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

While the search for new antineoplastic agents is in progress, optimization of delivery for existing drugs will remarkably improve the current scenario in the management of cancer. Paclitaxel, a new antineoplastic agent, is one such drug deserving attention in the field of regional drug delivery, offering immense pharmacokinetic as well as therapeutic advantage via localized delivery. The antiangiogenic activity of paclitaxel has been demonstrated using the chick chorioallantoic membrane model (CAM). This review focuses on the antiangiogenic activity of paclitaxel supported by the evidence that angiogenesis inhibitors display potential synergism with cytotoxic agents in the treatment of primary and metastatic cancers. Preclinical trials have confirmed that the biological and cytotoxic effects of paclitaxel on several tumor cell lines are enhanced by the increase in both the drug concentration and the duration of exposure. Sufficient experimental evidence has accumulated to state that localized delivery will exploit the multiple pharmacological effects of paclitaxel in the treatment of refractory and metastatic cancerous diseases. The drug delivery systems, namely, microspheres, surgical pastes and implants, fabricated for localized paclitaxel delivery are reviewed explaining the concept of increased tumor burden alleviating body burden as a consequence of such delivery systems. Some of the preclinical trials are very encouraging and speculate a promising future for these devices in the battle against solid tumors. Finally, the review briefs on the possibilities for better paclitaxel delivery and the future drug delivery systems for localized cancer chemotherapy.
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PMID:Localized paclitaxel delivery. 1036 Nov 59

Paclitaxel is a potent anti-tumor drug used in the treatment of breast cancer. It induces de-centralization of the microtubular system in tumor cells, blocking cell division. In the search for dissemination to a secondary site, cancer cells are capable of degrading most components of the extracellular matrix via an extracellular proteolytic cascade, including urokinase-type plasminogen activator (uPA) and the matrix metalloproteinases (MMPs). In the present study, the effects of paclitaxel and nocodazole, 2 drugs known to affect microtubules with opposite mechanisms of action, have been tested for their effect on the secretion of uPA and MMPs in cultures of F3II mouse mammary-tumor cells. Tumor-derived uPA activity significantly increased after pre-treatment of tumor cells for 24 hr with micromolar concentrations of paclitaxel (4 microM), while decreasing after pre-treatment with nocodazole (1 microM). A similar modulation was found for MMP-9 by zymographic analysis. Immunofluorescence and Western-blot analysis confirmed the formation of parallel microtubule fragments in paclitaxel-treated cells and almost complete de-polymerization of microtubules in nocodazole-treated ones. Our data suggest that, through opposite actions on microtubule organization and dynamics, paclitaxel and nocodazole exert inverse modulation of tumor-derived proteolytic activity in mammary tumor cells.
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PMID:Modulation of urokinase-type plasminogen activator and metalloproteinase activities in cultured mouse mammary-carcinoma cells: enhancement by paclitaxel and inhibition by nocodazole. 1047 34

Paclitaxel and docetaxel are potent drugs that are effective in the treatment of malignant tumors. The cytotoxic action of these drugs is not fully understood, but it appears to be mediated mainly through mitotic arrest and subsequent apoptosis. Because no information is available on the antiangiogenesis action of docetaxel, the investigations were performed to determine whether inhibition of neoangiogenesis plays a role in docetaxel's antitumor efficacy. Four different mouse tumors, two squamous cell carcinomas (SCC-IV; SCC-VII) and two adenocarcinomas (MCA-4; MCA-29) were assayed for angiogenic activity using the in vivo i.c. angiogenesis assay. Tumor cells (5 x 10(5)) were injected i.c. into the skin flap over the abdominal wall, and the number of new blood vessels at the tumor cell injection site was determined 2, 4, 6, 8, 10 and 12 days later. The mice were treated with docetaxel (Taxotere--31.3 mg/kg i.v.) 1 or 4 days after tumor cell injection. The number of new blood vessels increased with time. Docetaxel reduced the number of newly formed blood vessels in MCAs, but not in SCCs. The reduction was associated with slower tumor growth. In a separate set of experiments we observed that docetaxel's inhibitory effect on the two MCAs was histologically associated with massive tumor cell destruction by means of both apoptosis and necrosis. This was not observed for the two SCCs. Since no reduction in blood vessels occurred in tumors unresponsive to docetaxel, the inhibition of neoangiogenesis in docetaxel-responsive tumors was likely the result of a decrease in angiogenic stimuli due to docetaxel's destruction of tumor cells.
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PMID:[Inhibition of tumor neo-angiogenesis and induction of apoptosis as properties of docetaxel (taxotere)]. 1047 67

