Radiation-induced changes in bone perfusion and angiogenesis.
OBJECTIVE
To determine whether blood flow of bone is altered by limb irradiation and whether bFGF, an angiogenic cytokine, might alleviate any flow or growth abnormality resulting from 30 Gy single fraction irradiation.


METHODS
C3H mice received whole right hind limb radiation at doses of 0 to 30 Gy. Additional groups received 30 Gy, and then beginning 1 or 5 weeks later received intravenous bFGF at a dose of 6 microg/mouse, twice a week for 4 weeks. Serial X-ray films were taken to measure the tibias. At 33 weeks, laser Doppler flow (LDF) measurements were made of both limbs. Cytokine measurements were made using ELISA and RNase protection.


RESULTS
Bone growth was reduced following radiation in a dose dependent manner. bFGF improved bone growth after radiation even when begun 5 weeks after radiation, however, we detected no significant improvement in LDF of the irradiated bone or periosteum. Muscle tissue surrounding bone of the irradiated leg showed no increase in isoforms of TGFbeta, TNF, or IFN. There was also no difference in the circulating plasma TGFbeta1 in irradiated mice. In contrast, LDF increased significantly as a function of radiation dose in the nonirradiated tibia. Systemic delivery of bFGF appears to further enhance the increase in flow seen in the nonirradiated limb.


CONCLUSIONS
Radiation induces a chronic antiangiogenic effect contributing to reduced limb growth. At 33 weeks the antiangiogenesis was not associated with local soft tissue elevations of TNF, IFN, or TGFbeta. Radiation toxicity to bone is alleviated by bFGF therapy suggesting that powerful locally-acting antiangiogenic mechanisms are involved. We postulate that the increased LDF of the contralateral tibia is due to circulating angiogenesis factors that are elevated to compensate for the radiation-induced antiangiogenesis.
Okunieff
P
P
Department of Radiation Oncology, Strong Memorial Hospital, Rochester, NY 14642, USA. okunieff@radonc.medinfo.rochester.edu
Wang
X
X
Rubin
P
P
Finkelstein
J N
JN
Constine
L S
LS
Ding
I
I
D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D001842:Bone and Bones / Q000098:blood supply* / Q000187:drug effects / Q000528:radiation effects*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D017078:Laser-Doppler Flowmetry; D008233:Lymphotoxin-alpha / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000528:radiation effects*; D011829:Radiation Dosage; D012039:Regional Blood Flow / Q000528:radiation effects; D016212:Transforming Growth Factor beta / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008233:Lymphotoxin-alpha; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2