We previously reported that pulsed high intensity focused ultrasound (p-HIFU) treatment of LewisY antigen-expressing A431 tumor implanted in nude mice shortened the peak tumor uptake time (24 vs 48 hr for the control) and increased the peak tumor uptake value (38 vs 25% ID/g for the control) of In-111-labeled B3, a monoclonal antibody directed against LewisY antigen. The HIFU effect on enhancing tumor uptake was greater at earlier times up to 24 hr, but the effect was gradually diminished thereafter. The area-under-curve (AUC) calculations for the 120 hr period of the study indicated that a single pulsed-HIFU treatment could increase the radiation exposure dose of the radiolabeled antibody to tumors by 36%, compared to untreated control tumors (J Nucl Med 2008;49:295). Objectives: The goals of the research in the past year were to investigate if pulsed high intensity focused ultrasound (p-HIFU) exposures could increase the therapeutic efficacy of Y-90-labeled B3 alone and its combination with taxol. Groups of nude mice (n = 5-9 mice/group) were inoculated s.c. with A431 tumor cells expressing the LewisY antigen on the right hind flank. When the tumor size was 200 cubic mm, the mice received i.v. Y-90-labeled B3 alone (60 micro-Ci/150 micro-g B3 or 100 micro-Ci /150 micro-g B3), i.p. taxol alone (40 micro-g /Kg), the two agents together (Y-90-labeled B3 and after 24 hr, taxol), or no treatment. To investigate the effect of p-HIFU, the tumor was treated first with pulsed-HIFU, and within 10 min after p-HIFU, the mice received i.v. Y-90-labeled B3 with or without taxol. The tumor volume and the body weight were measured daily for the first 7 days and thereafter, two or three times a week. Mice were euthanized when the tumor size was 2 cm in diameter. Results: The tumors in the control mice without treatment grew rapidly with a median survival time of < 6 days. The taxol treatment stabilized the tumor growth for 5 days and thereafter, the tumors started re-growing with a median duration of survival of 16 days. The Y-90-labeled B3 treatment showed a dose-dependent response with a median survival time of 18 days for the 60 micro-Ci/150 micro-g B3 group and 21 days for the 100 micro-Ci /150 micro-g B3 group. The combination therapy with 60 micro-Ci/150 micro-g B3 plus taxol and 100 micro-Ci /150 micro-g B3 plus taxol showed a synergistic effect in reduction of tumor volume and prolongation of the survival time; 40% of tumors treated with 60 micro-Ci/150 micro-g B3 plus taxol completely disappeared by day 24 whereas by that time 70% of tumors treated with 100 micro-Ci /150 micro-g B3 plus taxol completely disappeared. The p-HIFU coupled with 60 micro-Ci/150 micro-g B3 treatment showed an additive effect in delaying the tumor growth with the median survival time comparable to the group treated with 100 micro-Ci /150 micro-g of Y-90 B3 without p-HIFU treatment. The p-HIFU treatment combined with 60 micro-Ci/150 micro-g B3 plus taxol treatment also showed an additive effect in delaying the tumor growth compared to the combination therapy without p-HIFU during the first 8 day period, thereafter the growth inhibition curve became almost superimposed with that of the combination therapy without p-HIFU. However, on day 21, the two curves started to diverge; the mean volume of tumors untreated with p-HIFU started to increase , whereas the mean volume of tumors treated with p-HIFU continued to decrease for 4 more days before the mean volume started to increase. Conclusion: In the nude mouse model of human epidermoid A431 tumor, the combination therapy of the Y-90-B3 with taxol showed a synergistic effect. The p-HIFU treatment provided an additive effect to the Y-90-B3 treatment alone as well as in the combination therapy of the Y-90-B3 with taxol. This additive effect appears to be due to the delivery enhancement of Y-90-B3 to the tumor sites. The additive effect of p-HIFU treatment to the synergistic combination therapy of Y-90-B3 and taxol appears to increase the efficacy of the combination therapy at a Y-90 B3 dose (60 micro-Ci) equivalent to 25% of the maximum tolerated dose (200-300 micro-Ci) and a clinically achievable taxol dose (40 mico-g/Kg). These findings are very encouraging and warrant further studies on this additive p-HIFU effect as well as the synergistic effect of the combination therapy.
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