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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using the sulforhodamine B assay, we compared the cytotoxic properties of the novel microtubule agent taxol and the semi-synthetic related compound Taxotere in nine human ovarian-carcinoma cell lines, including three pairs of cell lines rendered resistant to cisplatin or carboplatin. In addition, the cytotoxicity of the commonly used anticancer drugs cisplatin and adriamycin and the topoisomerase II inhibitor etoposide was determined. The results of continuous drug exposure showed that taxol [mean concentration producing 50% growth inhibition (IC50), 1.1 x 10(-9) M; range, 2.8 x 10(-9)-5 x 10(-10) M and Taxotere (mean IC50, 5.1 x 10(-10) M; range, 7.2-3.3 x 10(-10) M) were greater than 1,000 times more cytotoxic than either cisplatin (mean IC50, 3.1 x 10(-6) M; P less than 0.05) or etoposide (mean IC50, 2.3 x 10(-6) M; P less than 0.05) and greater than 100 times more cytotoxic than Adriamycin (mean IC50, 6.9 x 10(-8) M; P less than 0.05). Taxotere was more cytotoxic than taxol; following continuous exposure, the mean difference across the cell lines was 2 orders of magnitude (range, 1.1-3.9 orders of magnitude for individual lines). Although this difference did not reach statistical significance for any individual cell line (P values ranged from 0.17 for HX/62 to 0.9 for OVCAR-3), when all IC50 values for the 96-h experiments were pooled, Taxotere was found to be significantly more potent than taxol (P = 0.05). Following 2 h exposure, the mean cytotoxicity of Taxotere was 3.9-fold greater than that of taxol across the nine lines (range, 0.75- to 10-fold; P less than 0.05 for the CH1 cell line; overall pooled IC50 data, P = 0.05). Although a 71-fold range of sensitivity to cisplatin was observed across the six parent cell lines (IC50 most resistant line/IC50 most sensitive line), this was largely abolished by treatment with taxol (5.6-fold range) and Taxotere (2.2-fold range). Following continuous exposure of the three pairs of lines exhibiting acquired resistance to platinum, no cross-resistance with either Taxotere or taxol was found (resistance factors, less than 1.5). In the 41M and 41McisR pair of lines, in which previous studies have shown resistance to be due to reduced platinum accumulation, taxol and Taxotere exhibited some collateral sensitivity (resistance factors, 0.69 and 0.66, respectively). Taxotere and, particularly, taxol showed a pronounced concentration times exposure duration (C x T) dependence as compared with cisplatin (P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
Cancer Chemother Pharmacol 1992
PMID:Comparative in vitro cytotoxicity of taxol and Taxotere against cisplatin-sensitive and -resistant human ovarian carcinoma cell lines. 135 49

A rapid, selective and reproducible high-performance liquid chromatographic (HPLC) method with ultraviolet detection was developed for the determination of the anti-cancer agent Taxotere in biological fluids. The method involves a solid-phase extraction step (C2 ethyl microcolumns) using a Varian Advanced Automated Sample Processor (AASP) followed by reversed-phase HPLC. The validated quantitation range of the method is 10-2500 ng/ml in plasma with coefficients of variation < or = 11%. The method is also suitable for the determination of Taxotere in urine samples under the same conditions. The method was applied in a phase I tolerance study of Taxotere in cancer patients, allowing the pharmacokinetic profile of Taxotere to be established.
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PMID:Determination of Taxotere in human plasma by a semi-automated high-performance liquid chromatographic method. 136 29

Taxotere (RP 56976; NSC 628503; N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol) is a new microtubule stabilizing agent. It is obtained by semisynthesis from a noncytotoxic precursor extracted from the needles of the tree, Taxus baccata L. Taxotere was evaluated for antitumor activity against a variety of transplantable tumors of mice. Taxotere had no marked schedule dependency and was found active by the i.v. and the i.p. routes. Upon i.v. administration, 9 of 11 tumor models tested responded to Taxotere. B16 melanoma was found highly sensitive to Taxotere, with a tumor growth inhibition of 0% and a 3.0 log10 tumor cell kill at the maximum tolerated dose. In the same trial, taxol produced only a 1.1 log10 tumor cell kill at the maximum tolerated dose. Taxotere cured early stage pancreatic ductal adenocarcinoma 03 (6 of 6 cures) and colon adenocarcinoma 38 (7 of 7 cures). It also effected greater than 80% complete regressions of advanced stage disease with both tumors. Taxotere was active against early and advanced stage colon adenocarcinoma 51, with 2.3 and 1.7 log10 cell kill, respectively. Four other tumors responded to a lesser extent: Lewis lung (5.5% tumor growth inhibition), Glasgow osteogenic sarcoma (27.2% tumor growth inhibition), L1210 and P388 leukemias (70 and 54% increase in life span, respectively). Because of its good preclinical activity and its unique mechanism of action, Taxotere has entered Phase I clinical trials.
Cancer Res 1991 Sep 15
PMID:Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxol analogue. 168 23

