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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A combination of platinum and a taxane is regarded by many as the optimum treatment for advanced epithelial ovarian carcinoma. A recent meta-analysis has suggested that the addition of an anthracycline to platinum-based chemotherapy is associated with a significant survival advantage. We are therefore conducting an ongoing phase I/II study combining drugs from these three classes. We report here the first phase using carboplatin at an area under the concentration-time curve of 7, doxorubicin 50 mg/m2, and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 175 mg/m2 over 3 hours. The treatment was given on a 3-weekly cycle and granulocyte colony-stimulating factor was given if the nadir neutrophil count fell below 0.5 x 10(9)/L and was continued until recovery. Toxicity was assessed according to the Common Toxicity Criteria. All patients were required to have advanced ovarian cancer (stage IC to IV) but be ineligible for standard chemotherapy trials or to have advanced gynecologic malignancy, such as mixed mullerian tumor, fallopian tube carcinoma, coelomic carcinoma, or primary peritoneal carcinoma. To date, seven patients have been treated, and all were of performance status 0 to 2, 18 to 70 years old, with a life expectancy of > or = 3 months. Hematologic toxicity was significant, with all patients having grade 3/4 thrombocytopenia and six of seven grade 3/4 leukopenia. There was, however, only one grade 3/4 infection. Three patients have experienced fatigue, which in two cases was severe, and one patient had grade 3/4 stomatitis. Dose reduction was due to myelosuppression and was required in five patients. Five patients were evaluable for response, all of whom have obtained complete or partial response. There has been no clinical evidence of cardiotoxicity, but four patients had grade 1/2 cardiotoxicity as measured by left ventricular ejection fraction. We conclude that this combination is active and has acceptable but significant toxicity. It is only suitable for very fit patients, and we are currently assessing ways of reducing toxicity.
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PMID:Taxane/platinum/anthracycline combination therapy in advanced epithelial ovarian cancer. 904 34

Several studies have presented evidence that paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) displays a radiation-sensitizing effect. We therefore analyzed the influence of paclitaxel and concomitant radiation on the proliferation kinetics of head and neck tumor cells and normal fibroblasts. Our data clearly support the notion that paclitaxel given with radiation exerts an additive effect on the clonogenic survival of squamous cell carcinoma cells and normal fibroblasts. Since concomitant radiochemotherapy has proven to be beneficial for the treatment of locally advanced head and neck cancer, we are testing the feasibility of simultaneous paclitaxel plus radiotherapy. Paclitaxel is given on a one-time weekly basis. Up to now, 13 evaluable patients have been treated, and the maximum tolerable dose has not been reached at 40 mg/m2. Mucositis is expected to be the dose-limiting toxicity.
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PMID:Paclitaxel in simultaneous radiochemotherapy of head and neck cancer: preclinical and clinical results. 904 42

Patients with locally advanced solid tumors of the lung, head and neck, and malignant astrocytomas usually succumb to their disease despite aggressive standard therapy. Laboratory data suggest that the addition of 1.0 to 10 nmol/L paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a microtubule stabilizing drug, to radiation therapy may result in significant radiation sensitization, perhaps due to accumulation of cells at G2/M. Relatively low concentrations (1.0 to 10 nmol/L) appear to be optimal for direct cytotoxicity and radiosensitization in vitro. Within this dose range, more prolonged exposure seems to result in higher response rates. The phase I trials reported here are designed to test the combination of paclitaxel, administered by continuous intravenous infusion (24 hours a day, 7 days a week), and standard, curative-intent radiation therapy. The ultimate goal of this study is to improve local and systemic control and survival for patients with these three tumor types. To date, 39 evaluable patients are enrolled in this study; there has been no dose-limiting toxicity up to 6.5 mg/m2/d. Observed toxicities include anemia, lymphopenia, mucositis, and cutaneous toxicities.
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PMID:Intensive radiation therapy concurrent with up to 7-week continuous-infusion paclitaxel for locally advanced solid tumors: phase I studies. 904 44

Although the current clinical formulation of paclitaxel (Taxol) is an important new anti-cancer agent, it has significant side effects, some of which are related to its formulation in Cremophor/ethanol. Paclitaxel is difficult to formulate for i.v. administration because of its poor aqueous solubility. Here, we report the therapeutic effects of 2 liposome formulations of paclitaxel against human ovarian A121 tumor growing as an s.c. xenograft in athymic nude mice. The liposome formulations used were ETL and TTL, which have I or 3 lipid components, respectively. TTL was used as a reconstituted lyophilate or as a stable aqueous suspension. ETL was used as a reconstituted lyophilate only. Both paclitaxel-liposome formulations were much better tolerated than Taxol after i.v. or i.p. administration. The acute reactions seen after Taxol administration did not occur when paclitaxel-liposome formulations were administered. All ETL and TTL preparations significantly delayed A121 tumor growth similarly to Taxol at equivalent doses and schedules. Based on pharmacokinetic data, it is possible that paclitaxel rapidly dissociates from ETL or TTL after i.v. administration and distributes in a manner similarly to Taxol. ETL and TTL formulations may be useful clinically not only for eliminating toxic effects of the Cremophor/ethanol vehicle but also for allowing alterations in route and schedule of drug administration.
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PMID:Activity of paclitaxel liposome formulations against human ovarian tumor xenografts. 909 72

Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol (paclitaxel) is more effective in the presence of mutant p53. (90)Y-labeled DOTA-peptide-ChL6 ((90)Y-ChL6, where ChL6 is chimeric L6 antibody and DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid) is a novel radioimmunoconjugate for targeting radiation to cancer. It has a stable metal chelator and a peptide linker that can be catabolized by hepatic lysozymes. This study was designed to assess potential synergism between Taxol and (90)Y-ChL6 in a highly anaplastic breast cancer model, HBT 3477. There was no tumor response in mice receiving ChL6 or Taxol alone. In mice receiving (90)Y-ChL6 alone, 79% (15 of 19) of tumors responded although none were cured. If Taxol was administered 24-72 hours before (90)Y-ChL6, again, 79% (23 of 29) of tumors responded but 21% were cured. When Taxol was administered 6 or 24 hours after (90)Y-ChL6, 100% (46 of 46) of tumors responded and 48% were cured. Taxol given with (90)Y-ChL6 did not substantially increase toxicity. Enhancement of the therapeutic effect when Taxol was added to (90)Y-ChL6 therapy for HBT 3477 xenografts was striking. The synergistic therapeutic effect of Taxol with (90)Y-ChL6 may relate to the p53 mutant status and BCL2 expression in HBT 3477 cells, observations that increase the likelihood that the results of this study are relevant to therapy for breast cancer in patients. In conclusion, Taxol seemed to be synergistic with (90)Y-ChL6 in this human breast cancer model. Up to 50% of these anaplastic breast cancer xenografts were cured by combined modality therapy.
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PMID:Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: efficacy and toxicity in breast cancer xenografts. 910 94

Taxol cytotoxicity was evaluated in human head and neck squamous carcinoma cell lines growing as multicellular tumor spheroids (MTS) and compared with monolayered culture using conventional clonogenic assays. End points were respectively the concentration inhibiting 50% of the cellular growth (IC50) in clonogenic assays and the concentration required to induce a 50% decrease in the MTS volume (ID50) or number in the overall spheroid population (SCC50). A significant difference was observed when the cells were exposed for 10 days to Taxol as a consequence of the different growth kinetics of the spheroids. After 16 day exposure of spheroids to Taxol, no difference remained between ID50 and IC50. In addition, a significant correlation was found between individual spheroid sensitivity to Taxol (ID50) and the spheroid population sensitivity (SCC50). Both parameters (ID50 and SCC50) defined in cell models appear useful for the evaluation of chemosensitivity of three-dimensional structures known to be closer to in vivo tumor models.
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PMID:Evaluation of Taxol in head and neck squamous carcinoma multicellular tumor spheroids. 914 11

Tumor cells grown as multicellular spheroids are known to be intrinsically more resistant to a large and diverse array of anticancer chemotherapeutic drugs compared to the same cells grown as dispersed monolayer cell cultures. Some drugs, however, seem relatively insensitive to this multicellular drug resistance, e.g., cisplatinum. Whether the cytotoxic effects of Taxol, an anticancer drug of growing importance in the treatment of breast and ovarian carcinomas, are diminished by multicellular growth conditions is unknown. To study this question, we examined the relative sensitivity of a panel of four different human ovarian carcinoma cell lines to either Taxol or cisplatinum. Upon exposure to Taxol, all the cell lines manifested a relative drug-resistant phenotype when grown as multicellular tumor spheroids, compared to the same cells grown as sparse monolayer cultures. This multicellular-dependent drug-resistant phenotype was not observed when the same cells were exposed to cisplatinum for an equivalent length of time. Monolayer but not spheroid cultures exposed to Taxol demonstrated an accumulation of cells at G2-M and a sub-G1 apoptotic region. In addition, Taxol-induced apoptosis was detected in monolayer conditions but not in the spheroid cultures. The relative sensitivity of the monolayer cell cultures was associated with a decrease in bcl-X(L) protein levels after Taxol exposure, an effect not observed in drug-exposed spheroids. Taken together, these results suggest that some aspects of intrinsic Taxol resistance in ovarian carcinoma may be due to multicellular-dependent or -associated mechanisms. This raises the possibility of using antiadhesive agents to reverse multicellular-dependent Taxol resistance in certain circumstances as a potential means of increasing the initial efficiency of Taxol therapy against ovarian carcinoma.
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PMID:Abrogation of taxol-induced G2-M arrest and apoptosis in human ovarian cancer cells grown as multicellular tumor spheroids. 919 15

