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 standard approaches of surgery or radiotherapy cure only a minority of patients with esophageal cancer. Because of these poor results and the frequent systemic pattern of recurrences, combined-modality therapy employing chemotherapy has been extensively studied. Preoperative chemotherapy, both alone and given concurrently with radiation, has not shown a significant impact on survival and remains investigational. Concurrent chemoradiation as definitive therapy is an alternative to surgery for localized disease. Paclitaxel and vinorelbine have significant activity as single agents in metastatic disease. Paclitaxel is currently under investigation in combination therapy for metastatic disease, as a radiosensitizer for locally advanced disease, and as preoperative therapy. For palliation of locally advanced esophageal cancer, a variety of endoscopic techniques are available to relieve dysphagia. Laboratory studies have identified growth factor pathways and tumor-suppressor genes as potential new pharmacologic targets.
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PMID:Management of esophageal cancer. 888 28

Paclitaxel alone is active against the CD8F1 murine spontaneous mammary cancer, and when administered following an ATP-depleting combination of N-(phosphonacetyl)-L-aspartate (PALA) + 6-methylmercaptopurine riboside (MMPR) + 6-aminonicotinamide (6-AN) (PMA) produced significantly enhanced partial tumor regressions over that produced by either paclitaxel alone at the maximal tolerated dose (MTD), or by the PMA drug combination alone, against advanced, first passage spontaneous murine breast tumors. The anticancer activity of paclitaxel is due to enhancement and stabilization of microtubule polymerization. Pertinently, microtubule disassembly (an ATP-dependent process) is known to sharply decrease in the presence of ATP depletion. Thus, the dramatic therapeutic enhancement observed with paclitaxel in combination with PMA is in agreement with biochemical expectations, since PMA has been shown to deplete ATP in CD8F1 tumor cells. The augmented therapeutic results were obtained with approximately one-third the MTD of paclitaxel as a single agent and suggest the potential clinical benefit of more effective treatment with lesser amounts of drug.
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PMID:Marked enhancement in vivo of paclitaxel's (taxol's) tumor-regressing activity by ATP-depleting modulation. 891 34

Paclitaxel, a recently approved antineoplastic agent, is cleared slowly from the peritoneal cavity after i.p. injection, and therefore appears to be promising for intracavitary therapy of malignancies confined to the peritoneal cavity. However the dose-limiting toxicity of Taxol, the clinical formulation of paclitaxel, was severe abdominal pain, likely caused by the excipients (Cremophor EL and ethanol) that are required to overcome low drug solubility. We tested the hypothesis that a liposome-based formulation could modulate paclitaxel toxicity independent of antitumor activity. The dose-dependence of toxicity and antitumor effect of paclitaxel liposomes was evaluated after i.p. administration against i.p. P388 leukemia. Liposomal paclitaxel showed antitumor activity similar to that of free paclitaxel (as Taxol), but was better tolerated by both healthy and tumor-bearing mice.
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PMID:Paclitaxel-liposomes for intracavitary therapy of intraperitoneal P388 leukemia. 894 23

