Edward H. Abraham

Pentoxifylline in the Treatment of Radiation-Induced Fibrosis

PURPOSE Fibrotic sequelae remain the most important dose-limiting toxicity of radiation therapy to soft tissue. Functionally, this is reflected in loss of range of motion and muscle strength and the development of limb edema and pain. Tumor necrosis factor alpha and fibroblast growth factor 2 (FGF2), which are abnormally elevated in irradiated tissues, may mediate radiation fibrovascular injury. PATIENTS AND METHODS In an open label drug trial, we studied the effects of pentoxifylline (400 mg orally tid for 8 weeks) on 30 patients who displayed late, radiation-induced fibrosis at 1 to 29 years posttreatment (40 to 84 Gy). The primary outcome measurement was change in physical impairments thought to be secondary to radiation, including active and passive range of motion (AROM and PROM), muscle strength, limb edema, and pain. Plasma levels of cytokines (tumor necrosis factor alpha and FGF2) also were measured. Twenty-seven patients completed baseline and 8-week assessments, and 24 patients completed baseline, 8-week, and 16-week assessments. RESULTS After 8 weeks of pentoxifylline intervention, 20 of 23 patients with impaired AROM and 19 of 22 with impaired PROM improved; 11 of 19 patients with muscle weakness showed improved motor strength; five of seven patients with edema had decreased limb girth; and nine of 20 patients had decreased pain. Pretreatment FGF2 levels dropped from an average of 44.9 pg/mL to 24.0 pg/mL after 8 weeks of treatment. CONCLUSION Patients receiving pentoxifylline demonstrated improved AROM, PROM, and muscle strength and decreased limb edema and pain. Reversal of these delayed radiation effects was associated with a decrease in circulating FGF2.

Cystic fibrosis transmembrane conductance regulator in human and mouse red blood cell membranes and its interaction with ecto‐apyrase

Elevated blood ATP and increased red blood cell (RBC) ATP transport is associated with cystic fibrosis (CF). In this report, we demonstrate the presence of the wild‐type and the ΔF508 mutant form of the CF transmembrane conductance regulator protein in RBC membranes and its putative interaction with ecto‐apyrase, an ATP hydrolyzing enzyme also present in the RBC membrane. RBC membranes of control and ΔF508 individuals and of wild‐type and CF transmembrane conductance regulator‐knockout mice were examined by immunoblot using several antibodies directed against different epitopes of this protein. These experiments indicated that human RBC membranes contain comparable amounts of the wild‐type CF transmembrane conductance regulator protein and the ΔF508 mutant form of the protein, respectively. CF transmembrane conductance regulator protein was also detected in wild‐type mouse RBC membranes but not in the gene knockout mouse RBC membranes. Antibodies directed against ecto‐apyrase co‐immunoprecipitated CF transmembrane conductance regulator protein of human RBC membranes indicating a physical interaction between these two membrane proteins consistent with ATP transport and extracellular hydrolysis. We conclude that RBCs are a significant repository of CF transmembrane conductance regulator protein and should provide a novel system for evaluating its expression and function.

Basic Fibroblast Growth Factor Radioprotects Bone Marrow and not RIF1 Tumor

We examined the potential of bFGF to function as a radioprotector of bone marrow (BM). Total intravenous doses of bFGF ranged from 1 to 24 micrograms/mouse, in 2 divided doses. Whole body radiation (WBI) was given in a single fraction to C3H mice. Histologic observations were performed on femur BM at various times after bFGF (or placebo) treatment. Thigh radiation in thigh-tumor bearing mice was delivered in a single fraction. bFGF increased the LD50/30 of mice in a dose dependent fashion, with an apparent maximum protection obtained with > or = 6 micrograms given half 24 h and half 4 h before irradiation. BM histology shows prominent recovery of megakaryocytes and all cell lineages along with less loss in cellularity compared to control irradiated animals. No radioprotection of RIF1 tumors after bFGF was detected. These results indicate that bFGF may be a selective radioprotector of normal tissue.

Effect of Intraperitoneal ATP on Tumor Growth and Bone Marrow Radiation Tolerance

Transplants of a spontaneous murine fibrosarcoma (FSaII) treated with intraperitoneal ATP were studied in vitro, and in both C3H and nu/nu mice. Daily ATP treatment prolonged tumor volume doubling time in vivo and in vitro. Daily ATP treatments at the maximally tolerated dose (2 mmol/kg i.p.) did not significantly affect the pH or the PCr/Pi, or beta ATP/Pi ratios (measured by MRS). In contrast to the reduced tumor growth rate, there was no change in bone marrow recovery after whole body irradiation. ATP is minimally toxic to animals at active dose levels. It slows tumor growth rate without adversely affecting bone marrow radiation tolerance. ATP might therefore be useful as a biological modifier of chemotherapy or radiation therapy.