Gerald A. Poore

Selective targeting of magnetic albumin microspheres to the Yoshida sarcoma: Ultrastructural evaluation of microsphere disposition

Magnetic albumin microspheres (1 micron average diameter) were selectively targeted to subcutaneous solid Yoshida sarcoma tumors (average size 450 mm2) in Holtzman rats. This was accomplished by placing an external magnet adjacent to the tumor while the microspheres were infused. Microspheres contained ultra-fine particles of Fe3O4 and no drug (placebo). Placebo microspheres were used due to the previously demonstrated rapid tumoricidal effect of targeted low-dose doxorubicin microspheres. Animals were killed 10 min, 60 min, 30 min, 24 hr and 72 hr after microsphere administration and tumors were examined by transmission electron microscopy to determine the in vivo disposition of the magnetically targeted microspheres. Using placebo microspheres, we have demonstrated microspheres endocytosed in endothelial cells as early as 10 min after infusion. By 30 min microspheres can be seen in the extravascular compartment, sitting adjacent to tumor cells and occasionally in tumor cells. By 24 hr the majority of microspheres have been endocytosed by tumor cells. Microspheres were still observed within tumor cells as late as 72 hr after administration. The rapid extravasation and cellular uptake of magnetically focused microspheres explains the extremely rapid tumoricidal effect previously observed when doxorubicin-containing microspheres were targeted to the tumor.

Enzymes in pyrimidine biosynthesis

Summary The activities of the first two enzymes in the pyrimidine biosynthetic pathway, carbamyl-aspartate-transferase (CATase) and dihydroorotase (DHOase), were measured in a series of Morris hepatomas; and they were compared to values from livers of normal and tumor bearing rats. The effects of fasting, fasting and refeeding, and partial hepatectomy on the two enzymes were studied. Fasting or fasting-refeeding did not significantly alter the activity of carbamyl-aspartate-transferase or dihydroorotase. Neither enzyme was significantly altered in 24 hr regenerating livers or in livers of sham-operated rats. However, carbamyl-aspartate-transferase and dihydroorotase activities were increased in the 48 hr regenerating livers (129–147% and 126–130% N, respectively). The activity of carbamyl-aspartate-transferase increased proportionately with the rate of growth of the Morris hepatomas; 7800 (153% N), 5123-D (168% N), 7288-C (252% N), 3924-A (606% N), and the 3683 (796% N). All values were compared to livers from non-tumor bearing rats, since the host livers from the rats with the hepatomas 3924-A and 3683 showed a significant increase in carbamyl-aspartate-transferase (138 and 125% N, respectively). No increase was observed in the enzyme activity in livers from the hosts of slower growing hepatomas. Dihydroorotase also showed an increase in activity as the rate of growth of the hepatomas increased: 7800, 145% N; 5123-D, 163%; 7288-C, 188%; 3924-A, 298% N, and the 3683, 418% N. The host liver from 3683 and 3924-A showed no significant increase in enzyme activity. However, the host livers from the 7800, 5123-D and 7288-C showed a 54–56% decrease in enzyme activity. Increased enzyme activities of both carbamyl-aspartate-transferase and dihydroorotase show a correlation with rate of growth. These enzymes may aid in controlling the rate of pyrimidine and RNA biosynthesis and, ultimately, in the control of tumor growth.