Clinical Research Papers:

Maintenance chemotherapy in children with ALL exerts metronomic-like thrombospondin-1 associated anti-endothelial effect

Nicolas Andre _, Sylvie Cointe, Vincent Barlogis, Laurent Arnaud, Romaric Lacroix, Eddy Pasquier, Françoise Dignat-George, Gérard Michel and Florence Sabatier

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Oncotarget. 2015; 6:23008-23014. https://doi.org/10.18632/oncotarget.3984

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Nicolas Andre1,2,3, Sylvie Cointe4,5, Vincent Barlogis1, Laurent Arnaud5 Romaric Lacroix4,5, Eddy Pasquier2,3, Françoise Dignat-George4,5, Gérard Michel1 and Florence Sabatier4,5

1 Service d’Hématologie et Oncologie Pédiatrique, Centre Hospitalo-Universitaire Timone Enfants, AP-HM, Marseille, France

2 Aix-Marseille Université, INSERM, CRO2 UMRS-911, Marseille, France

3 Metronomics Global Health Initiative, Marseille, France

4 Aix-Marseille Université INSERM, Vascular Research Center of Marseille UMRS-1076, Marseille, France

5 Laboratoire d’Hématologie, Centre Hospitalo-Universitaire Conception, AP-HM, Marseille, France

Correspondence to:

Nicolas Andre, email:

Keywords: leukemia, maintenance therapy, metronomic chemotherapy, immune system, angiogenesis

Received: February 10, 2015 Accepted: April 15, 2015 Published: May 04, 2015


Maintenance chemotherapy is an important part of the treatment of ALL in children. It relies on the long-term oral administration of daily low-dose mercaptopurin and weekly low-dose methotrexate. Although it has been used in the clinic for decades, its mechanisms of action remain unclear. Here, we investigated different angiogenic and immune biomarkers to gain insights into the mechanisms of action of maintenance therapy in children with ALL. We thus monitored circulating endothelial cells (CEC), endothelial progenitor cells (EPC) and endothelial microparticles (EMP), pro-angiogenic factors (VEGF, VEGFR-1 and Ang-2), anti-angiogenic factor thrombospondin-1 (THBS1) and regulatory T lymphocytes (Treg) in 47 children with ALL during the maintenance phase of their treatment (at treatment initiation and after 6, 12 and 18 months). We observed a statistically significant decrease in EPC and EMP counts throughout the maintenance phase associated with a significant increase in THBS1 levels. No significant change was detected in other angiogenic markers or in Treg numbers.

The results presented here indicate that maintenance therapy in children with ALL exerts its antitumor activity at least in part through anti-angiogenic effects, similar to those induced by metronomic chemotherapy. Larger studies are now warranted to validate these findings and determine their clinical implications.

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PII: 3984