSRs). HSRs were overcome by pretreatment with anti-histamines and over 24 hours administration. It was also reported that Taxol was administered safely by over 3 hours infusion with reduced myelotoxicity, but the incidence of HSRs may be increased. Clinical trials of intraperitoneal administration and combination with Carboplatin (CBDCA) are ongoing. Taxotere, an analog of Taxol, is also effective as Taxol with a low incidence of HSRs. Topoisomerase inhibitors (Irinotecan hydrochloride: CPT-11 and Topotecan) have promising antitumor activity for ovarian and cervical cancer. CPT-11 is a semisynthetic camptothesin analog developed in Japan. It was also effective for platinum-resistant ovarian cancer, such as mucinous and clear cell carcinoma. An adverse effect was observed in the combination of CPT-11 and CDDP. The phase 1 clinical trial showed a 40% response rate against recurrent ovarian cancer. CPT-11 50-60 mg/m2 (day 1,8,15) and CDDP 50-60 mg/m2 (day 1) are a recommended schedule. The major toxicities are neutropenia and diarrhea. Thrombocytopenia is not severe and diarrhea is also controllable. Topotecan is also a promising topoisomerase inhibitor and reported superior result to Taxol for platinum refractory ovarian cancer. A phase II trial is ongoing for ovarian and cervical cancer in Japan. Nedaplatin, a new analog of cisplatin, has similar activity especially for cervical cancer with less myelotoxicity and nephrotoxicity.
 ...
PMID:[Promising new drugs for gynecological cancer]. 935 Feb 38

Treatment of anthracycline-resistant metastatic breast cancer with new antineoplastic agents remains a challenge for the next future. The 5-year survival for this disease is only 15%, and hormonal and chemotherapeutic options remain essentially palliative. New treatment drugs or drug combinations are urgently needed to improve the prospects for patients with metastatic breast cancer, particularly for those with disease characteristics indicating a particularly poor prognosis. Taxanes are promising new drugs and have shown encouraging activity in patients with disease resistant to anthracyclines and in patients with visceral metastases, both with a poor prognosis. Paclitaxel (taxol) is applied with a dose of 175 mg/m2 in a 3 hour infusion and docetaxel (taxotere) with a dose of 100 mg/m2 q 3 weeks. Remission rates are expected between 6-30% for taxol and between 29-48% for docetaxel. Highly active in patients with anthracycline-resistant disease appears to be the vinca-alkaloid vinorelbine too. In patients treated with adriamycin objective remissions between 15-33% can be obtained. The long time known 5-fluorouracil comes to the third place of the effective drugs. Continuous infusion or addition of folic acid increases the intracellular efficacy and results in 5-53% objective remissions. In second-line chemotherapy platin-analogues together with etoposide, vincristine and 5-FU achieve partial or complete remissions between 19-37% for cisplatin containing and 5-12 for carboplatin containing combinations. This may eventually play a role especially if three drug combinations containing paclitaxel, epirubicin and vinorelbine will be used, which are reported to result in 20-33% complete response rates and 66% objective response. The indication for other new drugs like tomudex, topoisomerase-I-inhibitor and gemcitabine for anthracycline-resistant breast cancer remains to be established in multicenter studies.
 ...
PMID:[Therapy of anthracycline-resistant metastatic breast carcinoma]. 962 23

Paclitaxel (Taxol) is known to act by polymerizing and stabilizing microtubules. In spite of a known target, the existence of additional targets is suggested by a poor understanding of the mechanism(s) underlying eventual cell death by paclitaxel and by the drug's high efficacy, as compared to other spindle poisons. Based on the enhanced sensitivity of a mutant DNA double-strand break repair-deficient Chinese hamster ovary cell line to paclitaxel as well as to various topoisomerase (Topo) II poisons, it was hypothesized that paclitaxel, in addition to having an effect on microtubules, may also alter the activity of Topo II. This study demonstrates the unique, in vitro effects of paclitaxel on Topo II activity as investigated by monitoring the decatenation of kinetoplast DNA and relaxation of supercoiled plasmid DNA by Topo II. Unlike classical anti-topoisomerase drugs, low concentrations of paclitaxel (0.02-500 nM) stimulated Topo II catalytic activity, while higher concentrations over 5 microM inhibited the activity of Topo II. Furthermore, these effects of paclitaxel appear to be mediated through a direct interaction of paclitaxel with Topo II rather than an interaction with DNA or DNA-Topo II complexes. Collectively, the evidence presented suggests the existence of an atypical interaction between Topo II and paclitaxel that may disrupt the normal functioning of the enzyme.
 ...
PMID:A unique paclitaxel-mediated modulation of the catalytic activity of topoisomerase IIalpha. 1037 75

