Protection of mouse jejunal crypt cells by WR-2721 after small doses of radiation.

The ability of WR-2721 to protect jejunal crypt cells after single doses and multifractionated doses of radiation was studied. Effective dose survival curves for jejunal crypt cells were constructed over the dose range of 230 to 1600 cGy. WR-2721 was given 30 minutes before each fraction, in a regimen consisting of 200 mg/kg before the first radiation fraction, followed at 3 hr intervals by 100 mg/kg for a total of 12 drug doses for the largest number of fractions. Fractionation protocols were designed with common dose fractions in regimens with different fraction numbers, allowing a test of the hypothesis of equal effect per fraction and an estimate of the initial number of clonogens per crypt in both the drug treated and non-drug treated mice. The hypothesis of equal effect per fraction could not be rejected in either the drug or non-drug treated mice. An average number of 137 clonogens per crypt was estimated for the non-drug treated mice and 81 clonogens per crypt in the drug treated mice; the difference between these two values was not significant. The protection factor decreased with decreasing dose ranging from a high of 1.47 (95% C.L. = 1.44 to 1.50) after a single dose of 2000 cGy to a low of 1.21 (95% C.L. = 1.08 to 1.37) after 200 cGy. Analysis of the data using either the linear quadratic (LQ) or two-component (TC) model of cell survival showed that WR-2721 was not dose-modifying over the dose range tested. Analysis using the LQ model showed that both beta and alpha were modified by WR-2721, by 50% and 20% respectively. These data indicate that protection by WR-2721 can be expected to decrease with dose although there is some protection after clinically relevant doses.

Cholesterol lowering bile acid binding agents: novel lipophilic polyamines.

A series of novel lipophilic polyamines was synthesized by the sodium cyanoborohydride-mediated reductive amination of various ketones and aldehydes with the polyamine tris(2-aminoethyl)amine. Two of these compounds, N,N-bis[2-(cyclododecylamino)ethyl]-N'-benzyl-1,2-ethanediamine trihydrochloride (36.3HCl) and N,N-bis[2-(cyclododecylmethylamino)ethyl]-N',N'-dimethyl-1,2-ethan ediamine (23), are 29 and 24 times more potent than colestipol hydrochloride, respectively, for lowering animal serum cholesterol levels.

Late functional and biochemical changes in mouse lung after irradiation: differential effects of WR-2721.

The radioprotective effect of WR-2721 on late damage after whole thorax irradiation has been studied after split doses of radiation using the standard death and breathing rate assays at monthly intervals between 3 and 15 months after irradiation, as well as two biochemical measurements of injury at 15 months, hydroxyproline (HP), an indicator of tissue fibrosis, and DNA content, an indicator of tissue cellularity. A comparison of HP/lung and breaths per minute (BPM) in each dose group in the WR-2721 and non-WR-2721-treated mice 15 months after irradiation showed that the relationship between these two assays of late lung injury was not the same. There were large dose-related increases in breathing rate corresponding to relatively small changes in HP in the lungs of mice given radiation alone. In contrast, the mice given WR-2721 before irradiation showed large dose-related increases in HP/lung, but BPM remained relatively constant independent of dose. These data suggest then that changes in breathing rate and deaths later than 9 months after whole lung irradiation may not be due to collagen accumulation in the lung. WR-2721 did protect better against late lung functional changes (protection factors (PF) = 1.6) and late deaths (PF = 1.51) than against earlier changes in these same assays (PF = 1.4 and 1.28, respectively). Although the earlier-appearing injury after whole thoracic irradiation is most likely related to lung damage with deaths and increases in breathing rate resulting from pneumonitis, the cause of the late-appearing functional injury in the lung after radiation is not clear. Thus protection of late lung damage measured from either lethality or breathing rate is not related to the prevention of lung fibrosis.

The kinetics of repair in mouse lung after fractionated irradiation.

The kinetics of repair of sublethal damage in mouse lung was studied after fractionated doses of 137Cs gamma-rays. A wide range of doses per fraction (1.7-12 Gy) was given with interfraction intervals ranging from 0.5 to 24 h. The data were analysed by a direct method of analysis using the incomplete repair model. The half-time of repair (T1/2) was 0.76 h for the pneumonitis phase of damage (up to 8 months) and 0.65 h for the later phase of damage up to 12 months. The rate of repair was dependent on fraction size for both phases of lung damage and was faster after large dose fractions than after small fractions. The T1/2 was 0.6 h (95 per cent c.1. 0.53, 0.69) for doses per fraction greater than 5 Gy and 0.83 h (95 per cent c.1 0.76, 0.92) for doses per fraction of 2 Gy. Repair was nearly complete by 6 h, at least for the pneumonitis phase of damage. To the extent that extrapolation of these data to humans may be valid, these results imply that treatments with multiple fractions per day that involve the lung will not be limited by the necessity for interfraction intervals much longer than 6 h.