The development of new chemotherapeutic agents for cancer treatment is pursued with the hope of finding compounds with novel chemical characteristics, unique mechanisms of action, and with improved therapeutic indexes. Seven novel agents at different stages of clinical development have been selected for review. D1694 is a thymidylate synthase inhibitor that has intriguing preclinical activity. The anthrapyrazoles consist of three analogues that are undergoing phase II testing at present. One of these agents, CI-941, has been reported to have significant clinical activity in breast cancer. Lometrexol is an inhibitor of glycinamide ribonuclide transformylase, a critical enzyme in purine biosynthesis, that is undergoing phase II testing. Taxotere, a semisynthetic analogue of taxol that stabilizes microtubules, is currently undergoing phase I testing. Gemcitabine, a fluorinated analogue of deoxycytidine that can inhibit ribonucleotide reductase and be incorporated into DNA, is undergoing phase II testing. BMY-25067 is a mitomycin C analogue that is less myelosuppressive and more active than mitomycin C in preclinical models. Topotecan, a topoisomerase I inhibitor, has been shown to cause myelosuppression as the dose-limiting toxicity in phase I testing. Although each of these agents have some unique and novel characteristics that merit their clinical testing, these agents' long-range clinical role will depend on their efficacy in randomized phase III comparative trials.
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PMID:Novel chemotherapeutic agents in clinical development. 168

Docetaxel, a novel anticancer agent, was given to 26 patients by short i.v. infusion (1-2 h) at various dose levels (70-115 mg/m2, the maximum tolerated dose) during 2 phase I studies. Two population analyses, one using NONMEM (nonlinear mixed-effect modeling) and the other using NPML (nonparametric maximum-likelihood), were performed sequentially to determine the structural model; estimate the mean population parameters, including clearance (Cl) and interindividual variability; and find influences of demographic covariates on them. Nine covariates were included in the analyses: age, height, weight, body surface area, sex, performance status, presence of liver metastasis, dose level, and type of formulation. A three-compartment model gave the best fit to the data, and the final NONMEM regression model for Cl was Cl = BSA(Theta1 + Theta02 x AGE), expressing Cl (in liters per hour) directly as a function of body surface area. Only these two covariates were considered in the NPML analysis to confirm the results found by NONMEM. Using NONMEM [for a patient with mean AGE (52.3 years) and mean BSA (1.68 m2)] and NPML, docetaxel Cl was estimated to be 35.6 l/h (21.2 lh-1 m-2) and 37.2 l/h with interpatient coefficients of variations (CVs) of 17.4% and 24.8%, respectively. The intraindividual CV was estimated at 23.8% by NONMEM; the corresponding variability was fixed in NPML in an additive Gaussian variance error model with a 20% CV. Discrepancies were found in the mean volume at steady state (Vss; 83.21 for NPML versus 1241 for NONMEM) and in terminal half-lives, notably the mean t1/2 gamma, which was shorter as determined by NPML (7.89 versus 12.2 h), although the interindividual CV was 89.1% and 62.7% for Vss and t1/2 gamma, respectively. However, the NPML-estimated probability density function (pdf) of t1/2 gamma was bimodal (5 and 11.4 h), probably due to the imbalance of the data. Both analyses suggest a similar magnitude of mean Cl decrease with small BSA and advanced age.
Cancer Chemother Pharmacol 1995
PMID:Population pharmacokinetics of docetaxel during phase I studies using nonlinear mixed-effect modeling and nonparametric maximum-likelihood estimation. 749 96

Taxanes are an important new class of anticancer agents that inhibit cell division by the unique mechanism of increasing the rate of microtubule assembly and preventing microtubule depolymerisation. Using the colony inhibition assay, we compared the cytotoxicity of paclitaxel and docetaxel in three human neuroblastoma (NB) cell lines, SH-SY5Y, BE(2)M17 and CHP100. Different exposure times (3, 6, 12, 24, 48 and 72 h) and different concentrations ranging from 0.1 nM to 10 microM were tested. Both paclitaxel and docetaxel show antineoplastic activity in human NB cell lines. Taxanes' antitumour activity varied among the different cell lines, CHP100 being the most sensitive and SH-SY5Y the least sensitive. Paclitaxel cytotoxicity appears schedule-dependent, with marked cell kill observed only for exposures of 24 h or longer. Docetaxel cytotoxicity was dependent upon prolonged exposure only in the SH-SY5Y cell line, while an exposure time of 3-6 h resulted in exponential cell kill in the other two cell lines. Docetaxel was more cytotoxic than paclitaxel with a mean ratio of (paclitaxel/docetaxel) IC50 values ranging from 2 to 11. For both taxanes, we observed good correlation between cytotoxic effect and percentage of cells blocked in G2/M phase. A cytotoxic effect occurred at concentrations comparable with those achieved in the plasma of patients treated with these agents in initial clinical trials. The full potential of prolonged infusion or repeated daily administrations of taxanes should be explored in clinical studies, and responses to taxanes in neuroblastoma should be assessed in paediatric phase II studies.
Eur J Cancer 1995
PMID:Cytotoxicity of paclitaxel and docetaxel in human neuroblastoma cell lines. 757 52

