Biodistribution of 6-[211At]astato-2-methyl-1,4-naphthoquinol bis(diphosphate salt) and 211At- in mice with a transplanted rectal adenocarcinoma.
6-[211At]astato-MNDP is currently being investigated as a potential high LET endoradiotherapeutic drug. Biodistribution and whole-body radiation retention studies have been carried out with 6-[211At]astato-MNDP and 211At- in a murine rectal tumour model; results indicate that the 211At-C bond in the compound is metabolically stable for at least 6 h. The Mean Biological Concentration of 6-[211At]astato-MNDP in tumour tissue ranged from 170-253% over an initial 12 h period; this was higher than that observed for the [211At]astatide anion. Conversely, the uptake of compound into radiobiologically critical organs was significantly lower.
Radiotoxicity of systematically administered [211At]astatide in B6C3F1 and BALB/c (nu/nu) mice: a long-term survival study with histologic analysis.
PURPOSE
The present study undertook to establish the dose (LD) of systematically administered (via tail vein) sodium [211At]astatide that would kill 10% (LD10) of exposed animals in two mouse models and to evaluate the resulting histologic lesions.


METHODS AND MATERIALS
Three dose escalation experiments were carried out using groups of 10 3- to 4-week-old, 20 +/- 2 g B6C3F1 mice, and one dose escalation experiment was carried out with groups of 10 4- to 6-week-old, 22 +/- 2 g BALB/c (nu/nu) mice. All animals were weighed daily and checked twice daily for general health; autopsies were performed within 12 h of death.


RESULTS
The LD10 (95% confidence interval) level of free [211At]astatide at 360 days was 15.1 microCi (5.2-19.1 microCi) in B6C3F1 mice and was associated with a 37.8% weight difference from saline controls (p < 0.001). In the BALB/c (nu/nu) mice, the LD10 at 360 days was 7.7 microCi (0-14.2 microCi), while a dose of 10 microCi (0.42 microCi g(-1)) was associated with a 9.44% weight difference vs. saline controls (p < 0.05). Exclusive of the well-known effects on thyroid, [211At]astatide activity levels were associated with severe bone marrow depression, testicular atrophy, focal alopecia, and nuclear atypia of the epidermoid mucosa of the fore-stomach in the B6C3F1 mice; at activity levels approximating LD10 at 360 days, mild changes in the heart, liver, stomach, and spleen were observed. For BALB/c (nu/nu) mice, administration of 10 microCi was associated at autopsy with mild histologic lesions in the heart, stomach, liver, and spleen.


CONCLUSIONS
These studies provide a basis for the design of further investigations of [211At]-labeled compounds as therapeutic agents.
Reversible and irreversible effects of tissue culture on enzyme patterns of spontaneous mouse tumors and mouse and human embryo tissues.
The DNA:protein ratio and enzyme patterns of four spontaneous mouse tumors (one male and one female mammary carcinoma, a muscle sarcoma, and a uterine fibrosarcoma) were determined. Tissue culture cell lines established from these tumors and from mouse embryo and human embryo lung tissues showed quantitative changes in DNA:protein ratio and most of the 13 enzymes studied. Although there were wide variations in enzyme patterns between the tumors and between the embryo tissues, the pattern in tissue culture cells, whatever their origin, tended to be similar. Most of the tumor cell enzyme changes were reversible after reimplantation into syngeneic hosts, with the exception of alkaline phosphatase, which did not reappear in muscle sarcoma and female mammary carcinoma derived from tissue culture cells. In tissue culture, the mitochondrial enzymes succinic dehydrogenase and cytochrome oxidase were particularly affected. Surface enzymes were also altered. Alkaline phosphatase was decreased or lost and 5′-nucleotidase was increased in all cultures. The enzymes of the male mammary carcinoma were less affected by culture than those of the other tumors.