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been studied primarily on a 3-week schedule as a 3-, 24-, or 96-hour infusion at doses ranging from 135 to 250 mg/m2. The observed toxicity profile seems to be both dose and schedule dependent. Dose densification of paclitaxel given weekly over 6 weeks on a split-dose schedule for an overall increase in dose intensity was thought to improve the therapeutic index of paclitaxel in a variety of advanced malignancies and to be suitable for outpatient administration. For this study, chemotherapy consisted of a weekly 1-hour infusion of paclitaxel at a starting dose of 40 mg/m2/wk for 6 weeks, followed by a 2- to 3-week interval. Paclitaxel dosage was escalated in 10 mg/m2/wk increments in subsequent patients, to a maximum dosage of 90 mg/m2/wk. Intravenous dexamethasone, cimetidine, clemastine, and ondansetron were administered immediately before the paclitaxel infusion. Fifty patients participated in the study. The male to female ratio was 21 to 29, the median age was 53.2 years (age range, 33 to 74), and the median performance status was 1. All patients were chemotherapeutically pretreated. Overall response included five complete responses (10%), 15 partial responses (30%), 19 no change (38%), and 11 disease progressions (22%). Median dose intensity was 410 mg/m2/6 wk (range, 200 to 540 mg/m2/6 wk). Hematologic toxicity was mild, with no grade 3 or 4 toxicity up to 90 mg/m2/wk. No hypersensitivity reactions or neurologic or cardiac toxicities were documented. Dose-densified, weekly paclitaxel is concluded to be active in a variety of pretreated tumor entities. The overall low hematologic and peripheral toxicity profile suggests that further dose intensification of weekly paclitaxel and/or combination with other cytotoxic agents (eg, cisplatin/carboplatin, ifosfamide, etoposide) may be warranted. Paclitaxel can be given safely in the outpatient setting. Paclitaxel 90 mg/m2/wk is recommended for single-agent treatment. Dose-densified paclitaxel may be considered a valuable and promising alternative to standard 3-week treatment, with further options possible in combination chemotherapy.
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PMID:Schedule- and dose-intensified paclitaxel as weekly 1-hour infusion in pretreated solid tumors: results of a phase I/II trial. 900 18

In a clinical phase II trial, escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) were given with concurrent radiation to patients with stage IIIA/B non-small cell lung cancer. Radiotherapy was given in daily doses of 2 Gy, 5 days a week, in weeks 1 through 3 and 6 through 8. Paclitaxel was given on day 1 of weeks 1 through 3 and 6 through 8, at a starting dose level of 50 mg/m2. Subsequent paclitaxel dose levels were 60, 72, 86, and 103 mg/m2. Three to six patients were included at each dose level until intolerable toxicity (World Health Organization grade 3 or 4 leukopenia) occurred in three of six patients. To date, 27 patients have entered the protocol. Hematologic toxicity was mild with no severe myelosuppression up to the 86-mg/m2 dose level. At paclitaxel 103 mg/m2, four of six patients developed grade 3 or 4 leukopenia, and dose escalation was stopped. The maximum tolerated dose was thus determined to be 86 mg/m2. The main clinical toxicity was the occurrence of pulmonary infections (seven patients), one of whom had Pneumocystis carinii infection; the six others had interstitial infections with no pathogen isolated. Mild to moderate esophagitis was seen in five patients. Thus far, of 24 patients evaluable for response, 18 showed decreased tumor size. Four patients achieved major responses (near-complete disappearance of radiologic tumor signs), 11 patients achieved partial remission, and three patients had a minor response. The overall response rate was 75%. In summary, the maximum tolerated dose of paclitaxel in this study has been determined to be 86 mg/m2 weekly. Pulmonary infections represent the major clinical toxicity, and the high response rate merits further clinical evaluation of this regimen.
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PMID:Paclitaxel and simultaneous radiation in the treatment of stage IIIA/B non-small cell lung cancer. 900 35

