Y-90 CHIMERIC L6 THERAPY OF HUMAN BREAST-CANCER IN NUDE-MICE AND APOPTOSIS-RELATED MESSENGER-RNA EXPRESSION

Radioimmunotherapy (RIT) in breast cancer patients using I-131-chimeri c L6 (ChL6) and in human breast cancer xenografts in nude mice using Y -90-1,4,7,10-tetraazacylododecant N,N',N'',N'''-tetraacetic acid-pepti de ChL6 (Y-90-ChL6) has shown promise. Tumor cell response to low-dose rate (5-25 rads/h) irradiation from Y-90-ChL6 RIT, therefore, was cor related with levels of tumor cell mRNA for selected genes linked to pr ogrammed cell death (apoptosis), Three groups of 10-16 mice with 1-2 H BT 3477 xenograft tumors were treated with 100, 150, or 250 mu Ci Y-90 -ChL6, Three tumors were taken before and two tumors each were taken 3 , 6, and 24 h after injection of 150 mu Ci Y-90-ChL6. Tumor expression of mRNA was amplified by PCR for p53, PIC1, c-myc, and transforming g rowth factor-beta(1); quantitated; and standardized to N-ras. Tumors r eceived radiation doses of 2000, 3000, and 5000 rads, respectively, fo r the groups of mice that received 100, 150, and 250 mu Ci Y-90-ChL6, and tumor regression occurred in each group, with mean tumor volumes d ecreased by 10, 50, and 95% at nadir after Y-90-ChL6 injection. At the highest dose level, 30% of mice had complete remissions, and no treat ment deaths occurred, although tumors subsequently recurred. Continuou s up-regulation of transforming growth factor-beta(1) and c-myc mRNA e xpression was observed from 3 to 24 h after treatment, Expression of p 53 and PIC1 increased at 3 h and subsequently decreased to the untreat ed control levels. These observations are consistent with previous obs ervations of early responses of p53 and PIC1 to cellular DNA damage an d subsequent G(1) cell cycle arrest or apoptosis. Apoptosis-associated gene expression patterns observed in this tumor model provide evidenc e that changes are initiated in the first 24 h of RIT associated with radiation doses of 100-700 reds, These preliminary data suggest that i nsight into the molecular basis of RIT-induced tumor regression may be gained by further studies using different radiation doses.