Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paclitaxel is a highly active single agent as therapy for previously untreated as well as doxorubicin-refractory metastatic breast cancer, with associated response rates of 62% and 20-48%, respectively. Complete responses with paclitaxel occur chiefly in breast cancer patients whose metastatic disease has not been previously treated with chemotherapy. Early data suggest a possible dose-response relationship for paclitaxel in metastatic breast cancer, but the optimal dose has not yet been defined. The optimal duration of infusional paclitaxel treatment is also not yet known. A study of 96-hour infusional paclitaxel in the treatment of doxorubicin- or mitoxantrone-refractory metastatic breast cancer patients has demonstrated a 48% response rate suggesting that prolonged exposures to paclitaxel may offer a therapeutic advantage. Randomized trials of 3- vs 96-hour paclitaxel are ongoing or planned. The relative efficacy of paclitaxel versus standard chemotherapy as front-line or salvage therapy for metastatic breast cancer is currently under study. In addition, two randomized trials are under way in node positive breast cancer patients to study whether treatment with paclitaxel following standard or high dose doxorubicin and cyclophosphamide adjuvant therapy results in improved patient benefit. Combining paclitaxel with other active agents in the treatment of metastatic breast cancer is an area of active investigation. Combined paclitaxel and doxorubicin, administered concurrently or sequentially, is associated with modest complete response rates in metastatic breast cancer patients. Sequential paclitaxel-->doxorubicin administration is associated with more mucositis than is doxorubicin-->paclitaxel when paclitaxel is administered over 24 hours. High doses of cyclophosphamide can be combined with 24- or 72-hour infusional paclitaxel, and phase II studies of this combination are warranted. Early data suggest that administering biweekly paclitaxel and cisplatin to previously untreated metastatic breast cancer patients is associated with high response rates, and confirmatory studies of this combination and schedule are planned. Preclinical data suggest that cell cycle considerations may be important in combining doxorubicin and possibly other agents with paclitaxel. Paclitaxel is an excellent substrate for P-glycoprotein, the protein product of the multidrug resistance-1 (mdr-1) gene, and phase I trials are under way combining paclitaxel with several known blockers of Pgp function. Finally, pilot studies are under way to determine whether the radiation sensitizing effects of paclitaxel can be exploited as part of radiation therapy for patients with locally advanced breast cancer.
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PMID:Current status of paclitaxel in the treatment of breast cancer. 774 30

The search for new active agents and strategies to improve the prognosis for patients with stage IV breast cancer has led to examination of paclitaxel. Several clinical trials have been undertaken to determine its optimal use and clarify its role in the treatment of breast cancer and other malignancies. Several phase II trials involving breast cancer patients with limited prior therapy have yielded overall response rates (complete response and partial response) of 44% to 62% among women receiving paclitaxel. Treatment was generally well tolerated, with febrile neutropenia the most common side effect. An interim analysis of the European-Canadian Randomized Trial in Metastatic Breast Cancer demonstrated safety and efficacy of paclitaxel in a multicenter setting. Among the 234 patients evaluable for response, 29% (34/117) responded at 175 mg/m2 paclitaxel and 22% responded (26/117) at 135 mg/m2. Treatment was well tolerated at both dose levels; responses continue to evolve in patients who remain on study. Among patients with extensive prior therapy (> 2 prior regimens for stage IV disease), paclitaxel also has demonstrated safety and efficacy. At Memorial Sloan-Kettering Cancer Center, responses were noted among 36% of patients who had received two prior treatments and 21% of those who had received 3 or more. Paclitaxel was administered at 200 mg/m2 plus G-CSF. Other studies involving heavily pretreated patients yielded overall response rates as high as 53%. The concerns about cross-resistance between paclitaxel and doxorubicin (or other agents for which resistance is thought to be at least partly due to P-glycoprotein-mediated pleiotropic drug resistance) also are addressed.
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PMID:Single-agent use of Taxol (paclitaxel) in breast cancer. 786 28

Microtubules, which are composed of polymerized tubulin dimers, play an important role in various cell functions. For example, they maintain cell shape, form mitotic spindles in M phase of cell cycle, and carry an axonal transport in nerve cells. Microtubules have also been an important target of cancer chemotherapy. Vinca alkaloids depolymerize microtubules, the mechanisms of which action have extensively been investigated recently. Clinical trials of vinorelbine (navelbine), a new semisynthetic vinca alkaloid, are ongoing in Japan. One of advantages of the drug is reduced risk of neurotoxicity. Estramustine may act on microtubule-associated proteins (MAPs) as well as tubulin. It shows additive or synergistic cytotoxicity preclinically when used in combination with vinblastine. This combination was active against hormone-refractory prostate cancer. Another novel drug rhizoxin, which has a similar mechanism of action to that of vinca alkaloids, is also a promising cytotoxic agent and is examined clinically in Europe. Taxanes, which include paclitaxel (Taxol) and taxotere, are interesting drugs because they promote polymerization of tubulin and stabilize microtubules. They show promising antitumor activity against breast, ovarian and lung cancers. Phase I and II trials are ongoing in Japan. Paclitaxel may also potentiate cytotoxicity of radiation. There are several mechanisms of resistance to microtubule-acting drugs. One is multidrug resistance mediated by P-glycoprotein. Other mechanisms include mutation of tubulin.
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PMID:[Microtubules and antineoplastic drugs]. 790 90

