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)

The authors define the dose-limiting toxicities and the recommended phase II doses of paclitaxel combined with etoposide, without and with filgrastim support. Patients with advanced solid tumors were eligible if they had a performance status of 0 to 2 and normal renal, hepatic, and bone marrow function. Patients with cardiac arrhythmias or congestive heart failure requiring medical therapy were excluded. Prior radiation was allowed only if it involved less than 30% of the marrow-containing skeleton. The dose of etoposide was fixed at 100 mg/m2/d for 3 days beginning on day 1. Paclitaxel was administered over 3 hours on day 4. The dose of paclitaxel was escalated until the maximum tolerated dose (MTD), without and with filgrastim 5 microg/kg (or 300 microg total dose) subcutaneously beginning on day 5, was reached. Treatment cycles were repeated every 21 days. Of 39 patients entered, 37 were evaluable for toxicity and 30 for response. The principal toxicity was neutropenia. Without filgrastim, the MTD of paclitaxel was 150 mg/m2. With filgrastim, the dose of paclitaxel was escalated to 250 mg/m2 in combination with etoposide 100 mg/m2. One episode of pulmonary toxicity was observed. Five patients responded: two with previously treated non-small-cell lung cancer (NSCLC), two with refractory small-cell lung cancer (SCLC), and one with refractory germ-cell tumor (GCT). We conclude that paclitaxel and etoposide can be given in combination at clinically relevant doses with filgrastim support. In this phase I trial, a dose of paclitaxel of 200 mg/m2 on day 4 and etoposide at 100 mg/m2/d on days 1-3, with filgrastim 5 microg/kg beginning on day 5, was found to be well tolerated, and can be recommended for future studies. Without filgrastim, a paclitaxel dose of 150 mg/m2 with the same dose of etoposide can also be recommended.
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PMID:Phase I study of paclitaxel and etoposide for metastatic or recurrent malignancies. 953 96

Paclitaxel (Taxol), a chemotherapeutic agent used to treat breast and ovarian tumors, has been reported to induce a predominantly sensory neuropathy. Co-treatment with neurotrophic factors and paclitaxel has been proposed for preventing or reversing paclitaxel-induced peripheral neuropathy. Prosaposin, the precursor of saposins A, B, C and D was recently identified as a neurotrophic factor and was reported to facilitate nerve regeneration in vivo. Peptides (prosaptides) encompassing the neurotrophic sequence located in the saposin C domain, have neurotrophic activity similar to the holoprotein (O'Brien et al. 1995). In the present study, we investigated the effect of a 14-mer prosaptide, TX14(A), or a 22-mer prosaptide, 769P, on paclitaxel-induced neutrotoxicity in vitro and in vivo. Paclitaxel treatment (1 microM) decreased cell viability of both PC12 and Schwann cells. TX14(A) (10 nM) prevented paclitaxel-induced loss of cell viability in PC12 cells but not in Schwann cells. Systemic injections (i.p.) of paclitaxel (1.2 mg/kg/day) given five times per week for three weeks (cumulative dose 18 mg/kg) or given every third day (25, 12.5 and 12.5 mg/kg) for 10 ten days (cumulative dose 50 mg/kg) in adult rats induced thermal hypoalgesia that was not accompanied by morphological changes in the sciatic nerve or changes of nerve conduction velocity. Co-administration of paclitaxel with prosaptides (cumulative dose 3 or 10 mg/kg) prevented paclitaxel-induced thermal hypoalgesia. In the short-term high dose study, paclitaxel treated rats lost 10% of their body weight, had reduced erythrocyte counts, hematocrit and hemoglobin concentrations which were not prevented by treatment with prosaptide. TX14(A) did not diminish paclitaxel cytotoxicity of breast cancer cells in vitro. These findings suggest that prosaptide prevents the neurotoxic effects of paclitaxel while not interfering with its anti-tumor activity.
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PMID:Prosaptide prevents paclitaxel neurotoxicity. 955 60

