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

Paclitaxel (Taxol), a promoter of microtubule polymerization and a radiosensitizing agent, is one of the more active anticancer drugs in the current treatment of solid tumors. In this study, we show that paclitaxel possesses an antiangiogenic property associated with a down-regulation of vascular endothelial growth factor (VEGF) in a highly-vascularized transgenic murine breast cancer (Met-1). Paclitaxel, at non-cytotoxic doses of 0, 3 and 6 mg/kg/day, was administered intraperitoneally for 5 days to nude mice bearing the Met-1 breast tumor. Extent of intratumoral angiogenesis, as indicated by microvessel tortuosity and microvessel density, was significantly reduced by paclitaxel in a dose-dependent manner. Paclitaxel also suppressed expression of VEGF in the Met-1 cells transplanted in nude mice or maintained in cell culture. These results indicate that antiangiogenesis associated with a down-regulation of VEGF is an additional mode of action of paclitaxel.
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PMID:Paclitaxel (Taxol): an inhibitor of angiogenesis in a highly vascularized transgenic breast cancer. 1085 Feb 85

Paclitaxel, a potent anti-tumor agent, shifts the cytoskeleton equilibrium towards assembly of altered and extraordinarily stable microtubules. These cellular modifications lead to reduced proliferation, migration, and signal transduction. It is highly lipophilic, which promotes a rapid cellular uptake, and has a long-lasting effect in the cell due to the structural alteration of the cytoskeleton. This makes paclitaxel a promising candidate for local drug delivery intended to address the proliferative and migratory processes involved in restenosis. In this article, results of our in vitro and in vivo studies with paclitaxel are presented. Cell culture experiments with monocultures of human arterial smooth muscle cells as well as co-cultures with human endothelial cells showed that paclitaxel leads to an almost complete growth inhibition within a dose range of 1.0-10.0 mumol/l, even after a short (20 min) single dose application. The comparison of an active, semi-active, and passive delivery system (porous balloon, microporous balloon, and double balloon) favored the double balloon for the following in vivo experiments. Tubulin staining and electron microscopy enabled visualization of paclitaxel-induced vessel wall alterations. In the rabbit model, locally delivered paclitaxel resulted in reduced neointima formation and enlargement in vessel size; in the pig model, however, after stenting, this inhibition was not significant. Both reduced proliferation and enlargement in vessel size contribute to a preservation of vessel shape and are likely to be caused by a structural alteration of the cytoskeleton, which is also supported by vascular contraction force experiments.
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PMID:[Paclitaxel: a chemotherapeutic agent for prevention of restenosis? Experimental studies in vitro and in vivo]. 1090 Jun 68

An important goal in cancer chemotherapy is to sensitively and quantitatively monitor the response of individual patients' tumors to successful, or unsuccessful, therapy so that regimens can be altered iteratively. Currently, tumor response is monitored by frank changes in tumor morphology, yet these markers take long to manifest and are not quantitative. Recent studies suggest that the apparent diffusion coefficient of water (ADCw), measured noninvasively with magnetic resonance imaging, is sensitively and reliably increased in response to successful CTx. In the present study, we investigate the combination chemotherapy response of human breast cancer tumor xenografts sensitive or resistant to Paclitaxel by monitoring changes in the ADCw. Our results indicate that there is a clear, substantial, and early increase in the ADCw after successful therapy in drug sensitive tumors and that there is no change in the ADCw in p-glycoprotein-positive tumors, which are resistant to Paclitaxel. The mechanism underlying these changes is unknown yet is consistent with apoptotic cell shrinkage and a concomitant increase in the extracellular water fraction.
Neoplasia 1999 Jun
PMID:Early increases in breast tumor xenograft water mobility in response to paclitaxel therapy detected by non-invasive diffusion magnetic resonance imaging. 1093 44