Paclitaxel (Taxol) is a new cytotoxic agent with considerable activity in phase II studies on metastatic breast cancer. Paclitaxel for clinical use is dissolved in the solvents cremophor EL and ethanol. In this study, we added paclitaxel, formulated either in cremophor EL and ethanol or only in ethanol, in increasing concentrations to two parental human breast cancer cell lines (ZR 75-1 and HS 578T) and their corresponding sublines with acquired doxorubicin resistance and P-glycoprotein expression. Paclitaxel dissolved either in ethanol or ethanol plus cremophor EL, resulted in steep and almost identical dose-response curves for the parental lines ZR 75-1 and HS 578T, respectively, independent of the solvent used. When paclitaxel was formulated only in ethanol the effects on the corresponding doxorubicin-resistant sublines were significantly reduced compared with paclitaxel dissolved in ethanol plus cremophor EL. These effects by cremophor EL may partly explain some of the antitumoral effects observed by paclitaxel in anthracycline failing patients.
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PMID:Paclitaxel-induced cytotoxicity--the effects of cremophor EL (castor oil) on two human breast cancer cell lines with acquired multidrug resistant phenotype and induced expression of the permeability glycoprotein. 791 8

Patients with non-Hodgkin's lymphoma (NHL) recurrent after chemotherapy exhibit clinical characteristics compatible with the phenomenon of multidrug resistance (MDR) and frequently have detectable levels of P-glycoprotein (P-gp). Paclitaxel has been used in recurrent NHL with limited success. To test whether clinical resistance to paclitaxel can be reversed, we treated patients having paclitaxel-resistant NHL with paclitaxel plus quinine and measured the effects of quinine on paclitaxel pharmacokinetics. Eligible patients had recurrent and measurable NHL. Patients initially received paclitaxel, 120 mg/m2 (dose determined by a phase I trial of paclitaxel plus quinine), as a 20-24 h infusion every 3 weeks until there was evidence of clinical resistance. Patients then received paclitaxel at the same dose rate plus oral quinine at a fixed dose rate of 400 mg three times each day. Paclitaxel pharmacokinetics were studied in each patient using paired samples from plasma obtained at the end of the 24 h paclitaxel infusion as an estimate of the steady-state drug level. Of 14 patients treated with paclitaxel alone, one patient obtained a partial response (7%). At the time of disease progression, one patient (same patient) obtained a partial response with paclitaxel plus quinine (7%). Steady-state paclitaxel levels were obtained in 12 patients. In 11 of 12 patients the steady-state paclitaxel level was substantially lower with the addition of quinine. The average ratio of end of infusion plasma levels (paclitaxel alone/paclitaxel plus quinine) was 0.6 (range 0.31-0.97) indicating a 40% decrease in paclitaxel levels with the addition of quinine (p=0.001). We conclude that paclitaxel given by this dose and schedule has modest activity in recurrent NHL. The addition of quinine to paclitaxel also has limited activity, but the combination did reverse paclitaxel resistance in one patient, adding support to the hypothesis that clinical drug resistance can be overcome with chemosensitizers in individual patients. Pharmacokinetic studies indicate that the reversal of drug resistance in this study cannot be attributed to changes in clearance of paclitaxel (which appears to increase with quinine), but more likely to the sensitization of lymphoma cells.
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PMID:A phase I/II trial of paclitaxel for non-Hodgkin's lymphoma followed by paclitaxel plus quinine in drug-resistant disease. 951 Apr 99