Synergy (or antagonism) between two chemical agents is an in vitro empirical phenomenon, in which the observed effect of the combination is more (or less) than what would be predicted from the effects of each agent working alone. Although mathematical synergy is not directly provable in the clinical setting, it does predict a favorable outcome when the two therapeutics are combined in vivo and strongly suggests the presence of in vivo synergy. In contrast, overt antagonism warns of future problems. Sophisticated three-dimensional statistical modeling was used to evaluate the presence of synergistic, additive, or antagonistic efficacy between adenovirus (Ad)-mediated p53 gene therapy (p53 Ad) and paclitaxel (Taxol) in a panel of human tumor cell lines. Cells were either pretreated with paclitaxel 24 h before p53 Ad or treated with both agents simultaneously. Cell proliferation was measured 3 days later. Paclitaxel had synergistic or additive efficacy with p53 gene therapy. In no case was the interaction antagonistic. Cell cycle analysis demonstrated that p53 Ad arrested cells in G0/G1 prior to apoptotic cell death, whereas paclitaxel arrested cells in G2-M prior to apoptotic cell death. When combined, the relative concentration of each agent determined the dominant cellular response. These results are consistent with the previously reported cell cycle effects of p53 or paclitaxel, respectively; however, these data fail to explain the observed drug synergy. We found that low concentrations of paclitaxel (1-14 nM) increased the number of cells transduced by recombinant Ad 3-35% in a dose-dependent manner, which is one possible mechanism for the observed synergy. Of particular note, the concentrations of paclitaxel responsible for increased Ad transduction were lower than the concentrations required for microtubule condensation. The efficacy of combination therapy was also evaluated in vivo. In the p53null SK-OV-3 xenograft model of ovarian cancer, a dosing schedule of p53 Ad that, by itself, had a relatively minimal effect on tumor burden (16%) caused a much greater decrease in tumor burden (55%) when combined with paclitaxel. Greater combined efficacy was also observed in the p53mut DU-145 prostate, p53mut MDA-MB-468 breast, and p53mut MDA-MB-231 breast cancer xenograft models in vivo. In summary, p53 Ad for cancer shows enhanced efficacy when combined with paclitaxel. This combination is recommended for clinical cancer trials.
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PMID:Adenovirus-mediated p53 gene therapy and paclitaxel have synergistic efficacy in models of human head and neck, ovarian, prostate, and breast cancer. 956 76

Paclitaxel (Taxol) is becoming increasingly important in the treatment of many tumors, although a large proportion of tumors fail to respond to this drug. The identification of the processes that confer cellular paclitaxel resistance could provide potential targets for novel therapies that may help to eliminate paclitaxel-resistant tumors. Recent reports suggest that the Raf-1 protein kinase may have a profound influence on the level of paclitaxel-induced apoptosis. We have critically evaluated the relationship between Raf-1 kinase activity and de novo paclitaxel resistance in early-passage human cervical tumors. In the 12 cell lines studied, Raf-1 kinase activity was inversely correlated (P = 0.0016) with the level of cytotoxicity induced by 60 nM paclitaxel. The relationship between these two parameters seems to be more than an epiphenomenon, because genetic down-regulation of Raf-1 kinase activity led to an approximately 4-fold increase in paclitaxel-induced cytotoxicity. The data from both our transfection studies and those on the 12 unperturbed cell lines are consistent with Raf-1 kinase being a negative determinant of paclitaxel-induced cytotoxicity. Because the cytotoxicity of paclitaxel is primarily attributable to apoptosis, these data suggest that Raf-1 kinase acts to suppress paclitaxel-induced apoptosis. These data suggest that the clinical effectiveness of paclitaxel could be substantially improved by the use of Raf-1 kinase inhibitors, provided that a similar relationship between Raf-1 kinase activity and paclitaxel cytotoxicity exists in the clinic, especially in those tumor sites where paclitaxel is the current treatment of choice e.g., ovarian and breast cancer.
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PMID:High Raf-1 kinase activity protects human tumor cells against paclitaxel-induced cytotoxicity. 960 67