Most patients that present in the clinic with prostate cancer have either localized or recurrent postradiotherapy therapy tumors that may be amenable to injectable treatments using slow-release cytotoxic drugs. The objective of this preclinical study was to design an injectable polymeric paste formulation of paclitaxel for intratumoral injection into nonmetastatic human prostate tumors grown s.c. in mice. Paclitaxel was dissolved (10% w/w) in a blend of a biodegradable triblock copolymer of a random copolymer of D,L-lactide and epsilon-caprolactone (PLC) with poly(ethyleneglycol) [PEG; PLC-PEG-PLC] blended with methoxypoly(ethylene glycol) in a 40:60 ratio. Human prostate LNCaP tumors grown s.c. in castrated athymic male mice were injected with 100 microl of this paste at room temperature. Changes in tumor progression were assessed using both serum prostate-specific antigen (PSA) levels and tumor size. Paclitaxel inhibited LNCaP cell growth in vitro in a concentration-dependent fashion with an IC50 of 1 nM. Apoptosis was documented using DNA fragmentation analysis. The paste formulation solidified over a period of 1 h both in vivo and in aqueous media at 37 degrees C as the methoxypoly(ethylene glycol) component partitioned out of the insoluble PLC-PEG-PLC/paclitaxel matrix. The semisolid implant released drug at a rate of about 100 microg/day in vitro. In control mice treated with paste without paclitaxel, serum PSA levels increased from 2-8 ng/ml (mean, 4.3+/-2 ng/ml) to 60-292 ng/ml (mean, 181+/-88 ng/ml), and tumor volume increased from 30 to 1000 mm3. In mice treated with a single 100-microl injection 3 weeks after castration (early-phase treatment group), tumors decreased in volume from a mean of 43+/-19 mm3 to nonpalpable, and PSA levels decreased from a mean of 22+/-8 to 2+/-1 ng/ml by 8 weeks after castration. In mice treated 5 weeks after castration (androgen-independent tumors; late-phase treatment group), tumors decreased in volume from a mean of 233+/-136 mm3 to nonpalpable, and serum PSA decreased from 24+/-8 to 9+/-4 ng/ml. Observed side effects of the treatment were limited to minor ulceration at the needle injection site in paclitaxel-treated mice only. The controlled-release formulation can be injected via 22-gauge needles and is effective in inhibiting LNCaP tumor growth and PSA levels in mice bearing multiple nonmetastatic tumors. Paclitaxel may be an effective therapy for patients with localized tumors recurring after radiotherapy and for some patients with localized tumors who are not candidates for radical treatment.
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PMID:The suppression of human prostate tumor growth in mice by the intratumoral injection of a slow-release polymeric paste formulation of paclitaxel. 1094 22

Anaplastic thyroid carcinoma is a rare, lethal disease with no effective systemic therapies. Preclinical studies demonstrated antineoplastic activity of paclitaxel. This prompted a prospective phase 2 clinical trial to determine activity of paclitaxel against anaplastic thyroid carcinoma in patients with persistent or metastatic disease despite surgery or local radiation therapy. Twenty patients, entered through 6 of 12 study sites, were treated with 96-hour continuous infusion paclitaxel every 3 weeks for 1 to 6 cycles; the first 7 patients received 120 mg/m2 per 96 hours and the rest received 140 mg/m2 per 96 hours. Total responses to therapy were assessed using modified criteria with response durability acceptable at 2 or more weeks, due to the exceedingly rapid growth rate of this tumor. Plasma samples were obtained for pharmacokinetic analyses. Off-protocol, data showed that 9 patients were later treated with 225 mg/m2 paclitaxel as weekly 1-hour infusions. Nineteen evaluable patients demonstrated a 53% total response rate (95% confidence interval, 29%-76%) with one complete response and nine partial responses (including one off protocol). Results of historical review off-protocol showed 2 of 7 patients, with prior partial responses to the 96-hour infusion, had subsequent partial responses to weekly treatment and 1 of 2 prior nonresponders gained a partial response to weekly therapy. No toxicities greater than grade 2 were seen with 96-hour infusions, while peripheral neuropathy (up to grade 3) was most common with postprotocol weekly infusions. Paclitaxel appears to be the only agent with significant clinical systemic activity against anaplastic thyroid carcinoma; however, it is not capable of altering the lethality of this malignancy, suggesting the need for additional therapeutic innovations. Decreased time intervals between paclitaxel infusions may be more efficacious.
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PMID:Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group. 1095 11

