Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Docetaxel (Taxotere) has been shown to be one of the most active cytotoxic agents in patients with breast cancer, achieving response rates of 41% when used as second-line treatment for metastatic breast cancer (34% in anthracycline-refractory patients) and 50-72% when used as first-line therapy. In both situations meaningful response durations of 7-8 months have been obtained. Based on these results, docetaxel is a promising candidate for new therapeutic strategies in patients with breast cancer. Studies comparing docetaxel with paclitaxel or anthracyclines in first-line therapy are ongoing. These studies should allow for an unequivocal definition of activity of docetaxel, yet not alter--as such--therapeutic strategies. A number of regimens are currently being explored combining docetaxel with anthracyclines, vinorelbine, 5-fluorouracil, cyclophosphamide and cisplatin. The preliminary conclusions are as follows: the main side-effect is non-cumulative neutropenia of short duration, and response rates are > 75%. Further, no cumulative cardiotoxicity has been observed with doxorubicin. The duration of response and length of the progression-free survival cannot yet be defined. Another option for combination chemotherapy is sequential combinations, the value of which has been demonstrated in advanced breast cancer as well as in the adjuvant setting. The short duration and non-cumulative character of docetaxel-induced neutropenia are good rationales for the use of dose-densified docetaxel-containing regimens. A dose of 100 mg/m2/14 days can be used as single-agent therapy. A phase I trial combining cyclophosphamide at doses increased from 750 to 1200 mg/m2 and docetaxel at doses increased from 66 to 100 mg/m2 every 2 weeks, is ongoing; at the first dose-levels, the combination appears feasible although cumulative asthenia has been observed. Further, responses have been observed at all dose levels. The value of single-agent chemotherapy added to tamoxifen has been emphasised for stage I-II breast cancer in postmenopausal patients. A randomised phase III study comparing tamoxifen (20 mg/day for 5 years) and epirubicin (50 mg/m2 days 1 and 8/28 days for 6 cycles) with the same regimen with epirubicin for 3 months followed by docetaxel (100 mg/m2/21 days x 3) was initiated at the end of 1996. Thus, docetaxel is currently under study in most therapeutic situations to better define its impact on the prognosis and curability of patients with breast cancer.
Eur J Cancer 1997 Aug
PMID:Prospects with docetaxel in the treatment of patients with breast cancer. 948 1

Docetaxel is a new antimicrotubule agent that has been shown to be active against a variety of solid tumors. Ifosfamide is an alkylating drug that has demonstrated activity against non-small cell lung cancer, testicular cancer, breast cancer, and soft tissue sarcoma. This phase I study of the combination of these drugs was performed to assess the feasibility of using the two agents together, to determine the maximum tolerated dose and the side effects, and to propose a safe schedule for further phase II studies. Thirty-four patients with histologically confirmed solid tumors who had not been treated previously with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-hour infusion followed by ifosfamide as a 24-hour infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg/m2 and ifosfamide doses from 2.5 to 5.0 g/m2. Grades 3 and 4 granulocytopenia were observed in 89% of courses and appeared to be of short duration and related to the ifosfamide dose. Febrile neutropenia and sepsis occurred in 17% and 2% of courses, respectively. Severe anemia and thrombocytopenia were uncommon. Nonhematologic toxicities were mild to moderate, and included alopecia, nausea, vomiting, mucositis, diarrhea, sensory neuropathy, skin and nail toxicity, hypersensitivity reactions, and edema. Schedule B appeared to induce more gastrointestinal toxicity than schedule A. One complete response in soft tissue sarcoma and two partial responses, one in cancer of unknown primary and the other in non-small cell lung cancer, were documented. The dose-limiting toxicity for schedule A was neutropenic fever at a dose of 85 mg/m2 docetaxel and 5 g/m2 ifosfamide. The dose-limiting toxicity for schedule B was neutropenic fever at a dose of 75 mg/m2 docetaxel and 4 g/m2 ifosfamide. A dose of 75 mg/m2 docetaxel combined with 5 g/m2 ifosfamide according to schedule A can be recommended for further studies.
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PMID:Docetaxel and ifosfamide in patients with advanced solid tumors: results of a phase I study. 953 8