Development of the taxoids has progressed rapidly in the 1990s. In vitro studies have demonstrated that docetaxel (Taxotere) has a longer residence time and higher accumulation within tumor cells than paclitaxel (Taxol), possibly accounting for its greater cytotoxicity. Animal studies have shown docetaxel to possess high antitumor activity. In clinical studies, docetaxel as a single agent has been shown to be highly active against a variety of solid tumors. It is at least as active in metastatic disease as other agents currently used, and it has demonstrated effectiveness against tumors resistant to anthracyclines or paclitaxel. Docetaxel shows some activity in cell lines resistant to fluorouracil (5-FU), vincristine, cisplatin (Platinol), and etoposide (VePesid). Its unique mechanism of action and lack of cross-resistance or overlapping toxicities with many agents may also contribute to its efficacy and safety in combination therapy.
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PMID:Docetaxel in breast cancer and a rationale for combination therapy. 921 21

Two ovarian cancer cell lines, OVC432 and the newly established CVU4I, were used to study the effect of Taxal on cell growth and simultaneous CA 125 antigen expression. Growth of both cell lines was effectively inhibited by drug concentrations of 0.1 microM and higher. Complete inhibition of cell growth may result from high concentrations of Cremophor EL present in the Taxol formulation. Immunohistochemical analysis demonstrated that both cell lines retained the CA 125 expression on the cell surface during exposure to paclitaxel. This was reflected in a constant statistically significant correlation between cell numbers and CA 125 concentrations found in cell lysates. CA 125 levels in the culture medium showed a significant relation to cell numbers and, consequently, to the response of the cell line to the administered anticancer drug. It may be concluded from this study that CA 125 seems to be a reliable tumor marker in monitoring tumor response during paclitaxel treatment.
Tumour Biol 1997
PMID:Effect of paclitaxel (Taxol) on CA 125 expression and release by ovarian cancer cell lines. 921 8

Taxol (Paclitaxel) is a novel anti-cancer drug which has shown excellent clinical activity in a variety of solid tumors, particularly in metastatic breast and ovarian cancer. 70-80% of patients with metastatic non-seminomatous germ cell tumor (NSGCT) attain disease-free status with standard cisplatin-based combination chemotherapy but the emergence of drug resistance still prevents a small proportion of these patients from achieving long-term remission. Here we report the results of pre-clinical studies investigating whether taxol exhibits cross-resistance to cisplatin or ifosfamide in human NSGCT cell lines and in a cisplatin refractory xenograft model of human NSGCT. Following 96-h drug exposure in a 5-day sulphohodamine B (SRB) in vitro assay, taxol demonstrated potent cytotoxicity in cell lines which were cisplatin sensitive (577 LM, H32, H12.1; mean IC50s 1.5-3.0 nM) or those with acquired or intrinsic cisplatin resistance (H12DDP, H23.1; mean IC50s 2.5 nM). Compared to the drug-sensitive cell line, H12.1, the IC50 values of taxol were increased in cell line 1777NRp Cl-A with intermediate level resistance to cisplatin and ifosfamide (4.7 nM; p > 0.05) and significantly elevated in cell line 1411HP, with a high level of cisplatin resistance (6.9 nM; p < 0.01). The latter 2 cell lines may represent models corresponding to patients relapsing after high-dose platinum-based chemotherapy who seem to be resistant to taxol therapy. The IC50s of taxol in H32 and H12DDP were approximately 100-fold lower following drug exposure times exceeding 24 hours compared with short exposure times (1-6 h). Dose-dependent anti-tumor activity was observed with taxol in a cisplatin-refractory xenograft model of NSGCT (H23.1), with significant anti-tumor activity observed at a dose of 15 mg/kg/d injected intravenously on days 1 through 5. The results of this study are in accordance with the most recent clinical data which showed that taxol is a useful drug in relapsed or cisplatin-refractory testicular germ cell cancer, with significant anti-tumor activity being observed in 25% of patients, but poor activity in patients previously treated with high-dose therapy. Further pre-clinical research, especially using models such as 1411HP and 1777NRp Cl-A, on the combinations of taxol with other regimens are required to enable successful treatment of the most drug-resistant relapsed germ cell tumors.
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PMID:Pre-clinical activity of taxol in non-seminomatous germ cell tumor cell lines and nude mouse xenografts. 922 Feb 87


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