Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2008

Open Access 01-12-2008 | Research

Should tumor VEGF expression influence decisions on combining low-dose chemotherapy with antiangiogenic therapy? Preclinical modeling in ovarian cancer

Authors: David O Holtz, Robert T Krafty, Alisha Mohamed-Hadley, Lin Zhang, Ioannis Alagkiozidis, Benjamin Leiby, Wensheng Guo, Phyllis A Gimotty, George Coukos

Published in: Journal of Translational Medicine | Issue 1/2008

Login to get access

Abstract

Because of its low toxicity, low-dose (LD) chemotherapy is ideally suited for combination with antiangiogenic drugs. We investigated the impact of tumor vascular endothelial growth factor A (VEGF-A) expression on the efficacy of LD paclitaxel chemotherapy and its interactions with the tyrosine kinase inhibitor SU5416 in the ID8 and ID8-Vegf models of ovarian cancer. Functional linear models using weighted penalized least squares were utilized to identify interactions between Vegf, LD paclitaxel and antiangiogenic therapy. LD paclitaxel yielded additive effects with antiangiogenic therapy against tumors with low Vegf expression, while it exhibited antagonism to antiangiogenic therapy in tumors with high Vegf expression. This is the first preclinical study that models interactions of LD paclitaxel chemotherapy with antiangiogenic therapy and tumor VEGF expression and offers important lessons for the rational design of clinical trials.
Appendix
Available only for authorised users
Literature
1.
Folkman J: Fundamental concepts of the angiogenic process. Curr Mol Med. 2003, 3 (7): 643-651. 10.2174/1566524033479465.CrossRefPubMed
2.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. The New England journal of medicine. 2004, 350 (23): 2335-2342. 10.1056/NEJMoa032691.CrossRefPubMed
3.
Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S: Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol. 2005, 23 (16): 3706-3712. 10.1200/JCO.2005.00.232.CrossRefPubMed
4.
Laskin JJ, Sandler AB: First-line treatment for advanced non-small-cell lung cancer. Oncology (Williston Park, NY. 2005, 19 (13): 1671-6; discussion 1678-80.
5.
Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005, 23 (4): 792-799. 10.1200/JCO.2005.05.098.CrossRefPubMed
6.
Gasparini G: Metronomic scheduling: the future of chemotherapy?. Lancet Oncol. 2001, 2 (12): 733-740. 10.1016/S1470-2045(01)00587-3.CrossRefPubMed
7.
Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O'Reilly MS, Folkman J: Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer research. 2000, 60 (7): 1878-1886.PubMed
8.
Bocci G, Nicolaou KC, Kerbel RS: Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer research. 2002, 62 (23): 6938-6943.PubMed
9.
Kerbel RS, Kamen BA: The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004, 4 (6): 423-436. 10.1038/nrc1369.CrossRefPubMed
10.
Bertolini F, Paul S, Mancuso P, Monestiroli S, Gobbi A, Shaked Y, Kerbel RS: Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer research. 2003, 63 (15): 4342-4346.PubMed
11.
Shaked Y, Emmenegger U, Man S, Cervi D, Bertolini F, Ben-David Y, Kerbel RS: Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood. 2005, 106 (9): 3058-3061. 10.1182/blood-2005-04-1422.PubMedCentralCrossRefPubMed
12.