Paclitaxel (Taxol) has been shown to be clinically effective in treatment of patients with breast and ovarian cancer. It has also shown promising results in various other solid tumours. Paclitaxel has induced apoptosis in the G2/M phase of the cell cycle in both HL-60 and U937 human leukaemia cells. A recent study has shown a dose-dependent cytotoxicity for both taxanes: paclitaxel (taxol) and docetaxel (Taxotere) on fresh leukaemia cells in primary culture from 16 ALL and four AML patients and proposed their use in treatment of acute leukaemia patients. AML is a heterogeneous disease in which malignant transformation and disease progression occur at the level of CD34 positive cells. Also, the multi-drug resistance gene product, P-glycoprotein is expressed only in CD34 positive AML cells. Therefore, an in vitro evaluation of the efficacy of paclitaxel, a P-glycoprotein substrate, in CD34 positive AML cells is warranted before considering its clinical use in acute leukaemia patients. Since all in vitro studies of paclitaxel reported so far have involved only CD34 negative (HL-60, U937, K562) human AML cells, the aim of the present study was to evaluate paclitaxel efficacy against CD34 positive AML cells. The IC50 of paclitaxel for apoptosis was significantly higher in MHH225 CD34 positive cells (12 +/- 2 microM) than in U937 CD34 negative cells (1.7 +/- 0.2 microM), P < 0.001. Paclitaxel has a significantly weaker cytotoxic effect on CD34 positive AML cells. One log higher concentration of paclitaxel was required in MHH225 CD34 positive AML cells to achieve the same apoptosis level achieved in U937 CD34 negative leukaemia cells. Also, at the high concentration achievable in vivo: 10 microM paclitaxel, only half the MHH225 CD34 positive AML cells were apoptotic versus 72% of U937 CD34 negative leukaemia cells. Clearly, paclitaxel has only weak or modest in vitro efficacy compared with several conventional anti-leukaemia drugs used in AML treatment. The present results support the poor level of in vivo induction of apoptosis achieved during a phase I clinical study with paclitaxel therapy in 26 leukaemia patients. Also, the present results have shown a significant increase in nitric oxide production during paclitaxel-induced apoptosis in U937 monocytic leukaemia cells, confirming the vital role of nitric oxide in mediating paclitaxel-induced apoptosis by monocytic cells. In conclusion, the present study has demonstrated a clear difference between the effect of paclitaxel on CD34 negative and CD34 positive AML cells. Given its poor performance in the phase I clinical study of 26 acute leukaemia patients and the present weak in vitro cytotoxic effect, it is unlikely that paclitaxel will have a role in the treatment of acute leukaemia. Also, the present study emphasises the need to use CD34 positive AML cells such as MHH225 rather than the unsuitable lineage-specific CD34 negative cells such as HL-60 or U937 for in vitro pre-clinical screening of potential novel effective anti-leukaemia agents.
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PMID:Divergent effect of taxol on proliferation, apoptosis and nitric oxide production in MHH225 CD34 positive and U937 CD34 negative human leukaemia cells. 976 54

Paclitaxel is currently formulated in a vehicle of 50% ethanol and 50% polyethoxylated surfactant cremophor EL. Cremophor EL has been reported to reverse P-glycoprotein-mediated multidrug resistance (MDR) at doses which are clinically achievable. It has also been reported to have a cytotoxic effect per se. In this study we used two different methods to evaluate the survival of cells exposed to paclitaxel with or without cremophor EL and the vehicle alone. Two laryngeal SCC cell lines (UT-SCC-19A and UT-SCC-29) and two ovarian adenocarcinoma cell lines (UT-OC-3 and UT-OC-5) established in our laboratory were investigated. Northern hybridisation was used to study the mdr-1 mRNA expression of the cell lines. With sensitive Northern analyses, these four lines yielded mdr-1 mRNA signals of the expected 4.5 kb size and of variable intensity, generally at higher levels than those in the positive control cell line KB. The 96-well plate clonogenic assay was used to obtain the fraction survival data and apoptosis was recorded by time-lapse video microscopy. Both methods indicate that cremophor EL alone has no effect on cellular survival. Consequently, paclitaxel without cremophor EL is as active as paclitaxel with cremophor EL in vitro.
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PMID:Effects of paclitaxel with or without cremophor EL on cellular clonogenic survival and apoptosis. 1044 72

The purpose of this study was to retrospectively predict the chemotherapy response to paclitaxel in non-small cell lung cancer (NSCLC) using technetium-99m methoxyisobutylisonitrile (Tc-99m MIBI) chest single-photon-emission computed tomography (SPECT) to detect the expression of multidrug-resistance-mediated Mr 170,000 P-glycoprotein. Before chemotherapy with Paclitaxel (Taxol), 30 patients with stage IIIb or IV NSCLC were enrolled in this study. Early chest SPECT 10 min after i.v. injection of Tc-99m MIBI was performed to qualitatively interpret Tc-99m MIBI chest SPECT visually and quantitatively calculate early tumor:normal lung ratios (T:NL) for quick assessment of multidrug-resistant P-glycoprotein expression in NSCLC. On the basis of qualitatively visual interpretation of early Tc-99m MIBI chest SPECT, all of 15 (100%) cases with good response to chemotherapy with Taxol could be detected but 10 (67%) of 15 cases with poor response could not be detected. Early Tc-99m MIBI chest SPECT could correctly predict chemotherapy response in 25 (83%) of 30 of cases. The early T:NL were 3.30 +/- 0.82 for 15 patients with good response and 2.02 +/- 0.19 for 5 patients with poor response. The differences were significant (P < 0.05) by independent Student t tests. However, no significant differences were found for other prognostic factors (age, sex, tumor size, tumor location, stage, and cell type) between good-response and poor-response patients. Early Tc-99m MIBI chest SPECT has the potential to predict chemotherapy response to Paclitaxel.
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PMID:Quickly predicting chemotherapy response to paclitaxel-based therapy in non-small cell lung cancer by early technetium-99m methoxyisobutylisonitrile chest single-photon-emission computed tomography. 1074 2

