Upregulation of Insulin-like Growth Factor-I in Response to Chemotherapy in Children with Acute Lymphoblastic Leukemia

Author:

Kocadag Helin Berna1,Weischendorff Sarah1,De Pietri Silvia1,Nielsen Claus Henrik2,Rathe Mathias3ORCID,Als-Nielsen Bodil1,Hasle Henrik4,Juul Anders567ORCID,Müller Klaus126ORCID,Sørum Maria Ebbesen1ORCID

Affiliation:

1. Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital—Rigshospitalet, 2100 Copenhagen, Denmark

2. Institute for Inflammation Research, Copenhagen University Hospital—Rigshospitalet, 2100 Copenhagen, Denmark

3. Hans Christian Andersen Children’s Hospital, Odense University Hospital, 5000 Odense, Denmark

4. Department of Pediatrics, Aarhus University Hospital, 8200 Aarhus, Denmark

5. Department of Growth and Reproduction, Copenhagen University Hospital—Rigshospitalet, 2100 Copenhagen, Denmark

6. Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark

7. International Research Centre for Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital—Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark

Abstract

The treatment of childhood cancer is challenged by toxic side effects mainly due to chemotherapy-induced organ damage and infections, which are accompanied by severe systemic inflammation. Insulin-like growth factor I (IGF-I) is a key regulating factor in tissue repair. This study investigated associations between the circulating IGF-I levels and chemotherapy-related toxicity in pediatric acute lymphoblastic leukemia (ALL). In this prospective study, we included 114 patients (age: 1–17 years) with newly diagnosed ALL treated according to The Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2013 and 2018. The patients’ plasma levels of IGF-I, and the primary binding protein, IGFBP-3, were measured weekly during the first six weeks of treatment, including the induction therapy. The patients’ systemic inflammation was monitored by their C-reactive protein (CRP) and interleukin (IL)-6 levels and their intestinal epithelial damage by their plasma citrulline levels. IGF-I and IGFBP-3 were converted into sex-and age-adjusted standard deviation scores (SDS) using 1621 healthy children as reference. At ALL diagnosis, IGF-I levels were decreased (median (quartiles): −1.2 SDS (−1.9 to −0.5), p = 0.001), but increased significantly following the initiation of chemotherapy, peaking on day 8 (0.0 SDS (from −0.8 to 0.7), p < 0.001). This increase correlated with the levels of CRP (rho = 0.37, p < 0.001) and IL-6 (rho = 0.39, p = 0.03) on day 15, when these markers reached maximum levels. A larger IGF-I increase from day 1 to 15 correlated with a slower recovery rate of the intestinal damage marker citrulline from day 15 to 29 (rho = −0.28, p = 0.01). Likewise, IGFBP-3 was reduced at diagnosis, followed by an increase after treatment initiation, and was highly correlated with same-day IGF-I levels. This study demonstrates a chemotherapy-induced increase in IGF-I, with a response that appears to reflect the severity of tissue damage and systemic inflammation, preceding CRP and IL-6 increases. IGF-I may have potential as an early reactive biomarker for acute toxicity in patients with ALL.

Funder

The Danish Childhood Cancer Foundation

Publisher

MDPI AG

Reference60 articles.

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