Lam T, Hetherington JW, Greenman J, Maraveyas A: From total empiricism to a rational design of metronomic chemotherapy phase I dosing trials. Anti-cancer drugs. 2006, 17 (2): 113-121. 10.1097/00001813-200602000-00001.CrossRefPubMed
13.
Orlando L, Cardillo A, Rocca A, Balduzzi A, Ghisini R, Peruzzotti G, Goldhirsch A, D'Alessandro C, Cinieri S, Preda L, Colleoni M: Prolonged clinical benefit with metronomic chemotherapy in patients with metastatic breast cancer. Anti-cancer drugs. 2006, 17 (8): 961-967. 10.1097/01.cad.0000224454.46824.fc.CrossRefPubMed
14.
Correale P, Cerretani D, Remondo C, Martellucci I, Marsili S, La Placa M, Sciandivasci A, Paolelli L, Pascucci A, Rossi M, Di Bisceglie M, Giorgi G, Gotti G, Francini G: A novel metronomic chemotherapy regimen of weekly platinum and daily oral etoposide in high-risk non-small cell lung cancer patients. Oncology reports. 2006, 16 (1): 133-140.PubMed
15.
Young SD, Whissell M, Noble JC, Cano PO, Lopez PG, Germond CJ: Phase II clinical trial results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib in patients with advanced solid tumors. Clin Cancer Res. 2006, 12 (10): 3092-3098. 10.1158/1078-0432.CCR-05-2255.CrossRefPubMed
16.
Bocci G, Tuccori M, Emmenegger U, Liguori V, Falcone A, Kerbel RS, Del Tacca M: Cyclophosphamide-methotrexate 'metronomic' chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol. 2005, 16 (8): 1243-1252. 10.1093/annonc/mdi240.CrossRefPubMed
17.
Ramalingam S, Belani CP: Taxanes for advanced non-small cell lung cancer. Expert opinion on pharmacotherapy. 2002, 3 (12): 1693-1709. 10.1517/14656566.3.12.1693.CrossRefPubMed
18.
Kerbel RS, Klement G, Pritchard KI, Kamen B: Continuous low-dose anti-angiogenic/ metronomic chemotherapy: from the research laboratory into the oncology clinic. Ann Oncol. 2002, 13 (1): 12-15. 10.1093/annonc/mdf093.CrossRefPubMed
19.
Klement G, Huang P, Mayer B, Green SK, Man S, Bohlen P, Hicklin D, Kerbel RS: Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts. Clin Cancer Res. 2002, 8 (1): 221-232.PubMed
20.
Shah MA, Ramanathan RK, Ilson DH, Levnor A, D'Adamo D, O'Reilly E, Tse A, Trocola R, Schwartz L, Capanu M, Schwartz GK, Kelsen DP: Multicenter Phase II Study of Irinotecan, Cisplatin, and Bevacizumab in Patients With Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma. J Clin Oncol. 2006, 24 (33): 5201-5206. 10.1200/JCO.2006.08.0887.CrossRefPubMed
21.
Wright JD, Hagemann A, Rader JS, Viviano D, Gibb RK, Norris L, Mutch DG, Powell MA: Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: A retrospective analysis. Cancer. 2006, 107 (1): 83-89. 10.1002/cncr.21969.CrossRefPubMed
22.
Zhang L, Yang N, Conejo-Garcia JR, Katsaros D, Mohamed-Hadley A, Fracchioli S, Schlienger K, Toll A, Levine B, Rubin SC, Coukos G: Expression of endocrine gland-derived vascular endothelial growth factor (EG-VEGF) in ovarian carcinoma. Clin Cancer Res. 2003, 9: 264-272.PubMed
23.
Hefler LA, Zeillinger R, Grimm C, Sood AK, Cheng WF, Gadducci A, Tempfer CB, Reinthaller A: Preoperative serum vascular endothelial growth factor as a prognostic parameter in ovarian cancer. Gynecologic oncology. 2006, 103 (2): 512-517. 10.1016/j.ygyno.2006.03.058.CrossRefPubMed
24.
Li L, Wang L, Zhang W, Tang B, Zhang J, Song H, Yao D, Tang Y, Chen X, Yang Z, Wang G, Li X, Zhao J, Ding H, Reed E, Li QQ: Correlation of serum VEGF levels with clinical stage, therapy efficacy, tumor metastasis and patient survival in ovarian cancer. Anticancer research. 2004, 24 (3b): 1973-1979.PubMed