Thymidine phosphorylase (dThdPase) is an essential enzyme for the activation of the cytostatics capecitabine (N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) and its intermediate metabolite [5'-deoxy-5-fluorouridine (5'-dFUrd)] to 5-fluorouracil in tumors. We have tried to identify the best partners of capecitabine in combination therapy, such as dThdPase up-regulators, which may enhance the efficacy of this compound. Among various cytostatics studied with the WiDr human colon cancer xenograft model, Taxol, Taxotere, and mitomycin C greatly increased levels of human dThdPase in tumors, and cyclophosphamide slightly increased the enzyme level. These cytostatics simultaneously increased the levels of human tumor necrosis factor alpha (TNFalpha), which is an up-regulator of dThdPase. In cultures of the WiDr cells, however, Taxol did not up-regulate TNFalpha to a detectable level and only slightly enhanced levels of dThdPase. These results suggest that Taxol might indirectly elevate TNFalpha in tumor cells, which in turn up-regulated dThdPase in the tumor cells in the WiDr cancer xenograft. In the combination therapy, the efficacy of Taxol and Taxotere with either capecitabine or 5'-dFUrd was more than just additive. In contrast, Taxol and either 5-fluorouracil or UFT (a mixture of tegafur and uracil) in combination showed only additive activity. Taxol and Taxotere might enhance the efficacy of capecitabine and 5'-dFUrd, probably by modulating dThdPase activity in tumor tissues.
Clin Cancer Res 1998 Apr
PMID:Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. 956 97

The antimicrotubule agent docetaxel (Taxotere), a semisynthetic taxoid, has demonstrated antitumor activity against colorectal cancer cell lines in vitro, and in murine tumor models. We sought to characterize its activity in a group of previously untreated patients with colorectal carcinoma. Eighteen previously untreated patients with advanced, measurable colorectal carcinoma were treated with a 60-min intravenous infusion of docetaxel with a dose of 100 mg/m2 administered every 21 days. Routine premedication with diphenhydramine was given. Patients were required to have normal organ function and a Karnofsky performance status (KPS) > or = 60%. No complete response (CR) or partial responses (PR) were observed. Median survival was 13 months, despite a median time to progression of only 1.3 months. Neutropenia was the most common dose-limiting toxicity, resulting in 5 episodes of febrile neutropenia requiring hospitalization and intravenous antibiotics. One patient experienced a grade 4 hypersensitivity reaction (HSR) requiring treatment termination. No toxic deaths occurred. Despite encouraging preclinical data, docetaxel is an inactive drug in advanced colorectal cancer when given in the dose and on the schedule examined in the present study, and has significant, although reversible, toxicities.
Cancer Invest 1998
PMID:Phase II trial of docetaxel (Taxotere) for untreated advanced colorectal carcinoma. 962 78

The taxanes, paclitaxel and docetaxel, have favorable response rates in patients with breast, gynecologic, and lung cancers and have demonstrated activity against a variety of malignancies. In human trials, paclitaxel pharmacokinetics are nonlinear and are best fit by a three-compartment model with nonlinear distribution into the second compartment as well as nonlinear elimination. This finding is important for patients receiving paclitaxel at high doses or as a short infusion, as it results in disproportionately high peak concentrations and delayed elimination. The presence of nonlinear processes in docetaxel pharmacokinetics has not previously been examined. Therefore, plasma concentration data obtained from 53 patients receiving docetaxel at 55-115 mg/m2 over 1-24 h as part of phase I studies were modeled using the nonlinear three-compartment model found most suitable for paclitaxel and the results were compared with those obtained using the linear version. Docetaxel disposition was best described by the three-compartment nonlinear model in 28 of 53 data sets (53%). However, the difference in curve fit observed between the two models was modest (did not improve Akaike criteria) and unlikely to be of relevance. This study suggests that nonlinear processes in docetaxel pharmacokinetics may exist, but, unlike the case of paclitaxel, they are not likely to have a significant impact at the dose and administration schedule used in routine clinical practice (60-100 mg/m2 given over 1 h by infusion). The presence of nonlinear docetaxel pharmacokinetics at doses above 115 mg/m2 will have to be determined in case of further dose escalation.
Cancer Chemother Pharmacol 1998
PMID:Evaluation of the linearity of docetaxel pharmacokinetics. 965 16

