Table 1

Prevention trial. The average number ±SD of angiogenic islets of control (PBS) and treated mice and the reduction in the number of angiogenic islets (%) are shown. The reduction in angiogenic islet incidence in treated (T) versus control (C) mice was calculated by the formula (1 – T/C) × 100. Statistical analysis was done with a two-tailed, unpaired Mann-Whitney test comparing experimental groups to (phosphate-buffered saline (PBS)–injected control mice. P values less than 0.1 are considered statistically significant. “N start” indicates the number of animals at the beginning of the trial; “N stop” indicates the number of animals at the end of the trial; and “N trials” indicates the number of independent experiments. The endostatin fragment of collagen XVIII and the angiostatin fragment of plasminogen were each fused at their respective NH2-termini to the constant region of immunoglobulin G (Fc), the hybrid genes were expressed in murine myeloma cells, and the fusion proteins were isolated as described (12). BB-94 was homogenized in 0.02% Triton and PBS (pH 7.0) and given as an emulsion. AGM-1470 was dissolved in 5% dextrose water. Mice were treated with 25 mg per kilogram of body weight (25 mg/kg) of AGM-1470 s.c. every other day; or with 30 mg/kg of BB-94 i.p. every day; or with 15 mg/kg of Fc-endostatin s.c. every day, and/or with 20 mg/kg Fc-angiostatin s.c. every day. The dose of 15 mg/kg of Fc-endostatin was the maximal tolerable dose because of an inflammatory side effect produced by the fusion protein, which resulted in swollen faces and hair loss (or white hair on the head) but did not provoke an evident specific immune response in the form of T and B cell infiltration in the pancreas (15). Neither the Fc fragment alone nor endostatin without the Fc fragment elicited such allergic reactions.

Treatment groupAverage number of angiogenic islets (± SD)N startNstopN trialsP valueReduction in angiogenic islets (%)
PBS control46.0  ±   6.75, 55, 520
AGM-147040.6  ±  10.15, 55, 520.364111.7
BB-9423.5  ±   4.74, 43, 320.001448.9
Fc-endostatin18.0  ±   4.84, 53, 420.000860.9
Fc-angiostatin33.8  ±   5.26610.005726.5
Fc-angiostatin + Fc-endostatin17.0  ±   4.65510.002763.0