Paclitaxel (Taxol): An Inhibitor of Angiogenesis in a Highly Vascularized Transgenic Breast Cancer

Lau, Derick H; Xue, Ling; Young, Lawrence J.T.; Burke, Patricia A.; Cheung, Anthony

doi:10.1089/cbr.1999.14.31

Cited by 156 publications

(76 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Paclitaxel at low nanomolar concentrations can also affect tumor angiogenesis indirectly either by reducing the tumor secretion of angiogenic growth factors, such as VEGF (10) or by decreasing its secretion by endothelial cells, which may act in an autocrine fashion (Merchán and Sukhatme, unpublished findings). 5 Other possible mechanisms that may explain the antiangiogenic effects of this combination include a decrease in circulating endothelial precursor number and viability, as previously demonstrated with metronomic cyclophosphamide.…”

Section: Discussionmentioning

confidence: 99%

“…Among these compounds are the microtubule-interfering agents vinblastine, paclitaxel and docetaxel. 3,[7][8][9][10][11][12][13][14] Paclitaxel is a microtubule-polymerizing agent that is widely used in the treatment of solid tumors. In addition to its known cytotoxic effects, it inhibits endothelial cell migration, invasion, capillary tube formation and proliferation in vitro at concentrations ranging from picomolar to nanomolar, depending on the endothelial cell type and the assay conditions.…”

mentioning

confidence: 99%

“…3,15,16 In addition, paclitaxel has been shown to significantly reduce microvessel density and decrease vascular endothelial growth factor production in vivo. 3,10,12 The mechanism(s) responsible for the exquisite sensitivity of ECs to paclitaxel have not been elucidated. Because ECs appear to be particularly sensitive to paclitaxel, we hypothesized that they may have the ability to accumulate paclitaxel to a greater degree than other cell types, which could contribute to their enhanced sensitivity to this agent.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Increased endothelial uptake of paclitaxel as a potential mechanism for its antiangiogenic effects: Potentiation by Cox‐2 inhibition

Merchan

Jayaram

Supko

et al. 2004

Intl Journal of Cancer

View full text Add to dashboard Cite

Paclitaxel has antiangiogenic properties, but the mechanisms for the enhanced sensitivity of endothelial cells (ECs) to this drug are not established. The aims of our study were to compare the distribution of paclitaxel into ECs with other cell types, to assess the effects of low doses of paclitaxel on Cox-2 expression and to determine the combined effects of paclitaxel and Cox-2 inhibitors on angiogenesis in vitro and in patients with cancer. Upon exposure to low (5 nM) concentrations of [ 3 H]-paclitaxel, uptake of radioactivity was more than 5 times higher in ECs than other cell types. Exposing human umbilical vein ECs to low nanomolar (1-50 nM) concentrations of paclitaxel enhanced Cox-2 expression more than 2-fold, as measured by ELISA. Combined treatment with paclitaxel and the Cox-2 inhibitor NS-398 resulted in increased antiendothelial effects as compared to each agent alone. To assess the biologic effects of the combined treatment in vivo, 4 cancer patients were treated with a prolonged intravenous infusion of paclitaxel (10 mg/m 2 /day) and the Cox-2 inhibitor celecoxib (400 mg p.o. BID), and plasma angiogenic activity and drug levels were measured. The treatment was well tolerated, providing steady-state concentrations of paclitaxel in plasma near 10 nM and potent plasma antiendothelial effects were observed. These findings suggest that antiangiogenic effects of paclitaxel may be due its preferential accumulation in ECs. Low dose paclitaxel in combination with a Cox-2 inhibitor is an attractive antiangiogenic and antitumor strategy that deserves further evaluation in clinical trials.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Increased endothelial uptake of paclitaxel as a potential mechanism for its antiangiogenic effects: Potentiation by Cox‐2 inhibition

Merchan

Jayaram

Supko

et al. 2004

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Microtubule-destabilising agents have been recently investigated as antivascular compounds (Iyer et al, 1998;Blakey et al, 2002), and an antiangiogenic potential has been reported for paclitaxel (PTX) and docetaxel (Belotti et al, 1996;Klauber et al, 1997;Lau et al, 1999;Schimming et al, 1999;Sweeney et al, 2001;Cassinelli et al, 2002). The antiangiogenic activity of PTX has been ascribed mainly to its ability to inhibit endothelial cell motility, rather than proliferation (Belotti et al, 1996) and to downregulate angiogenesis-related growth factors .…”

