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01-09-2006 | Original Article

The anti-tumour effect of low-dose continuous chemotherapy may partly be mediated by thrombospondin

Authors: Jan-Erik Damber, Christina Vallbo, Per Albertsson, Bo Lennernäs, Klas Norrby

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2006

Abstract

Background: Tumour growth is dependent on angiogenesis. Antiangiogenic chemotherapy, i.e. continuous or metronomic low-dose chemotherapy, is a method for administrating cytostatics at a low and well-tolerated concentration without prolonged breaks. The target is the genetically stable endothelial cells playing a pivotal role in angiogenesis within the tumour. Different mediators could mediate the antiangiogenic effect of metronomic chemotherapy. One of these mediators could be thrombospondin (TSP). TSP is a potent inhibitor of angiogenesis and might therefore be important in controlling tumour growth. This study was designed to evaluate the effects of low-dose continuous or moderate-dose bolus chemotherapy on tumour growth and on tumour expression of TSP. Materials and methods: Rats bearing a malignant prostate tumour (Dunning AT-1) not expressing TSP were treated systemically with cyclophosphamide, doxorubicin or paclitaxel and the combination of cyclophosphamide and doxorubicin. Tumour growth and body weight were measured during the treatment. CD36, one of TSP’s main receptors, was also analysed. The expression pattern of TSP-1, TSP-2 and CD36 was investigated using immunohistochemistry and Western blot analyses. Q-PCR was used to analyse TSP-1 mRNA expression. Results: Low-dose cyclophosphamide and paclitaxel re-induced the expression of TSP in the tumours. However, following a bolus dose of doxorubicin, tumours showed no expression of TSP. Both cyclophosphamide and doxorubicin treatments decreased the tumour weight by more than 60% compared with vehicle controls. When cyclophosphamide and doxorubicin were combined the tumour weight was reduced by 47%, while paclitaxel reduced the tumour weight by 18% compared to the vehicle controls. Conclusions: Systemic low-dose continuous treatment of a rat prostate cancer model with cyclophosphamide and paclitaxel induced the expression of TSP in tumour tissue and inhibited tumour growth. These findings support the hypothesis that the anti-tumour effect of low-dose metronomic chemotherapy, at least with certain chemotherapeutics, is partly mediated by induction of endogenous antiangiogenic factors.

Miller KD, Sweeney CJ, Sledge GW Jr (2001) Redefining the target: chemotherapeutics as antiangiogenics. J Clin Oncol 19(4):1195–1206PubMed

Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG (2000) Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res 60(5):1388–1393PubMed

Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O’Reilly MS et al (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60(7):1878–1886PubMed

Bergers G, Hanahan D (2002) Combining antiangiogenic agents with metronomic chemotherapy enhances efficacy against late-stage pancreatic islet carcinomas in mice. Cold Spring Harb Symp Quant Biol 67:293–300CrossRefPubMed

Bocci G, Francia G, Man S, Lawler J, Kerbel RS (2003) Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA 100(22):12917–12922CrossRefPubMed

Lawler J (2000) The functions of thrombospondin-1 and -2. Curr Opin Cell Biol 12(5):634–640CrossRefPubMed

Hamano Y, Sugimoto H, Soubasakos MA, Kieran M, Olsen BR, Lawler J et al (2004) Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. Cancer Res 64(5):1570–1574CrossRefPubMed

Doll JA, Reiher FK, Crawford SE, Pins MR, Campbell SC, Bouck NP (2001) Thrombospondin-1, vascular endothelial growth factor and fibroblast growth factor-2 are key functional regulators of angiogenesis in the prostate. Prostate 49(4):293–305CrossRefPubMed

Kwak C, Jin RJ, Lee C, Park MS, Lee SE (2002) Thrombospondin-1, vascular endothelial growth factor expression and their relationship with p53 status in prostate cancer and benign prostatic hyperplasia. BJU Int 89(3):303–309CrossRefPubMed

10.