Docetaxel is a taxoid cytotoxic agent which promotes tubulin assembly into microtubles and inhibits their depolymerisation. In vitro, docetaxel reduces murine and human tumour cell survival by 50% at concentrations of 4-35 ng/ml, with a greater cytotoxic effect on proliferating than on non-proliferating cells. In vivo, docetaxel is schedule-independent. Over 80% of murine transplantable tumours were found to be very docetaxel sensitive, with complete regression of advanced stage tumours. Activity was also observed in > 90% of advanced stage human tumour xenografts in mice. In combination therapy studies, synergism with 5-fluorouracil, cyclophosphamide and etoposide was observed in vivo. Docetaxel exhibited linear pharmacokinetics and long tumour retention in tumour-bearing mice; plasma protein binding ranged from 76 to 89%. In toxicological studies in mice and dogs, docetaxel produced haematological, gastrointestinal and neuromotor toxicity. The dog was found to be the most sensitive species to the toxic effects of docetaxel.
Eur J Cancer 1995
PMID:Preclinical pharmacology of docetaxel. 757 97

Docetaxel is a new taxoid drug with good activity against human breast cancer cells in vitro; a number of partial and minor responses have been obtained during phase I studies in patients with advanced breast cancer. In phase II trials, first-line use of docetaxel has produced an overall response rate (OR) of up to 73%. In addition, docetaxel has shown good activity when given as second-line therapy (OR 38%), particularly in patients with disease refractory to anthracyclines (OR 55%). Indeed, the high response rate in this latter group of patients clearly warrants further investigation of docetaxel in this setting. Neutropenia is the major dose-limiting toxicity of docetaxel, but other haematological effects are rare. Hypersensitivity and cutaneous reactions are ameliorated by premedication with corticosteroids and histamine antagonists; fluid retention may improve with longer use of prophylactic premedication. Docetaxel is mildly emetogenic, but no other premedication is necessary. In summary, docetaxel is an active new drug in the treatment of advanced breast cancer. Its role in the management of early stage disease awaits the results of prospective randomised trials.
Eur J Cancer 1995
PMID:An overview of phase II studies of docetaxel in patients with metastatic breast cancer. 757 98

Docetaxel has been evaluated in 293 patients with advanced ovarian cancer in three phase II trials. All patients had previously received cisplatin and/or carboplatin as first-line treatment. In all three studies, treatment comprised docetaxel 100 mg/m2 as a 1 h intravenous infusion every 3 weeks, without premedication for hypersensitivity reactions or emesis. To date, 200 patients are evaluable for response. Of these, 63 patients achieved complete or partial response, giving an overall response rate of 31.5% (95% confidence interval 24-39%) for all evaluable patients, or 21.5% for all patients entered in the studies. Of the 57 patients whose disease had progressed either during previous therapy or within 4 months of discontinuing previous therapy, 13 (23%) responded to docetaxel (EORTC data). Major adverse effects of docetaxel observed in approximately half the patients (particularly those who received more than four courses) included skin reactions and fluid retention. Grade III or IV neutropenia was common but short-lived. Severe acute hypersensitivity reactions occurred in approximately 5% of patients. Docetaxel now warrants evaluation as part of first-line therapy. Studies aimed at reducing the incidence of fluid retention and skin reactions with docetaxel are ongoing.
Eur J Cancer 1995
PMID:Docetaxel in advanced ovarian cancer: preliminary results from three phase II trials. EORTC Early Clinical Trials Group and Clinical Screening Group, and the MD Anderson Cancer Center. 757 99

Phase II studies have been conducted to evaluate the efficacy and tolerability of docetaxel in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Docetaxel was administered to patients with stage III and IV NSCLC at a dose of 100 mg/m2 intravenously over 1 h every 3 weeks. Patients included in these four phase II studies had received either no prior chemotherapy (n = 114) or treatment with cisplatin- or carboplatin-containing regimens (n = 57). Major objective response rates were reported in 33-38% of previously untreated evaluable patients and in 21-27% of previously treated evaluable patients. Neutropenia was the most common adverse event. Non-haematological adverse events included hypersensitivity reactions, skin rash, alopecia and fluid retention. Docetaxel demonstrates significant antitumour activity in patients with advanced NSCLC. Further investigations of this agent with corticosteroid premedication, colony-stimulating factors and other agents active in NSCLC are indicated.
Eur J Cancer 1995
PMID:Docetaxel in stage III and IV non-small cell lung cancer. 757


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