Chemotherapy for extensive-stage small-cell lung cancer (E-SCLC) produces high response rates and improved survival but few cures. We tested three new regimens for E-SCLC that might merit further investigation in a subsequent phase III trial. Cancer and Leukemia Group B 9430 was a randomized phase II study evaluating 4 treatment arms in 57 evaluable, previously untreated E-SCLC patients. Each arm consisted of the following: Arm 1: cisplatin plus topotecan; Arm 2: cisplatin plus paclitaxel; Arm 3: paclitaxel 230 mg/m2 plus topotecan; and Arm 4: paclitaxel 175 mg/m2 plus topotecan. Because of an accrual time difference, Arm 2 will not be discussed in this manuscript. Arm 1 (12 patients) produced 1 complete response (CR, 8%) and an overall response rate (ORR) of 42%. Toxicity was excessive, with 3 deaths (25%). Arm 3 (13 patients) produced no CRs, 7 partial responses (PRs, 54%), median survival of 13.8 months, and failure-free survival (FFS) of 7.41 months, with 3 toxic deaths (25%). Among 32 evaluable patients on Arm 4, there were 2 CRs (6%) and 20 PRs (63%) for an ORR of 69%, median survival of 9.9 months, FFS of 5.21 months, and 1-year survival of 40%. There was 1 possible treatment-related death (3%). Topotecan plus cisplatin, in the doses and schedule employed, produced excessive toxicity and modest efficacy in E-SCLC patients. Paclitaxel (230 mg/m2 on day 1) plus topotecan (1 mg/m2 on days 1-5) produced excessive toxicity that was ameliorated with an attenuated paclitaxel dose (175 mg/m2). With the latter regimen (Arm 4) in patients with a performance status of 0/1, CR rates, FFS, overall survival, and 1-year survival were similar to standard etoposide plus cisplatin chemotherapy. Further exploration of topoisomerase inhibitors and taxanes in SCLC patients is warranted.
 ...
PMID:Novel doublets in extensive-stage small-cell lung cancer: a randomized phase II study of topotecan plus cisplatin or paclitaxel (CALGB 9430). 1466 44

The purpose of the study was to determine whether paclitaxel inhibits the expression of heat shock protein 27 (HSP27) in two gynecologic cancer cell lines compared with other antineoplastic agents having different cytotoxic mechanisms. BG-1 ovarian cancer cells and HeLa uterine cancer cells were treated with a tubulin depolymerization inhibitor (paclitaxel), a topoisomerase-II inhibitor (etoposide), and two tubulin polymerization inhibitors (colcemid and vincristine). Cell kills were evaluated by counting the number of cells. Propidium iodide staining and flow cytometric analysis were applied for the determination of cell-cycle perturbation. HSP27 was stained by the indirect immunofluorescence technique and analyzed with a flow cytometer. In both BG-1 and HeLa cells, growth arrest and G2 / M accumulation were dependent on the dose of each cytotoxic agent. There were positive correlations between HSP27 overexpression and growth arrest and G2 / M accumulation when the cell lines were treated with etoposide, colcemid, or vincristine, but not with paclitaxel. Paclitaxel completely inhibited the expression of HSP27. The results of this study indicated that paclitaxel may possess unique mechanisms able to overcome drug resistance by inhibiting HSP27 expression.
 ...
PMID:Paclitaxel inhibits expression of heat shock protein 27 in ovarian and uterine cancer cells. 1530 55