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of the most active single agents for the treatment of non-small cell lung cancer, with response rates of 21% to 24%. We present a phase I study with paclitaxel and simultaneous radiation in previously untreated, locally advanced, inoperable, stage IIIA/B non-small cell lung cancer. The aims of the study were to determine the maximum tolerated dose, define the safety and toxicity, and obtain preliminary data about the activity of the combined modality. Patients received a fixed dose of radiotherapy (1.8 Gy/d, 5 days a week for 6.5 weeks, for a total dose of 59.4 Gy) and concomitant chemotherapy with paclitaxel 45 mg/m2 days 1, 8, and 15 in level 1; days 1, 8, 15, 22, and 29 in level 2; and days 1, 8, 15, 22, 29, 36, and 43 in level 3. The paclitaxel dosage was increased to 55 mg/m2 on days 1, 8, 15, 22, 29, 36, and 43 in level 4. Paclitaxel was administered as a 3-hour continuous intravenous infusion. Dexamethasone, clemastine, and ranitidine were given for hypersensitivity prophylaxis. Twenty-two patients (18 men and four women) entered the study; their median age was 66.5 years (age range, 38 to 74 years). Disease stage was IIIA in six of 22 patients and stage IIIB in 16. Six patients were treated at level 1, five at level 2, five at level 3, and six at level 4. There were 18 patients evaluable for toxicity and response. Side effects generally were moderate during the treatment period. One patient withdrew by request after the first course, one patient died of tumor bleeding after five courses, one patient died of progressive disease (lymphangiosis carcinomatosa of both lungs) after the sixth course, and one patient is too early for evaluation. Among the 18 patients evaluable for response, there were one complete and 10 partial remissions; seven patients reached a minor response. It is concluded that the therapy was well tolerated in these patients. Importantly, no severe adverse events were observed that could be associated with paclitaxel or radiotherapy. This combined modality appears to be a practicable and effective treatment of non-small cell lung cancer. The maximum tolerated dose has not yet been reached, and dose escalation is planned.
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PMID:Paclitaxel and simultaneous radiation in locally advanced stage IIIA/B non-small cell lung cancer: a clinical phase I study. 900 38

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a member of the taxanes, has been shown to have antitumor activity in a wide variety of cancers, such as breast cancer and ovarian cancer. Paclitaxel also has antitumor activity in certain previously relatively unresponsive tumors, such as lung, head and neck, esophageal, and bladder cancers. The optimal dose for each tumor has not been well defined. While 3-hour infusion appears to be the most convenient, studies of both longer and shorter infusions are in progress. Any incremental benefit of higher dose or longer schedule will need to be evaluated on the basis of the higher costs and toxicities. The results of many initial studies using combination chemotherapy with paclitaxel have generated considerable enthusiasm, but careful comparison studies and evaluation of toxicities are needed. Additional roles of paclitaxel include its ability to act synergistically with radiotherapy, and thus possibly help improve the local control of tumors, such as head and neck, esophageal, bladder, and lung cancers. Studies testing the role of the taxanes in neoadjuvant therapy before radiotherapy or surgery are just beginning. Paclitaxel is thus one of the very important new agents in the treatment of cancer, and further work is needed to define its optimal use.
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PMID:Paclitaxel in head and neck and other cancers: future prospects. 904 28

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

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

Paclitaxel shows a broad clinical activity in ovarian, breast and non-small cell lung cancers. However, controversy remains about the respective effects of doses and schedules in paclitaxel cytotoxicity. This study was conducted to compare the cytotoxic activity of short-term (1 h) versus prolonged exposure (14 days) to paclitaxel in human cancer cells. A soft-agar cloning system assay was used to determine the in vitro effects of 0.025-25.0 microg/ml paclitaxel against cancer cells taken directly from patients. A decrease in tumor colony formation resulting from drug exposure was considered an in vitro response if survival of colonies was up to 50% of that in positive controls. Among 11 evaluable patients' biopsies, both short- and long-term exposure to paclitaxel had significant concentration-dependent effects on the growth inhibition of human cancer cells. With the 1 h exposure schedule, in vitro responses were observed in 9,18 and 64% of evaluable tumor specimens at final concentrations of 0.25, 2.5 and 25.0 microg/ml, respectively. With the prolonged exposure schedule, concentrations of 0.25, 2.5 and 25.0 microg/ml induced 27, 45 and 91 in vitro response rates, respectively. In those patients' biopsies prolonged exposure to paclitaxel induced significantly more in vitro tumor responses than 1 h administration (p < 0.01). Similar trends were observed in ovarian, breast and non-small cell lung cancers. Our data indicate that the duration of exposure to paclitaxel is an important factor in paclitaxel cytotoxicity in human tumors and suggest that long-term exposure may improve the antitumor activity of paclitaxel.
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PMID:Effects of prolonged versus short-term exposure paclitaxel (Taxol) on human tumor colony-forming units. 918 Mar 92


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