Paclitaxel (Taxol), a naturally occurring antimitotic agent, has shown significant cell-killing activity in a variety of tumor cells through induction of apoptosis. The mechanism by which paclitaxel induces cell death is not entirely clear. Recent studies in our laboratory demonstrated that glucocorticoids selectively inhibited paclitaxel-induced apoptosis without affecting the ability of paclitaxel to induce microtubule bundling and mitotic arrest. This finding suggests that apoptotic cell death induced by paclitaxel may occur via a pathway independent of mitotic arrest. In the current study, through analyses of a number of apoptosis-associated genes or regulatory proteins, we discovered that paclitaxel significantly down-regulated IkappaB-alpha, the cytoplasmic inhibitor of transcription factor nuclear factor-kappaB (NF-kappaB), which in turn promoted the nuclear translocation of NF-kappaB and its DNA binding activity. In contrast, we found that glucocorticoids could antagonize paclitaxel-mediated NF-kappaB nuclear translocation and activation through induction of IkappaB-alpha protein synthesis. Northern blotting analyses demonstrated that the steady-state level of IkappaB-alpha mRNA was not affected by paclitaxel, which suggests that the down-regulation of IkappaB-alpha by paclitaxel is attributable to protein degradation rather than suppression of transcription. Furthermore, through transfection assays, we demonstrated that tumor cells stably transfected with antisense IkappaB-alpha expression vectors remarkably increased their sensitivity to paclitaxel-induced apoptosis. Finally, we found that a key subunit of IkappaB kinase (IKK) complex, IKKbeta, was up-regulated by paclitaxel, which implies that paclitaxel might down-regulate IkappaB-alpha through modulation of IKKbeta activity. All of these results suggest that the NF-kappaB/IkappaB-alpha signaling pathway may contribute to the mediation of paclitaxel-induced cell death in solid tumor cells.
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PMID:Nuclear factor-kappaB/IkappaB signaling pathway may contribute to the mediation of paclitaxel-induced apoptosis in solid tumor cells. 1096 88

This review evaluates tolerance and disease control for eight patients with muscle invasive bladder cancer treated with pelvic radiotherapy and concomitant paclitaxel/carboplatin chemotherapy. From October 1996 through February 1998, eight patients were treated with pelvic radiotherapy and concomitant paclitaxel/carboplatin chemotherapy. All received from 39.60-41.40 Gy to the pelvis followed by a boost to the initial site of disease. Final tumor doses ranged from 64.80-68.40 Gy. Most patients received paclitaxel at 150 mg/m2 and carboplatin at an area under the curve (AUC) of 7 at 3-week cycles during the radiation therapy. No patient required treatment interruption. With a median follow-up of 27 months, three patients remain free of local and distant disease at follow-up intervals of 24, 25, and 31 months. No surviving locally controlled patient demonstrated late urinary or gastrointestinal morbidity. All patients with a visibly complete transurethral resection of bladder tumor (TURBT) prior to radiotherapy achieved local disease control. For this group of patients, the absolute 2-year pelvic tumor control rate is 57%. The 2-year disease-specific survival is 43%. Paclitaxel/carboplatin chemotherapy can be delivered with continuous course pelvic radiation therapy without severe acute or apparent late toxicity. This combination also appears to be effective in achieving disease control in the urinary bladder, particularly in those patients who have undergone a thorough TURBT. The authors believe that it would be reasonable to investigate this combination in future bladder conservation protocols. The combination of paclitaxel and carboplatin with radiotherapy may be of particular value in elderly patients or those with renal impairment.
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PMID:Radiation therapy and concomitant paclitaxel/carboplatin chemotherapy for muscle invasive transitional cell carcinoma of the bladder: a well-tolerated combination. 1109 52

Paclitaxel has been reported to be effective for the treatment of CDDP resistant tumors. Thus, the efficacy of paclitaxel on CDDP resistant HEp-2 and KB head and neck squamous carcinoma cell lines was evaluated in monolayer and multicellular tumor spheroids (MTS). Cell lines with a tenfold resistance to CDDP were used in this study (Tanaka, K. et al, Keio J Med, 70. 1993). MTS were developed using the liquid overlay culture technique. After exposure to graded concentrations of drugs and different exposure time, the cells were subjected to a clonogenic assay. The effect of paclitaxel on both monolayer and MTS was dependent on the drug concentration and related to the exposure time. For HEp-2 MTS, 10(-7) M/L of paclitaxel resulted in a cell death rate of approximately 90% in both parent and resistant cells. For KB MTS, the cells were more resistant to paclitaxel than the HEp-2 cells, and a 72 hour exposure time was needed to achieve a cell death rate of approximately 90%. These data suggest that paclitaxel may be effective for treating CDDP resistant head and neck cancer.
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PMID:[Effect of paclitaxel on cisplatin resistant head and neck squamous multicellular tumor spheroids]. 1110 28