Paclitaxel (Taxol) kills tumor cells by inducing both cellular necrosis and apoptosis. A major impediment to paclitaxel cytotoxicity is the establishment of multidrug resistance whereby exposure to one chemotherapeutic agent results in cross-resistance to a wide variety of other drugs. For example, selection of MCF-7 breast cancer cells for resistance to doxorubicin (MCF-7ADR cells) results in cross-resistance to paclitaxel. This appears to involve the overexpression of the drug transporter P-glycoprotein which can efflux both drugs from tumor cells. However, MCF-7ADR cells possess a deletion mutation in p53 and have considerably reduced levels of the Fas receptor, Fas ligand, caspase-2, caspase-6, and caspase-8, suggesting that paclitaxel resistance may also stem from a bona fide block in paclitaxel-induced apoptosis in these cells. To address this issue, we examined the ability of the P-glycoprotein inhibitor valspodar to restore paclitaxel accumulation, paclitaxel cytotoxicity, and paclitaxel-induced apoptosis. Compared to drug sensitive MCF-7 cells, MCF-7ADR cells accumulated >6-fold less paclitaxel, were approximately 100-fold more resistant to killing by the drug, and were highly resistant to paclitaxel-induced apoptosis. In contrast, MCF-7ADR cells pretreated with valspodar were indistinguishable from drug-sensitive cells in their ability to accumulate paclitaxel, in their chemosensitivity to the drug, and in their ability to undergo paclitaxel-induced apoptosis. Valspodar, by itself, did not affect these parameters. This suggests that the enhancement of paclitaxel toxicity in MCF-7ADR cells involves a restoration of apoptosis and not solely through enhanced drug-induced necrosis. Morever, it appears that changes in the levels/activity of p53, the Fas receptor, Fas ligand, caspase-2, caspase-6, or caspase-8 activity have little effect on paclitaxel-induced cytotoxicity and apoptosis in human breast cancer cells.
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PMID:Role of specific apoptotic pathways in the restoration of paclitaxel-induced apoptosis by valspodar in doxorubicin-resistant MCF-7 breast cancer cells. 1083 93

The growth inhibitory effect of paclitaxel, docetaxel, and newly developed taxanes IDN5109, IDN5111, and IDN5127 was assessed on peripheral blood (PB) CD34+ maintained in liquid culture and on three human cancer cell lines (MDA-MB231, MCF-7 ADRr, CEM VBLr). Concomitantly, DNA analysis was also performed. For unfractionated peripheral blood progenitor cells (PBPC) toxicity was also assessed by clonogenic assay. The cytotoxic effects induced by taxanes toward PBPC as measured by clonogenic assay were correlated with those found for multidrug resistance (MDR)-positive cell lines (IDN5109 > IDN5111 > IDN5127 > docetaxel > paclitaxel). We established a therapeutic index (TI) between the antitumor activity in MDR-positive cells and the toxicity toward PBPC. Paclitaxel and IDN5109, as determined by TI, showed the best value in MDR-negative and MDR-positive cells, respectively. The ranking of the cytotoxic effects observed in PB CD34+ was not correlated with that obtained in clonogenic assay and in cancer cells (IDN5127 > IDN5109 > docetaxel > IDN5111). Remarkably, in DNA analysis docetaxel induced the maximal cell cycle blocking activity. Newly developed taxanes IDN5109 and IDN5111 are endowed of a profile of anticancer activity in MDR-bearing cells and toxicity toward hematopoietic progenitors better than that of docetaxel. However, mechanism(s) underlying toxicity toward hematopoietic progenitors could be, at least in part, different from that of docetaxel and likely dependent on the interaction with P-glycoprotein function in PB CD34+ cells.
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PMID:Cytotoxic effects toward human hematopoietic progenitor cells and tumor cell lines of paclitaxel, docetaxel, and newly developed analogues IDN5109, IDN5111, and IDN5127. 1085 Aug 88


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