mentioning

confidence: 99%

IDN 5390: an oral taxane candidate for protracted treatment schedules

et al. 2003

View full text Add to dashboard Cite

The recognition of the antiangiogenic properties of taxanes provides a basis for novel therapeutic approaches. A prolonged exposure to low drug concentrations has been proposed to be the most suitable approach to exploit the antiangiogenic potential of cytotoxic agents. Such schedule is required to target preferentially slowly dividing endothelial cells. The protracted use of taxanes could benefit from the availability of a taxane endowed with a favourable tolerability profile. Among compounds of a novel series of C-seco taxanes, IDN 5390 was originally selected on the basis of its potent antimotility activity and poor cytotoxicity on endothelial cells. The aim of the study was to investigate the preclinical pharmacologic profile of IDN 5390 in a variety of human tumour xenografts, including ovarian and colon carcinoma and a glioblastoma. IDN 5390, delivered by s.c. injection, daily for 5 days per week, exhibited a high activity against all tumours investigated (tumour growth inhibition was always 485%) in the range of well-tolerated doses. The maximum tolerated dose/injection (MTD), with no signs of systemic or local vesicant toxicity, was 120 mg kg À1 . In contrast, paclitaxel, delivered according to the same schedule, exhibited a variable antitumour efficacy associated with a substantial local toxicity (MTD ¼ 10 mg kg À1 ). Considering the remarkable efficacy of IDN 5390 delivered s.c. by protracted treatment schedule, the oral route of administration was further investigated, as the most suitable for daily treatment. Indeed, a good bioavailability of oral IDN 5390 was found. Oral IDN 5390 maintained a substantial efficacy against human tumour xenografts, including paclitaxel-resistant tumours, without loss of potency with respect to s.c. administration. In conclusion, the therapeutic advantages of IDN 5390, over paclitaxel, in protracted daily treatment schedules are represented by the oral efficacy and the high tolerability, which are favourable features to exploit the antiangiogenic potential and to design combinations with other effective agents.

show abstract

“…Furthermore, for S phase-specific drugs, more frequent dosing may expose more cells to the drug during the sensitive phase of the cell cycle. In addition, the use of weekly paclitaxel may have additional anti-angiogenic effects when used in a fractionated schedule (Belotti et al, 1996;Lau et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Extended weekly dose-dense paclitaxel/carboplatin is feasible and active in heavily pre-treated platinum-resistant recurrent ovarian cancer

et al. 2009

View full text Add to dashboard Cite

There is increasing evidence of the efficacy of dose-dense therapy in the management of platinum-resistant/refractory ovarian cancer. We report our experience of extended weekly carboplatin and paclitaxel in this population group. Twenty patients with platinumresistant/refractory ovarian cancer received carboplatin AUC 3 and paclitaxel 70 mg m À2 on day 1, 8, 15 q 4 weekly for six planned cycles. Toxicity was assessed using Common Toxicity Criteria. Response was evaluated using radiological and CA125 criteria. Median age was 61 years (range 40 -74 years). Median number of prior therapies is three (range 1 -8). Response rate was 60% by radiological criteria (RECIST) and 76% by CA125 assessment. Grade 3 toxicities consisted of neutropenia (29% of patients) and anaemia (5%). One patient experienced grade 4 neutropenia. No grade 3/4 thombocytopaenia was reported. Fatigue, nausea and peripheral neuropathy were the most frequent non-hematological side effects. Median progression-free survival was 7.9 months and overall survival was 13.3 months. The dynamics of response to dose-dense therapy were as rapid as with front-line therapy within the same patient. This dose-dense regimen can be extended to at least 18 weekly cycles over 6 months and is well tolerated with high response rates in heavily pre-treated, platinum-resistant ovarian cancer. It forms a highly active and tolerable cytotoxic scaffold to which molecular-targeted therapies can be added in platinum-resistant ovarian cancer.

show abstract

Paclitaxel (Taxol): An Inhibitor of Angiogenesis in a Highly Vascularized Transgenic Breast Cancer

Cited by 156 publications

References 6 publications

Increased endothelial uptake of paclitaxel as a potential mechanism for its antiangiogenic effects: Potentiation by Cox‐2 inhibition

Increased endothelial uptake of paclitaxel as a potential mechanism for its antiangiogenic effects: Potentiation by Cox‐2 inhibition

IDN 5390: an oral taxane candidate for protracted treatment schedules

Extended weekly dose-dense paclitaxel/carboplatin is feasible and active in heavily pre-treated platinum-resistant recurrent ovarian cancer

Contact Info

Product

Resources

About