Evaluation of insulin-like growth factor-1 in a mouse model of long-term abdominal radiation toxicity

Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Anticancer research (Impact Factor: 1.83). 01/2007; 27(1A):183-7.
Source: PubMed


The purpose of these experiments was to test whether a brief course of insulin-like growth factor-1 (IGF-1) injection (escalating doses) concomitant to irradiation ameliorates radiation-induced kidney dysfunction and lethal bowel toxicity in a mouse model of unilateral high-dose irradiation of the kidney and adjacent bowel. The kidney function was assessed by means of repeated 99mTc-dimercaptosuccinate scans (every six weeks) during a maximum follow-up of 49 weeks. The experiments with single fractions of 12 Gy and 15 Gy revealed only minor differences in the severity of kidney dysfunction and no reduction in lethal bowel toxicity from IGF-1 treatment In the absence of any significant radioprotective effect, other strategies of response modification need to be developed.

Full-text preview

Available from:
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Antibodies directed against tumor necrosis factor (TNF)-alpha are clinically used for Crohn's disease, rheumatoid arthritis and psoriasis. TNF-alpha is also an important cytokine in radiotherapy because it mediates inflammatory responses in normal tissues. To study the influence of TNF-alpha inhibition on radiation toxicity, we used a well-established mouse model of kidney irradiation, where the portal also includes parts of the intestine. Mice were treated with single-fraction radiotherapy to the right kidney with doses of 8 or 10 Gy with or without the monoclonal TNF-alpha antibody infliximab injected i.v. in three doses. The kidney function was assessed by means of repeated 99mTc-dimercaptosuccinate scans during a maximum follow-up of 49 weeks. Treatment with infliximab significantly exacerbated radiation nephropathy at all time points, both in the 8 Gy and 10 Gy groups. The drug itself is not known to cause renal impairment. In the control group irradiated with 10 Gy, one mouse died from delayed radiation-induced intestinal toxicity. Skin reactions and general performance status were also similar across the groups. These data suggest that administration of infliximab concomitant to radiotherapy causes profound alterations in the development of kidney dysfunction. Importantly, other radiation-related toxicities were similar across all groups.
    Preview · Article · Jul 2007 · Anticancer research
  • [Show abstract] [Hide abstract]
    ABSTRACT: The central nervous system (CNS) is among the critical late-responding normal tissues which influence radiation treatment planning and dose prescription. Both mouse and rat spinal cord are established radiobiological models. As late reactions in rodents develop many months after irradiation, long-term follow-up is necessary. Development of radioprotective strategies and refinement of optimum dose and administration schedules are therefore quite complicated and time consuming. Obviously, surrogate endpoints that allow for screening of radioprotective agents and optimisation of dosing with shorter follow-up would speed up and facilitate this type of radiobiological research. Such surrogate endpoints should be analyzable during the clinically asymptomatic latent period, ideally as early as possible. As unrepaired cellular damage is a prerequisite for overt side-effects of radiotherapy, detection of residual damage might predict for radiation myelopathy. Immunohistochemical evaluation of irradiated mouse spinal cord with phosphorylated histone H2AX (γ-H2AX) was performed. Preliminary data suggest that residual damage can be detected in mouse spinal cord and that such foci continue to be detectable over a long time period, which clearly extends into the phase where development of late reactions starts. Our initial findings justify further research which attempts to correlate γ-H2AX foci with the primary endpoint, i.e. radiation myelopathy. It can then be explored whether a given radioprotective agent reduces the number of foci and whether this translates into reduced incidence of radiation myelopathy. A rapid and reliable animal model would allow for screening of a large number of candidate drugs that might modify the radiation response of the spinal cord.
    No preview · Article · Feb 2011 · Anticancer research