Chemosensitivity to the drugs plays a crucial role in the treatment of ovarian cancer. In this study, we evaluate the cytotoxicity of chemotherapeutic agents in six ovarian cancer cell lines; four clear cell adenocarcinoma and two serous papillary adenocarcinoma, using seven single drugs and seven sets of drug combinations with tetrazolium-based semiautomated colorimetric (MTT) assay. The drug concentration which produced 50% growth inhibition (IC50) of cisplatin was within clinically achievable range in five cell lines. The area under the curve (AUC) at IC50 of cyclophosphamide was below the clinically achievable AUC in two serous papillary cell lines. Paclitaxel was more effective in clear cells than serous papillary cells. The intensification of cytotoxicity was observed in the combinations of paclitaxel and cisplatin, and cyclophosphamide and cisplatin or 5-fluorouracil irrespective of histopathological characteristics of the original tumor. Our results indicate that ovarian cancer cell lines respond to chemotherapeutic agents heterogeneously depending upon histopathological features, indicating individualized regimens may improve survival in ovarian cancer patients.
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PMID:Cyclophosphamide and 5-fluorouracil act synergistically in ovarian clear cell adenocarcinoma cells. 1112 61

SCH58500 (ACN53) is a replication-deficient, type 5 adenovirus (Ad) expressing human wild-type p53 tumor suppressor. It is currently undergoing clinical trials as a cancer therapeutic. Many SCH58500 clinical trials incorporate an arm comparing traditional chemotherapy against chemotherapy combined with SCH58500. Paclitaxel was chosen for combination therapy in the preclinical study reported here due to its extensive use as a first-line therapy in ovarian cancer, its synergy with SCH58500 in preclinical cancer models, and its activation of p53-independent apoptosis, which might result in a "lowered threshold" for tumor cell death. SCID mice bearing human tumor xenografts were dosed with intratumoral vehicle, control Ad vector, or SCH58500, with or without paclitaxel. Real-time quantitative reverse transcriptase polymerase chain reaction assays were developed and validated to quantitate expression of p53, the p53 downstream effector gene p21, and the apoptosis-related genes, bax, bcl-2, and survivin. Protein expression was confirmed using immunohistochemical assays for p53 and p21. Only tumors injected with SCH58500 had detectable levels of exogenous p53 DNA and mRNA. After SCH58500 treatment, 3-11-fold elevations of p21 expression were observed in tumor xenografts containing nonfunctional p53 (MDA-MB-468, MDA-MB-231, MIAPaCa2, DU-145, and SK-OV-3), but no change in p21 mRNA in wild-type p53 PA-1 tumors. Immunohistochemical assays confirmed induction of p21 protein in MDAMB-468 and SK-OV-3 cells, but not in PA-1 cells. Ad vector alone or paclitaxel alone had no effect on p21 mRNA levels in most tumors. However, paclitaxel suppressed p21 expression induced by SCH58500 4-fold in DU-145 and SK-OV-3 tumors. Paclitaxel also affected expression of the housekeeping gene gapdh. There was no consistent pattern to the changes in bax, bcl-2, or survivin after SCH58500 treatment with or without paclitaxel between tumor types, although there were consistent responses within individual tumor lines. The mRNA ratios for bax/bcl-2 and bax/survivin were also not informative across tumor types. Of the genes examined, only p21 gave a predictable response 24 hours after p53 gene therapy and therefore, p21 expression may be useful for confirming SCH58500 activity in human tumor biopsies.
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PMID:Development and validation of sensitive assays to quantitate gene expression after p53 gene therapy and paclitaxel chemotherapy using in vivo dosing in tumor xenograft models. 1112 89


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