Radioimmunotherapy using vascular targeted 213Bi: the role of tumor necrosis factor alpha in the development of pulmonary fibrosis.
A monoclonal antibody (201B) specific to murine thrombomodulin, covalently linked to cyclohexyl diethylenetriaminepentaacetic acid, successfully delivers chelated 213Bi, an alpha-particle emitter, (213Bi-201B) rapidly to lung vascular endothelium. When injected at doses of 1 MBq/mouse, 213Bi-201B destroyed most of the 100 colonies of EMT-6 mammary carcinomas growing as lung tumors of up to 2000 cells/colony. Some mice were cured of lung tumors, and others had extended life spans compared to untreated control animals but eventually succumbed to tumor recurrence. At injected doses of 4-6 MBq/mouse, 100% of lung tumor colonies were eliminated; however, 3-4 months later, these mice developed pulmonary fibrosis and died. The mechanisms leading to the fibrotic response in other pulmonary irradiation models strongly implicate tumor necrosis factor alpha (TNF-alpha), released from damaged tissues, as the pivotal inflammatory cytokine in a cascade of events that culminate in fibrosis. Attempts to prevent the development of pulmonary fibrosis, by using antibodies or soluble receptor (rhuTNFR:Fc) as inhibitors of TNF-alpha, were unsuccessful. Additionally, mice genetically deficient for TNF-alpha production developed pulmonary fibrosis following 213Bi-201B treatment. Interestingly, non-tumor-bearing BALB/c mice receiving rhuTNFR:Fc or mice genetically deficient in TNF-alpha production and treated with 213Bi-201B, had significantly reduced life spans compared to mice receiving no treatment or 213Bi-201B alone. We speculate that in normal mice, although TNF-alpha may induce an inflammatory response following alpha-particle radiation mediated tumor clearance and pulmonary damage, its effects in the post-tumor clearance time period may actually retard the development of fibrosis.
Davis
I A
IA
Life Sciences Division, Oak Ridge National Laboratory, Tennessee 37831-6101, USA.
Kennel
S J
SJ
D000818:Animals; D001729:Bismuth / Q000627:therapeutic use*; D005260:Female; D008175:Lung Neoplasms / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000209:etiology*; D016499:Radioimmunotherapy / Q000009:adverse effects*; D018180:Thrombomodulin / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D001729:Bismuth