Vallbo C, Wang W, Damber JE (2004) The expression of thrombospondin-1 in benign prostatic hyperplasia and prostatic intraepithelial neoplasia is decreased in prostate cancer. BJU Int 93(9):1339–1343CrossRefPubMed

11.

Vallbo C, Damber J-E (2005) Thrombospondins, metallo proteases and thrombospondin receptors messenger RNA and protein expression in different tumour sublines of the dunning prostate cancer model. Acta Oncol 44(3):293–298PubMedCrossRef

12.

Lennernas B, Albertsson P, Damber JE, Norrby K (2004) Antiangiogenic effect of metronomic paclitaxel treatment in prostate cancer and non-tumor tissue in the same animals: a quantitative study. APMIS 112(3):201–209CrossRefPubMed

13.

Isaacs JT, Isaacs WB, Feitz WF, Scheres J (1986) Establishment and characterization of seven Dunning rat prostatic cancer cell lines and their use in developing methods for predicting metastatic abilities of prostatic cancers. Prostate 9(3):261–281PubMedCrossRef

14.

Lennernas B, Albertsson P, Lennernas H, Norrby K (2003) Chemotherapy and antiangiogenesis—drug-specific, dose-related effects. Acta Oncol 42(4):294–303CrossRefPubMed

15.

Urakami S, Igawa M, Kikuno N, Yoshino T, Kishi H, Shigeno K et al (2002) Combination chemotherapy with paclitaxel, estramustine and carboplatin for hormone refractory prostate cancer. J Urol 168(6):2444–2450CrossRefPubMed

16.

Albertsson P, Lennernäs B, Norrby K (2005) On metronomic chemotherapy: modulation of angiogenesis mediated by VEGF-A. Acta Oncol (in press)

17.

Yoo GH, Piechocki MP, Ensley JF, Nguyen T, Oliver J, Meng H et al (2002) Docetaxel induced gene expression patterns in head and neck squamous cell carcinoma using cDNA microarray and PowerBlot. Clin Cancer Res 8(12):3910–3921PubMed

18.

Dameron KM, Volpert OV, Tainsky MA, Bouck N (1994) The p53 tumor suppressor gene inhibits angiogenesis by stimulating the production of thrombospondin. Cold Spring Harb Symp Quant Biol 59:483–489PubMed

19.

Watnick RS, Cheng YN, Rangarajan A, Ince TA, Weinberg RA (2003) Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell 3(3):219–231CrossRefPubMed

20.

Monestiroli S, Mancuso P, Burlini A, Pruneri G, Dell’Agnola C, Gobbi A et al (2001) Kinetics and viability of circulating endothelial cells as surrogate angiogenesis marker in an animal model of human lymphoma. Cancer Res 61(11):4341–4344PubMed

21.

Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7(11):1194–1201CrossRefPubMed

22.

Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T et al (2005) Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7(1):101–111PubMed

23.

Capillo M, Mancuso P, Gobbi A, Monestiroli S, Pruneri G, Dell’Agnola C et al (2003) Continuous infusion of endostatin inhibits differentiation, mobilization, and clonogenic potential of endothelial cell progenitors. Clin Cancer Res 9(1):377–382PubMed

24.

Ito H, Rovira II, Bloom ML, Takeda K, Ferrans VJ, Quyyumi AA et al (1999) Endothelial progenitor cells as putative targets for angiostatin. Cancer Res 59(23):5875–5877PubMed

25.

Pietras K, Hanahan D (2005) A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23(5):939–952CrossRefPubMed

26.

Ellis LM (2005) Bevacizumab. Nat Rev Drug Discov Suppl:S8–S9CrossRefPubMed

Title: The anti-tumour effect of low-dose continuous chemotherapy may partly be mediated by thrombospondin
Authors: Jan-Erik Damber
Christina Vallbo
Per Albertsson
Bo Lennernäs
Klas Norrby
Publication date: 01-09-2006
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2006
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-005-0163-8

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