Microvascular Endothelial Cell Responses in vitro and in vivo: Modulation by Zoledronic Acid and Paclitaxel?

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Abstract

Background/Aims: The cytotoxic agent paclitaxel and the anti-resorptive drug zoledronic acid are used in the early and advanced breast cancer setting, respectively. Both agents have been demonstrated to have anti-tumour and anti-endothelial actions. Combining paclitaxel with zoledronic acid induces a synergistic increase in apoptotic breast cancer cell death in vitro, suggesting an increased anti-tumour effect in vivo, but any specific effects on the normal microvasculature and potential side-effects of this combination remain to be established. Methods: The effects of zoledronic acid and paclitaxel were investigated, alone and in combination, on human microvascular endothelial cells in vitro, using functional assays including proliferation, migration, tubule formation and apoptosis. The in vivo effect of the drugs on the normal microvasculature was determined using the dorsal microcirculation chamber model. Results/Conclusion: Zoledronic acid reduced human dermal microvascular endothelial cell (HuDMEC) proliferation, caused accumulation of cells in S phase, and inhibited migration, tube formation and Rap1a prenylation. Paclitaxel significantly inhibited tube formation and proliferation, and increased endothelial necrosis; the combination induced HuDMEC apoptosis and further enhanced the inhibition of tube formation and migration. The combination caused minimal effects on the normal microvasculature in vivo, suggesting that this potential therapeutic strategy is not associated with deleterious microvascular side-effects.

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Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid.

JEANETTE WOOD, Laetitia Devy, Jean-Michel Foidart … (2002)

Bisphosphonate drugs inhibit osteoclastic bone resorption and are widely used to treat skeletal complications in patients with tumor-induced osteolysis. We now show that zoledronic acid, a new generation bisphosphonate with a heterocyclic imidazole substituent, is also a potent inhibitor of angiogenesis. In vitro, zoledronic acid inhibits proliferation of human endothelial cells stimulated with fetal calf serum, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (IC(50) values 4.1, 4.2, and 6.9 microM, respectively), and modulates endothelial cell adhesion and migration. In cultured aortic rings and in the chicken egg chorioallantoic membrane assay, zoledronic acid reduces vessel sprouting. When administered systemically to mice, zoledronic acid potently inhibits the angiogenesis induced by subcutaneous implants impregnated with bFGF [ED(50), 3 microg/kg (7.5 nmol/kg) s.c.]. These findings indicate that zoledronic acid has marked antiangiogenic properties that could augment its efficacy in the treatment of malignant bone disease and extend its potential clinical use to other diseases with an angiogenic component.

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Frequency and cost of chemotherapy-related serious adverse effects in a population sample of women with breast cancer.

Daniel J Hassett, James A O’Malley, C Earle … (2006)

The number, nature, and costs of serious adverse effects experienced by younger women receiving chemotherapy for breast cancer outside of clinical trials are unknown. From a database of medical claims made by individuals with employer-provided health insurance between January 1998 and December 2002, we identified 12,239 women 63 years of age or younger with newly diagnosed breast cancer, of whom 4075 received chemotherapy during the 12 months after the initial breast cancer diagnosis and 8164 did not. Diagnostic codes for eight chemotherapy-related adverse effects were identified. Total hospitalizations for all causes, hospitalizations or emergency room visits for adverse effects that are typically related to chemotherapy, and health care expenditures were compared between the two groups of women. All statistical tests were two-sided. Women who received chemotherapy were more likely than those who did not to be hospitalized or to visit the emergency room for all causes (61% versus 42%; mean difference = 19%, 95% confidence interval [CI] = 16.7% to 21.3%, P<.001) and for chemotherapy-related serious adverse effects (16% versus 5%, mean difference = 11%, 95% CI = 9.6% to 12.4%, P<.001). The percentages of chemotherapy recipients who were hospitalized or visited the emergency room during the year after their breast cancer diagnosis were 8.4% for fever or infection; 5.5% for neutropenia or thrombocytopenia; 2.5% for dehydration or electrolyte disorders; 2.4% for nausea, emesis, or diarrhea; 2.2% for anemia; 2% for constitutional symptoms; 1.2% for deep venous thrombosis or pulmonary embolus; and 0.9% for malnutrition. Chemotherapy recipients incurred large incremental expenditures for chemotherapy-related serious adverse effects (1271 dollars per person per year) and ambulatory encounters (17,617 dollars per person per year). Chemotherapy-related serious adverse effects among younger, commercially insured women with breast cancer may be more common than reported by large clinical trials and lead to more patient suffering and health care expenditures than previously estimated.

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Isoprenylated proteins.

James S. McTaggart (2006)

Isoprenoids are synthesized in all living organisms and are incorporated into diverse classes of end-products that participate in a multitude of cellular processes relating to cell growth, differentiation, cytoskeletal function and vesicle trafficking. In humans, the non-sterol isoprenoids, farnesyl pyrophosphate and geranylgeranyl-pyrophosphate, are synthesized via the mevalonate pathway and are covalently added to members of the small G protein superfamily. Isoprenylated proteins have key roles in membrane attachment and protein functionality, have been shown to have a central role in some cancers and are likely also to be involved in the pathogenesis and progression of atherosclerosis and Alzheimer disease. This review details current knowledge on the biosynthesis of isoprenoids, their incorporation into proteins by the process known as prenylation and the complex regulatory network that controls these proteins. An improved understanding of these processes is likely to lead to the development of novel therapies that will have important implications for human health and disease.

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Author and article information

Journal

Journal ID (publisher-id): JVR

Journal ID (nlm-ta): J Vasc Res

Journal ID (doi): 10.1159/issn.1018-1172

Title: Journal of Vascular Research

Publisher: S. Karger AG

ISSN (Print): 1018-1172

ISSN (Electronic): 1423-0135

Publication date Subscription-year: 2010

Publication date (Print): October 2010

Publication date (Electronic): 30 April 2010

Volume: 47

Issue: 6

Pages: 481-493

Affiliations

Academic Units of ^aClinical Oncology, ^bSurgical Oncology and ^cPathology, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK

Article

Publisher ID: 313876 Other ID: J Vasc Res 2010;47:481–493

DOI: 10.1159/000313876

PubMed ID: 20431297

SO-VID: 1f677291-fb4c-42e1-a2c9-a2f447e610ab

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 19 May 2009

Date accepted : 08 December 2009

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Figures: 7, References: 41, Pages: 13

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Microvascular Endothelial Cell Responses in vitro and in vivo: Modulation by Zoledronic Acid and Paclitaxel?

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Abstract

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Karger: Cardiovascular System

Most cited references 35

Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid.

Frequency and cost of chemotherapy-related serious adverse effects in a population sample of women with breast cancer.

Isoprenylated proteins.

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Cited by 10

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