The antiproliferative effect of paclitaxel, docetaxel, gemcitabine, topotecan, SN-38 and cis-platin was studied on 5 non-small cell lung cancer (NSCLC) cell lines, 3 of which were adenocarcinoma (ADK) and 2 squamous cell carcinoma (SCC). Cellular chemosensitivity was determined using the MTT in vitro assay after 48, 72 and 96 h of exposure to drug in concentration ranging from 0.001 to 100 microM. A concentration-dependent cell growth inhibition was observed for paclitaxel, gemcitabine, topotecan, SN-38 and cis-platin in all cell lines tested. Docetaxel showed a concentration-independent cytotoxicity and was 104 times more potent than cis-platin (IC50 = 0. 001 vs. 10 microM). Paclitaxel, gemcitabine, topotecan and SN-38 were 102 times more potent than cis-platin, with median IC50 = 0.1 microM at 72 h. The level of drug-induced cell growth inhibition appeared to be correlated, for some of the six drugs tested, with the tumor histological subtype. In particular, topotecan and cis-platin were more active in squamous cell carcinoma than in adenocarcinoma cell lines (p=0.006 and 0.001 respectively at 0.1 microM concentration), while paclitaxel was more active in ADK than in SCC cell lines (p=0.004 at 0.01 microM concentration). Ca-Lu-6, a cell line that, contrary to most other lung cancer cell lines, is wild-type for most oncogenes/tumor suppressor genes, was by far the most sensitive cell line used (p=0.002, 0.003, 0.01 for paclitaxel, topotecan and cis-platin respectively, at 1 microM concentration), showing a >50% growth inhibition to new drugs at a concentration of 0.01 microM. In conclusion, all these new compounds tested were found to be more potent than cis-platin in affecting cellular proliferation of six NSCLC cell lines studied. We suggest that the specific histological subtype and molecular pattern of the cell line being treated could affect the antiproliferative effect of these drugs.
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PMID:Pre-clinical evaluation of new antineoplastic agents in NSCLC cell lines: evidence of histological subtype-dependent cytotoxicity. 1049 63

Paclitaxel is a naturally occurring antimitotic agent that has been shown to stabilize microtubules, induce mitotic arrest, and ultimately induce apoptotic cell death. The favorable clinical activity of paclitaxel has prompted considerable interest in combining paclitaxel with numerous other antineoplastic agents. Our previous studies have suggested 5-fluorouracil (5-FU), an antineoplastic agent that usually arrests tumor cells at the G1-S phase of the cell cycle, in combination with paclitaxel significantly represses paclitaxel-induced mitotic arrest and apoptosis. In the present study, we have extended this investigation to include several other antimitotic agents (vinblastine, colchicine, and nocodazole) in various combination schedules with the G1-S arresting agents 5-FU and hydroxyurea (HU). We found 5-FU, as well as HU, could significantly interfere with the overall cytotoxicity as compared with treatment with antimitotic agents alone. It appeared that 5-FU or HU severely limited the antimitotic agents' cytotoxic effects on both mitotic arrest and apoptosis. No combination of a G1-S arresting agent with an antimitotic agent in any schedule produced an antitumor effect greater than that of the antimitotic agent alone. In addition, biochemical examination revealed that 5-FU and HU blocked the antimitotic agent-induced increase of p21WAF1/CIP1 protein levels, as well as prevented the hyperphosphorylation of the bcl-2 and c-raf-1 proteins. These findings suggest that careful considerations may be necessary when combining antineoplastic agents that exert their cytotoxic action at different phases of the cell cycle.
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PMID:Antagonistic interplay between antimitotic and G1-S arresting agents observed in experimental combination therapy. 1049 33