25.
Zhang L, Conejo-Garcia JR, Yang N, Huang W, Mohamed-Hadley A, Yao W, Benencia F, Coukos G: Different effects of glucose starvation on expression and stability of VEGF mRNA isoforms in murine ovarian cancer cells. Biophys Biochem Res Commun. 2002, 292: 860-868. 10.1006/bbrc.2002.6710.CrossRef
26.
Zhang L, Yang N, Wang W, Katsaros D, Mohamed-Hadley A, Rubin SC, Coukos G: Oncogene phosphatidyl inositol kinase-3 alpha subunit promotes angiogenesis in ovarian carcinoma via VEGF. Cancer Res. 2003, in Press:
27.
Mendel DB, Laird AD, Smolich BD, Blake RA, Liang C, Hannah AL, Shaheen RM, Ellis LM, Weitman S, Shawver LK, Cherrington JM: Development of SU5416, a selective small molecule inhibitor of VEGF receptor tyrosine kinase activity, as an anti-angiogenesis agent. Anticancer Drug Des. 2000, 15 (1): 29-41.PubMed
28.
Stopeck A, Sheldon M, Vahedian M, Cropp G, Gosalia R, Hannah A: Results of a Phase I Dose-escalating Study of the Antiangiogenic Agent, SU5416, in Patients with Advanced Malignancies. Clin Cancer Res. 2002, 8 (9): 2798-2805.PubMed
29.
Zhang L, Yang N, Conejo-Garcia JR, Mohamed A, Benencia F, Rubin SC, Allman D, Coukos G: Generation of a Syngeneic Mouse Model to Study the Effects of Vascular Endothelial Growth Factor in Ovarian Carcinoma. Am J Pathol. 2002, 161: 2295-2309.PubMedCentralCrossRefPubMed
30.
Ramsay JO, Silverman BW: Functional Data Analysis. 1997, New York , Springer-VerlagCrossRef
31.
Eubank R: Nonparametric Regression and Spline Smoothing. 1999, New York , Marcel Dekker
32.
Zhang X, Burt HM, Mangold G, Dexter D, Von Hoff D, Mayer L, Hunter WL: Anti-tumor efficacy and biodistribution of intravenous polymeric micellar paclitaxel. Anti-cancer drugs. 1997, 8 (7): 696-701. 10.1097/00001813-199708000-00008.CrossRefPubMed
33.
Sparreboom A, Wolff AC, Verweij J, Zabelina Y, van Zomeren DM, McIntire GL, Swindell CS, Donehower RC, Baker SD: Disposition of docosahexaenoic acid-paclitaxel, a novel taxane, in blood: in vitro and clinical pharmacokinetic studies. Clin Cancer Res. 2003, 9 (1): 151-159.PubMed
34.
Tomayko MM, Reynolds CP: Determination of subcutaneous tumor size in athymic (nude) mice. Cancer chemotherapy and pharmacology. 1989, 24 (3): 148-154. 10.1007/BF00300234.CrossRefPubMed
35.
Nychka D: Bayesian confidence intervals for smoothing splines. J Amer Stat Assoc. 1988, 83: 1134-1143. 10.2307/2290146.CrossRef
36.
Eubank RL, Huang C, Maldonado YM, Wang N, Wang S, Buchanan RJ: Smoothing spline estimation in varying-coefficient models. J Royal Stat Soc. 2004, 66: 653-667. 10.1111/j.1467-9868.2004.B5595.x.CrossRef
37.
Guo W: Functional Mixed Effects Models. Biometrics. 2002, 58: 121-128. 10.1111/j.0006-341X.2002.00121.x.CrossRefPubMed
38.
Marchetti P, Urien S, Cappellini GA, Ronzino G, Ficorella C: Weekly administration of paclitaxel: theoretical and clinical basis. Critical reviews in oncology/hematology. 2002, 44 Suppl: S3-13. 10.1016/S1040-8428(02)00109-9.CrossRefPubMed
39.
Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D: Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors.[comment]. Journal of Clinical Investigation. 2003, 111 (9): 1287-1295. 10.1172/JCI200317929.PubMedCentralCrossRefPubMed