Recurrent endometrial cancer has grave prognosis. Chemotherapy and hormonal therapy are mainstays of palliative treatment. Unfortunately the frequency of complete response and duration of progression-free interval are limited. This case report describes a patient with recurrent metastatic endometrial cancer who was initially treated with radiotherapy followed by surgery. Her recurrent tumor progressed during treatment with external radiation and a progestogen. She received paclitaxel (135 mg/m2 i.v. infusion over 24 h) and carboplatin (AUC 7.5 microg x h/ml) every 4 weeks with complete remission after 8 months which has persisted for 22 months. Paclitaxel and carboplatin combination should be considered for the treatment of endometrial cancer.
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PMID:Prolonged remission of endometrial cancer with paclitaxel and carboplatin. 962 39

Combined treatment with paclitaxel and anthracyclines is increasingly being tested in clinical practice. Epirubicin is in general administered before paclitaxel. We have investigated, using a murine mammary adenocarcinoma, whether the efficacy and toxicity of this combination is influenced by treatment sequence, different time intervals and dose intensity. The tumor was transplanted into the right hind foot of C3D2F1 female mice. Paclitaxel was administered i.p. in doses ranging from 15 mg/kg to 75 mg/kg and epirubicin (i.p. or i.v.) in doses from 9 mg/kg to 30 mg/kg. The hepatic and peritoneal toxicity observed with epirubicin administration increased in combined treatments (stronger with i.p. than i.v. epirubicin administrations) and was dose-dependent. When paclitaxel and epirubicin were administered simultaneously or paclitaxel was given 24 h before epirubicin, the same tumor growth delays were obtained in all groups. A smaller effect was observed when paclitaxel was administered 24 h after epirubicin. Increasing the epirubicin or paclitaxel dose led to higher tumor growth delays but also an increased toxicity. In conclusion, in this experimental model, the administration of 45 mg/kg paclitaxel before 15 mg/kg epirubicin was very effective and the increased toxicity can be limited by introducing an interval of 24 h between drug administrations. These results should be considered when designing clinical trials.
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PMID:Greater antitumor efficacy of paclitaxel administered before epirubicin in a mouse mammary carcinoma. 964 53

Transferrin is a serum glycoprotein involved in iron transport. Transferrin acts also in cell growth regulation through membrane receptors. The number of transferrin receptors is increased in tumor and other rapidly dividing cells. This renders transferrin suitable for use in cytotoxic drugs targetting tumor cells. Paclitaxel was derivatized on 2' carbon and coupled with trasferrin using glutaraldehyde. The cytotoxicity of the conjugate was evaluated on small cell carcinoma of the lung cell line (H69). As compared to paclitaxel, the conjugate exhibited a slight decrease in cytotoxicity.
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PMID:In vitro cytotoxicity of paclitaxel-transferrin conjugate on H69 cells. 976 72

Paclitaxel (Taxol) is a novel anti-cancer drug that has shown efficacy toward several malignant tumors, particularly ovarian tumors. We reported previously that paclitaxel can induce interleukin (IL)-8 promoter activation in subgroups of ovarian cancer through the activation of both AP-1 and nuclear factor kappaB. Further analysis of paclitaxel analogs indicates that the degree of IL-8 induction by analysis correlates with the extent of cell death; however, IL-8 itself is not the cause of cell death. This suggests that pathways that lead to IL-8 and cell death may overlap, although IL-8 per se does not kill tumor cells. To decipher the upstream signals for paclitaxel-induced transcriptional activation and cell death, we studied the involvement of protein kinases that lead to the activation of AP-1, specifically the c-Jun NH2-terminal kinase (JNK1), p38, and the extracellular signal-regulated kinase 1 (ERK1). The role of IkappaB in paclitaxel-induced cell death was also analyzed. Paclitaxel activated JNK, and to a lesser degree p38, but not ERK1. Paclitaxel-induced IL-8 promoter activation was inhibited by dominant-inhibitory mutants of JNK, p38, and the super-repressor form of IkappaBalpha, but not by dominant-inhibitory forms of ERK1. Dominant-inhibitory mutants of JNK1 also greatly reduced paclitaxel-induced cell death, and the kinetics of JNK induction was closely followed by DNA fragmentation. These results indicate (i) that paclitaxel activates the JNK signaling pathway and (ii) that JNK activation is a common point of paclitaxel-induced gene induction and cell death.
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PMID:Paclitaxel (Taxol)-induced gene expression and cell death are both mediated by the activation of c-Jun NH2-terminal kinase (JNK/SAPK). 977 47

