Preclinical safety and antitumor efficacy of insulin combined with irradiation.
OBJECTIVE
We have previously reported that insulin significantly enhances tumor oxygenation (pO(2)) and increases radiation-induced tumor regrowth delay in experimental models. Considering the large radiosensitizing effect, clinical trials might be envisioned. The aim of the present pre-clinical study was to obtain a more complete set of safety and efficacy data which would further justify the commencement of such clinical trials.


METHODS
Toxicity on normal (early and late-responding) tissues was measured by the intestinal crypt regeneration assay and the late leg contracture assay. Efficacy in terms of enhancement of pO(2) (measured by in vivo EPR oximetry) and increase in radiation-induced tumor regrowth delay was evaluated with a dose-response study on mice bearing FSaII fibrosarcoma.


RESULTS
The effect on regrowth delay was directly correlated with the effect on the tumor pO(2), with a maximal effect using 400 mU kg(-1) insulin. Importantly, there was no increase in the radiation toxicity for normal tissues. Finally, we found that the hypoglycaemia induced by insulin can be corrected by simultaneous glucose infusion without modification of efficacy.


CONCLUSIONS
Insulin here demonstrated a therapeutic gain and a lack of toxicity to normal tissues. The results of this study fully justify further larger preclinical assays such as the use of fractionated irradiation and a tumor control dose assay, before determining the utility of insulin as a radiosensitizer for human patients in the clinic.
Jordan
Bénédicte F
BF
Laboratory of Biomedical Magnetic Resonance, Université Catholique de Louvain, Brussels, Belgium. benedicte.jordan@rema.ucl.ac.be
Beghein
Nelson
N
Crokart
Nathalie
N
Baudelet
Christine
C
Grégoire
Vincent
V
Gallez
Bernard
B
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005354:Fibrosarcoma / Q000378:metabolism / Q000532:radiotherapy*; D007328:Insulin / Q000009:adverse effects* / Q000627:therapeutic use; D051379:Mice; D010100:Oxygen / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016019:Survival Analysis
D007328:Insulin; D011838:Radiation-Sensitizing Agents; D010100:Oxygen