40.
Zhang L, Yang N, Park JW, Katsaros D, Fracchioli S, Cao G, O'Brien-Jenkins A, Randall TC, Rubin SC, Coukos G: Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer research. 2003, 63 (12): 3403-3412.PubMed
41.
Bocci G, Man S, Green SK, Francia G, Ebos JM, du Manoir JM, Weinerman A, Emmenegger U, Ma L, Thorpe P, Davidoff A, Huber J, Hicklin DJ, Kerbel RS: Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies. Cancer research. 2004, 64 (18): 6616-6625. 10.1158/0008-5472.CAN-04-0401.CrossRefPubMed
42.
Lee L, Sharma S, Morgan B, Allegrini P, Schnell C, Brueggen J, Cozens R, Horsfield M, Guenther C, Steward WP, Drevs J, Lebwohl D, Wood J, McSheehy PM: Biomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK): translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases. Cancer chemotherapy and pharmacology. 2006, 57 (6): 761-771. 10.1007/s00280-005-0120-6.CrossRefPubMed
43.
Jubb AM, Hurwitz HI, Bai W, Holmgren EB, Tobin P, Guerrero AS, Kabbinavar F, Holden SN, Novotny WF, Frantz GD, Hillan KJ, Koeppen H: Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol. 2006, 24 (2): 217-227. 10.1200/JCO.2005.01.5388.CrossRefPubMed
44.
Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, Taber DA, Karrison T, Dachman A, Stadler WM, Vokes EE: Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2005, 23 (31): 8033-8040. 10.1200/JCO.2005.01.9661.CrossRefPubMed
45.
Byrd-Leifer CA, Block EF, Takeda K, Akira S, Ding A: The role of MyD88 and TLR4 in the LPS-mimetic activity of Taxol. European journal of immunology. 2001, 31 (8): 2448-2457. 10.1002/1521-4141(200108)31:8<2448::AID-IMMU2448>3.0.CO;2-N.CrossRefPubMed
46.
Mullins DW, Burger CJ, Elgert KD: Paclitaxel enhances macrophage IL-12 production in tumor-bearing hosts through nitric oxide. J Immunol. 1999, 162 (11): 6811-6818.PubMed
47.
Muenchen HJ, Aggarwal SK: Activation of murine peritoneal macrophages after cisplatin and taxol combination. Anti-cancer drugs. 1997, 8 (8): 784-789. 10.1097/00001813-199709000-00008.CrossRefPubMed
Metadata
Title
Should tumor VEGF expression influence decisions on combining low-dose chemotherapy with antiangiogenic therapy? Preclinical modeling in ovarian cancer
Authors
David O Holtz
Robert T Krafty
Alisha Mohamed-Hadley
Lin Zhang
Ioannis Alagkiozidis
Benjamin Leiby
Wensheng Guo
Phyllis A Gimotty
George Coukos
Publication date
01-12-2008
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2008
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-6-2

Other articles of this Issue 1/2008

Journal of Translational Medicine 1/2008 Go to the issue

Research

Multilineage hematopoietic recovery with concomitant antitumor effects using low dose Interleukin-12 in myelosuppressed tumor-bearing mice

Commentary

Correlation between NK function and response to trastuzumab in metastatic breast cancer patients

Research

The pituitary tumor transforming gene 1 (PTTG-1): An immunological target for multiple myeloma

Research

Identification of heterogeneity among soft tissue sarcomas by gene expression profiles from different tumors

Review

Merger of Ayurveda and Tissue Culture-Based Functional Genomics: Inspirations from Systems Biology

Research

A highly invasive human glioblastoma pre-clinical model for testing therapeutics
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits