1: Cancer Res  2002 Jun 15;62(12):3555-61 

Insulin increases the sensitivity of tumors to irradiation: involvement of an
increase in tumor oxygenation mediated by a nitric oxide-dependent decrease of
the tumor cells oxygen consumption.

Jordan BF, Gregoire V, Demeure RJ, Sonveaux P, Feron O, O'Hara J, Vanhulle VP,
Delzenne N, Gallez B.

Laboratory of Medicinal Chemistry and Radiopharmacy, Laboratory of Biomedical
Magnetic Resonance, Universite Catholique de Louvain, B-1200 Brussels, Belgium.

The effects of insulin on tumor oxygenation, perfusion, oxygen consumption,and
radiation sensitivity were studied on two different mouse tumor models (TLT, a
liver tumor, and FSAII, a fibrosarcoma). Anesthetized mice were infused with
insulin i.v. at a rate of 16 milliUnits/kg/min for 25 min. Local tumor
oxygenation measurements were carried out using two independent techniques:
electron paramagnetic resonance oximetry and a fiber-optic device (OxyLite). Two
complementary techniques were also used to assess the blood flow inside the
tumor: a laser Doppler system (OxyFlo) and contrast-enhanced magnetic resonance
imaging. The oxygen consumption rate of tumor cells after in vivo insulin
infusion was measured using high frequency electron paramagnetic resonance
oximetry. To know if insulin was able to enhance radiation-induced tumor
regrowth delay, tumor-bearing mice were treated with 16 Gy of 250 kV radiation
dose after insulin infusion. We provide evidence that insulin increases the
local pressure of oxygen of tumors (from 0-3 mm Hg to 8-11 mm Hg) as well as the
tumor response to irradiation (increasing regrowth delay by a factor of 2.11).
We found that the insulin-induced increase of tumor pressure of oxygen: (a) is
not caused by an increase in the tumor blood flow, which is even decreased after
insulin infusion; (b) is because of a decrease in the tumor cell oxygen
consumption (in vivo insulin consumed oxygen three times slower than control
cells); and (c) is inhibited by a nitric oxide (NO) synthase inhibitor,
Nomega-nitro-L-arginine methyl ester, when injected i.p. at 15 micromol/kg(-1),
1 h before insulin infusion. We demonstrate by immunoblotting that the NO
pathway involves a phosphorylation of endothelial NO synthase and showed a
concomitant increase in the cyclic GMP tumor level. These findings provide
unique insights into biological processes in tumors, new possible management for
treating cancer patients, and raise major questions about the role of insulin
secretion (fasting status and diabetes) in the clinical response of tumors to
radiation therapy.

PMID: 12068004 [PubMed - indexed for MEDLINE]