ANTITUMOR EFFECTS AND DISTRIBUTION OF ADRIAMYCIN INCORPORATED INTO HYDROXYAPATITE IMPLANTS IN A CANCER RAT MODEL BEARING SWARM RAT CHONDROSARCOMA

We investigated the antitumor effects and tissue distribution of adria mycin (ADR) incorporated into a hydroxyapatite (HAP) bead in a cancer rat model bearing Swarm rat chondrosarcoma. The Porous HAP bead (8.48 mm in diameter, 531+/-0.7 mg in weight) was used as a model bone graft . One ADR-HAP bead (ADR 0.4 mg-6.0 mg/bead) was implanted s.c. into a Sprague-Dawley rat at 6 days postinoculation of Swarm rat chondrosarco ma. ADR-HAP beads showed strong antitumor activities in a dose depende nt manner. The dose of 6.0 mg/bead showed the highest efficacy with no toxic death: It caused a 98% growth inhibition on Day 31 postinoculat ion and a survival advantage of a 339% increase in life span. After th e implantation of the ADR-HAP bead (0.4 mg/bead/body) and the i.v. adm inistration of an equal dose of free adriamycin, we determined the tis sue distribution of ADR for up to 90 days. ADR-HAP bead implanted in t he tumors released ADR over a 12-week period in the target area. The d iffusion of the drug to other organs such as the heart and liver was v ery low compared with the tumors. The area under the ADR concentration -time curve (AUG) of the tumors was 181.6 mu g.day/g and 5.22 mu g.day /g after the implantation of the ADR-HAP bead and the i.v. administrat ion of free ADR, respectively. The targeting index of the tumors, defi ned as the ratio of the AUC after the implantation of the ADR-HAP bead to that after administration of free ADR, was 34.8. The targeting ind ices of 0.16 and 0.17 for the heart and liver, respectively, indicate that the implantation of the ADR-HAP bead reduced delivery of ADR to t hese organs. These results demonstrate that this method of administrat ion may be useful in delivering adjuvant chemotherapy in order to prev ent local recurrence in the site of the bony defect after the surgical removal of bone tumors.