Paclitaxel is a deterpene with antitumor activity against a variety of human neoplasms. Paclitaxel cytotoxicity is thought to derive mainly from a stabilization of microtubules as a result of enhanced tubulin polymerization that leads to an accumulation of cells in the mitotic (M) phase of the cell cycle. Because cells in this phase of the cell cycle are known to be radiosensitive, it was thought that paclitaxel, in addition to its direct toxicity, may also sensitize tumor cell populations to radiation. Studies evaluating the radiosensitizing potential of paclitaxel in cultured cells have been equivocal, with only approximately 50% of the tested cell lines showing radiosensitization. To explain this variability, we advanced the hypothesis that the ability of paclitaxel to radiosensitize cells may be inversely correlated to the efficiency with which it induces apoptosis. To test this hypothesis, we studied paclitaxel-induced apoptosis and radiosensitization in seven human tumor cell lines. Approximately one-half of these cell lines showed radiosensitization that was associated with a low apoptotic index (<20% after a 48-h treatment with 10 or 20 nM paclitaxel). The results suggest that the level of apoptosis, after paclitaxel treatment, may predict for paclitaxel-induced radiosensitization, and that it could be introduced as a parameter for the optimization of combined treatment protocols.
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PMID:Apoptosis as a predictor of paclitaxel-induced radiosensitization in human tumor cell lines. 1049 36

Antibody to the Her-2/neu gene product has been shown to inhibit the growth of breast cancer cells overexpressing Her-2/neu and to have clinical utility in treating breast cancer. We studied a recombinant, humanized anti-Her-2/neu antibody (Herceptin) in preclinical models of human prostate cancer. The androgen-dependent CWR22 and LNCaP human prostate cancer xenograft models and androgen-independent sublines of CWR22 were used. Her-2/neu staining of the parental, androgen-dependent, and androgen-independent CWR22 tumors and LNCaP tumors demonstrated variable Her-2/neu expression. Herceptin was administered i.p. at a dose of 20 mg/kg twice weekly after the xenograft had been established. No effect of Herceptin on tumor growth was observed in any of the androgen-independent tumors; however, significant growth inhibition was observed in both of the androgen-dependent xenograft models, CWR22 (68% growth inhibition at the completion of the experiment; P = 0.03 for trajectories of the average tumor volume of the groups) and LNCaP (89% growth inhibition; P = 0.002). There was a significant increase in prostate-specific antigen (PSA) index (ng PSA/ml serum/mm3 tumor) in Herceptin-treated androgen-dependent groups compared with control (CWR22, 18-fold relative to pretreatment value versus 1.0-fold, P = 0.0001; LNCaP, 2.35-fold relative to pretreatment value versus 0.6-fold, P = 0.001). When paclitaxel (6.25 mg/kg s.c., five times/week) was given to animals with androgen-dependent and -independent tumors, there was growth inhibition in each group. Paclitaxel and Herceptin cotreatment led to greater growth inhibition than was seen for the agents individually. Thus, in these prostate cancer model systems, Herceptin alone has clinical activity only in the androgen-dependent tumor and has at least an additive effect on growth, in combination with paclitaxel, in both androgen-dependent and androgen-independent tumors. Response to Herceptin did not correlate with the PSA levels, because the PSA index markedly increased in the Herceptin-treated group, whereas it remained constant in the control group. These results suggest the utility of Herceptin in the treatment of human prostate cancer.
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PMID:Response of prostate cancer to anti-Her-2/neu antibody in androgen-dependent and -independent human xenograft models. 1051 79

Paclitaxel is an antimicrotubular agent that blocks the cells in the G2/M phase of the cell cycle. Due to this action, it is presumed that this drug could function as a radiation sensitizer. We studied the genotoxic effects of a combination of paclitaxel and radiation in four mammalian cell lines in the micronucleus assay. The results do not show a clear radiation-sensitizing effect. In the three cell lines, L5178Y, V79 and HeLa, the micronucleus frequencies varied around a theoretical additive effect of the single treatments (paclitaxel or radiation alone). Only the human breast cancer cell line MCF-7 showed consistently lower than additive micronucleus frequencies, although the deviation was not significant. Overall, it remains inconclusive whether paclitaxel exerts a radiosensitizing effect and, if so, whether this effect depends on the cell type or other characteristics of tumor biology.
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PMID:Combination of paclitaxel and radiation: genotoxicity in vitro in four mammalian cell lines. 1053 Jul 66