The response rate (RR) to single-agent chemotherapy with doxorubicin or ifosfamide in patients with advanced soft-tissue sarcoma (STS) is in the range of 20%. Paclitaxel is clinically useful in treating several solid tumors and has demonstrated activity in a series of human sarcoma cell lines. Twenty-eight patients with measurable advanced STS participated in this phase II trial of paclitaxel at 250 mg/m2 administered as a 3-hr i.v. infusion once every 3 weeks. All patients received granulocyte colony-stimulating factor (G-CSF) beginning on the day after paclitaxel and lasting until recovery from neutropenia. No prior chemotherapy had been used in 17 patients; 10 patients had had prior doxorubicin-based therapy; and 1 patient had had intraperitoneal therapy with edatrexate. Two partial responses (PRs) (7%; 95% confidence interval [CI] = 1-23%) were observed. The responding patients included a patient with angiosarcoma of the scalp who had complete regression of cutaneous lesions and improvement of nonmeasurable pulmonary disease lasting 6 months. The other PR occurred in a woman with metastatic uterine leiomyosarcoma and lasted 9 months. Seven patients had stable disease for 3-4 months. Median time to progression for all patients was 3.5 months (range: 2.5-9 months). The mean nadir in the white-blood-cell (WBC) count was 3.8 x 10(3)/microliter (range: [0.2-16.2] x 10(3)/microliter), with a mean nadir in the absolute neutrophil count (ANC) of 2.4 x 10(3)/microliter (range: [0.0-7.1] x 10(3)/microliter). Three patients died while in the study. Two patients with angiosarcoma of the scalp who did not qualify for this study were treated with paclitaxel off protocol, and experienced dramatic tumor regression. The overall response to paclitaxel observed in this heterogeneous group of patients was disappointing. However, the activity seen in angiosarcoma of the scalp suggests that further evaluation is warranted in patients with STS.
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PMID:Phase II trial of paclitaxel in patients with soft-tissue sarcoma. 977 50

The chemotherapeutic agent paclitaxel disrupts microtubule dynamics causing mitotic arrest, which leads to cell death. However, in paclitaxel-resistant tumor cells, treatment with paclitaxel induces abnormal progression through prophase resulting in a multimininucleated phenotype. Multimininucleation and subsequent polyploidization have been correlated with paclitaxel resistance. Paclitaxel treatment of HeLa cells resulted in cell death via typical activation of the apoptotic machinery, whereas treatment of the relative paclitaxel-resistant prostate cancer cell line PC-3 induced an attenuated caspase activation and multimininucleation. The multimininucleated phenotype could be mimicked in HeLa cells treated with paclitaxel and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), a peptide caspase inhibitor. Interestingly, we observed no discernible difference in the pattern of cdc-2 kinase activation or phosphorylation of bcl-2-like proteins in PC-3 and HeLa cells treated with paclitaxel, which demonstrated that these molecules could not be used as indicators for the degree of caspase activation. In this study, we establish a connection between relative paclitaxel resistance, caspase attenuation/inhibition, and the multimininucleated phenotype.
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PMID:Paclitaxel-associated multimininucleation is permitted by the inhibition of caspase activation: a potential early step in drug resistance. 978 20


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