Taxol and Taxotere propagate apoptosis in Jurkat T cells via molecular signals that coincide with the appearance of two distinct cell populations. Cell cycle arrest in G2-M phase and activation of cell cycle-dependent kinases begin within 2 h and extend to most cells by 16 h. Phosphorylation of Bcl-2 also begins within 2 h and intensifies from 2-16 h. Cell cycle arrest, activation of mitotic kinases, and phosphorylation of Bcl-2 coincided with the appearance of a population of metastable cells that accumulate YO-PRO-1 dye, are resistant to the caspase inhibitor carbobenzoxy-L-aspartyl-alpha-[(2,6-dichlorobenzoyl)oxy]methane, and have intact genomic DNA. Phosphorylation and deactivation of kinases that relay survival/mitogenesis signals in T cells begin after 8 h and are prominent by 12-16 h. Deactivated kinases include c-Raf-1, p44 extracellular receptor kinase, and the tyrosine kinases c-Lck and ZAP-70. Activation of Mr 40,000 and Mr 52,000 kinases is also prominent by 12-16 h. The modulation of all these kinases coincided with the activation of caspase-3 at 12 h and the appearance of a population of apoptotic cells that accumulate YO-PRO-1, are susceptible to the caspase inhibitor carbobenzoxy-L-aspartyl-alpha-[(2,6-dichloro-benzoyl)oxy]methane, and contain fragmented genomic DNA. This distinctive apoptosis signaling pathway may help account for the superior cytotoxic efficacy of taxanes in certain types of cancer.
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PMID:Taxanes propagate apoptosis via two cell populations with distinctive cytological and molecular traits. 971 85

Docetaxel tolerance and antitumor efficacy could be enhanced if drug administration was adapted to circadian rhythms. This hypothesis was investigated in seven experiments involving a total of 626 male B6D2F1 mice, synchronized with an alternation of 12 h of light and 12 h of darkness (12:12), after i.v. administration of docetaxel. In experiment (Exp) 1, the drug was given once a week (wk) for 6 wks (20 mg/kg/wk) or for 5 wks (30 mg/kg/wk) at one of six circadian times, during light when mice were resting [3, 7, or 11 hours after light onset (HALO)], or during darkness, when mice were active (15, 19, or 23 HALO). Endpoints were survival and body weight change. In Exp 2 and 3, docetaxel (30 mg/kg/wk) was administered twice, 1 wk apart, at one of four circadian stages (7, 11, 19, or 23 HALO). Endpoints were hematological and intestinal toxicities. In Exp 4, circadian changes in cell cycle phase distribution and BCL-2 immunofluorescence were investigated in bone marrow as possible mechanisms of docetaxel tolerability rhythm. In Exp 5 to 7, docetaxel was administered to mice bearing measurable P03 pancreatic adenocarcinoma (270-370 mg), with tumor weight and survival as endpoints. Mice from Exp 5 and 6 received a weekly schedule of docetaxel at one of six circadian stages (20 or 30 mg/kg/wk at 3, 7, 11, 15, 19, or 23 HALO). In Exp 7, docetaxel (30 mg/kg) was given every 2 days (day 1, 3, 5 schedule) at 7, 11, 19, or 23 HALO. Docetaxel dosing in the second half of darkness (19 or 23 HALO) resulted in significantly worse toxicity than its administration during the light span (3, 7, or 11 HALO). The survival rate ranged from 56.3% in the mice treated at 23 HALO to 93.8 or 87.5% in those injected at 3 or 11 HALO, respectively (Exp 1, P < 0.01). Granulocytopenia at nadir was -49 +/- 14% at 7 HALO compared with -84 +/- 3% at 19 HALO (Exp 2 and 3, P < 0.029), and severe jejunal mucosa necrosis occurred in 5 of 8 mice treated at 23 HALO as opposed to 2 of 18 receiving docetaxel at 7, 11, or 19 HALO (Exp 2 and 3, P < 0.02). The time of least docetaxel toxicity corresponded to the circadian nadir in S or G2-M phase and to the circadian maximum in BCL-2 immunofluorescence in bone marrow. Docetaxel increased the median survival of tumor-bearing mice in a dose-dependent manner (controls: 24 days; 20 mg/kg weekly, 33 days; 30 mg/kg weekly or day 1, 3, 5 schedule, 44 or 46 days, respectively; Exp 5-7). Survival curves of treated mice differed significantly according to dosing time for each dose and schedule (P from log rank <0.003 to P < 0.03). In Exp 5 and 6, the percentage of increase in life span was largest if docetaxel was administered weekly at 7 HALO (20 mg/kg, 220%; 30 mg/kg, 372%) and lowest after docetaxel dosing at 19 HALO (80% with 20 mg/kg) or at 15 HALO (78% with 30 mg/kg). In Exp 7, (day 1, 3, 5 schedule), docetaxel was most active at 11 HALO (percentage increase in life span, 390%) and least active at 23 HALO (210%). Docetaxel tolerability and antitumor efficacy were simultaneously enhanced by drug dosing in the light span, when mice were resting. Mechanisms underlying the tolerability rhythm likely involved the circadian organization of cell cycle regulation. Docetaxel therapeutic index may be improved with an administration at night in cancer patients, when fewest bone marrow cells are in S or G2-M phase.
Cancer Res 1998 Sep 01
PMID:Docetaxel chronopharmacology in mice. 973