The newer or 'third generation' chemotherapeutic agents (paclitaxel, docetaxel, vinorelbine, gemcitabine, irinotecan, topotecan) have all recently been shown to have substantial activity against non-small-cell lung cancer (NSCLC). Many of these agents are now being incorporated into the therapy for patients with advanced disease. Paclitaxel was the first 'third generation' drug to be studied. The use of paclitaxel and carboplatin has proven to be a well tolerated and quite active regimen with one-year survival in patients with stage IV disease of about 40% and two-year survival of about 20%. These survival rates are at least twice as good as previous platinum-based regimens. We have simplified the administration of paclitaxel by using a one-hour infusion and many other investigators and clinicians have followed suit. The results are equivalent to a three-hour infusion schedule. Given the degree of activity in patients with stage IV disease, it is imperative to begin neoadjuvant and adjuvant trials with the newer drugs and drug combinations. We and others have started a neoadjuvant strategy which has proven to be feasible and most patients tolerate surgery well. While the results are quite preliminary, we have seen some complete pathologic responses (about 20%) and are encouraged by these early data. In addition, we have routinely used adjuvant paclitaxel and carboplatin in patients with stage IB-IIIA disease who have been previously resected. Radiotherapy and a weekly schedule of paclitaxel and carboplatin have been incorporated for patients with stages II-IIIB (selected IIIB patients). Randomized comparisons are certainly needed in the neoadjuvant and adjuvant arena and the other 'third generation' drugs need to be quickly evaluated. We have chosen to add a third agent to paclitaxel and carboplatin. The evaluation of several triple combinations including the addition of gemcitabine, vinorelbine and topotecan, respectively to the paclitaxel-carboplatin combination has been completed. Preliminary results from these trials will be briefly summarized and plans for additional studies of the newer agents will also be discussed. Studies to learn the appropriate combinations, doses and schedules of the newer drugs in concert with radiotherapy and/or resection are also urgently needed. Since the newer 'third generation' drugs appear to genuinely improve the survival of patients with stage IV disease, it is likely that incorporation of these more active agents into therapy for lower stages of disease will make an even greater impact on overall survival for patients with this common neoplasm.
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PMID:Paclitaxel-based therapy in non-small-cell lung cancer: improved third generation chemotherapy. 1058 42

SCH58500 is an agent for gene therapy of cancer, consisting of a replication-deficient type 5 adenovirus (Ad5) expressing the human p53 tumor suppressor gene (Ad5/p53). An important question about the use of Ad5/p53 gene therapy is how to achieve the therapeutically effective delivery of an Ad5/p53 vector to the tumor. We wanted to determine the effective depth of penetration of an Ad5/p53 vector by dosing the vector in an experimental human xenograft/SCID model. To assess depth of penetration, we developed a novel methodology for scanning tissue sections by laser scanning cytometry (LSC). SCID mice were given intraperitoneal injections of either p53(null) SK-OV-3 human ovarian tumor cells or p53(mut) DU-145 human prostate tumor cells to establish xenograft solid tumors. Mice were then dosed once or twice at 24-hour intervals by intraperitoneal injection with SCH58500 (Ad5/p53), an adenovirus construct expressing beta-galactosidase (Ad5/beta-gal), or a buffer control. Additional groups of mice received a single intraperitoneal dose of 10 mg/kg paclitaxel either alone or coadministered with Ad5/p53. Twenty-four hours after each last dose, the human solid tumor xenograft and relevant mouse tissue were removed from each mouse for the analysis of Ad5/p53 penetration. Immunohistochemistry (IHC) for beta-galactosidase protein revealed a depth of penetration of between 1 and 10 cells from the tumor surface. In some mice, hepatocytes in the periportal regions of liver lobules were also positive, indicating systemic absorption of adenovirus from the peritoneal cavity. IHC staining for p53 and p21 proteins in SK-OV-3 solid tumor xenografts revealed similar Ad/p53 penetration. LSC was used to map and quantitate apoptosis in both tumor and liver tissue biopsies, with over 450,000 nuclei from liver tissue and 150,000 nuclei from tumor tissue being evaluated. LSC analysis demonstrated a high level of apoptosis in the tumors that had been removed from Ad5/p53-dosed mice (12.7-19.7%). This level of apoptosis was significantly higher (P < 0.05) than was observed for liver tissues taken from Ad5/p53-dosed mice (2.7-8.0%) or tumor tissues taken from either Ad5/beta-gal-dosed mice (3.0-6.4%) or buffer control-dosed mice (3.0-5.3%). Scan bit maps from the extensive LSC analyses confirmed that apoptosis was present to about the same depth (1-10 cells) as had been identified by IHC for beta-galactosidase, p53, and p21 proteins. Paclitaxel coadministered with Ad5/p53 had no effect on Ad5 penetration into solid tumors in vivo as measured by IHC for p53 or p21 protein. However, the combination therapy did cause an elevation in the number of tumor cells undergoing apoptosis.
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PMID:The use of laser scanning cytometry to assess depth of penetration of adenovirus p53 gene therapy in human xenograft biopsies. 1059 17


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