Docetaxel is a new taxoid with clinical activity in breast and lung cancer. Using docetaxel-sensitive and -refractory mammary and pancreatic murine tumours, as well as human-derived neoplasms, we investigated if a determinant of docetaxel sensitivity could be found at the level of its mechanism of action. Because microtubules represent the cellular targets of the drug, we studied their heterogeneity in the tumour models to try to explain the differences in drug sensitivity. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the expression of microtubular components showed that levels of Mbeta4-tubulin and Tau mRNAs were higher in the murine sensitive neoplasms than in the refractory ones. It was also found that Tau protein levels differed markedly among the tumours. In the human-derived sensitive neoplasm, beta-tubulins and some Tau isoforms were found to be more abundant than in the resistant one. Western blot analysis of MAP2 revealed the presence of several immunoreactive species. Some of these polypeptides were also found in higher amounts in the docetaxel-sensitive tumours. The possible meaning of these correlations is discussed in connection with the regulation of microtubule dynamics.
Br J Cancer 1998 Oct
PMID:Tau expression in model adenocarcinomas correlates with docetaxel sensitivity in tumour-bearing mice. 976 77

Although the radiosensitizing potential of paclitaxel has been investigated extensively in cancer treatment, a sister taxane, docetaxel, has been studied rarely. We investigated the ability of docetaxel to enhance in vivo tumor radioresponse and influence radiation injury to normal tissue. In addition, mitotic arrest and apoptosis in tumors and normal tissues were assessed after docetaxel administration to determine whether these cellular effects underly its radio-modifying action. Mice bearing in their legs 8-mm isotransplants of a murine mammary carcinoma, designated MCA-4, were treated with 33 mg/kg docetaxel i.v., 9-21 Gy single-dose local tumor irradiation, or both (in which case radiation was given 9 or 48 h after docetaxel). Tumor growth delay was the end point of the treatments. Mitotic arrest and apoptosis were assayed 1-72 h after treatment with docetaxel. Normal tissue radioresponse was determined using jejunal crypt cell survival 3.5 days after mice were exposed to 9.2-14.8 Gy single-dose, total-body irradiation; the mice were treated with 33 mg/kg docetaxel i.v. 3, 9, or 48 h before irradiation. Docetaxel was assessed for its ability to induce mitotic arrest and apoptosis in jejunum 1-72 h after treatment. Docetaxel induced both mitotic arrest and apoptosis in both tumor and jejunum. Mitotic arrest preceded apoptosis and peaked in the tumor at 9-12 h after treatment; it peaked at 3 h in jejunum. Docetaxel enhanced tumor radioresponse by a factor of 1.45 when the drug was given 9 h before radiation and 2.33 when it was given 48 h before. In contrast, it only slightly enhanced radiation-induced damage of the jejunum and only when given 3 or 9 h before irradiation. Thus, docetaxel given within 2 days before irradiation acted as a potent enhancer of tumor radioresponse and increased the therapeutic gain of irradiation.
Clin Cancer Res 1997 Dec
PMID:Docetaxel enhances tumor radioresponse in vivo. 981 44

Docetaxel activity has been documented in many solid tumors, including metastatic breast cancer and non-small cell lung cancer. However, as clinical studies in other tumor types are now being conducted, the validation of an optimal sampling strategy would allow the performance of pharmacokinetics/pharmacodynamics studies with minimum inconvenience for the patient. Six optimal sampling strategies with one to six sampling times were computed, based on the D-optimality theory, using population pharmacokinetic parameters estimated from a large pharmacokinetic database of 547 patients treated in previous Phase II studies. Validation of these sampling strategies was performed on a set of 35 patients, from two Phase I studies, who received docetaxel as a 1-h infusion at doses ranging from 50 to 100 mg/m2. Validation consisted of comparing clearance assessed by maximum likelihood estimation obtained using complete plasma concentration-time data (considered as the reference) and clearance determined by Bayesian estimation with an optimal design. For all of the optimal sampling strategies tested, clearance was found to be well estimated when at least two samples were taken. Bayesian estimation with two measured levels (at the end of infusion and at 6 h after the start of infusion) can be selected, because it allows adequate estimation of clearance with a nonsignificant bias of +1.37% and a precision of 12.3%.
Clin Cancer Res 1997 Sep
PMID:Optimal sampling strategies for bayesian estimation of docetaxel (Taxotere) clearance. 981 40


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