Yttrium-90 chimeric L6 therapy of human breast cancer in nude mice and apoptosis-related messenger RNA expression

Academic Article

Abstract

  • Radioimmunotherapy (RIT) In breast cancer patients using 1-131-chimeric 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-peptide 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 correlated with levels of tumor cell mRNA for selected genes linked to programmed cell death (apoptosis). Three groups of 10-16 mice with 1-2 HBT 3477 xenograft tumors were treated with 100, 150, or 250 μCi Y-90-ChL6. Three tumors were taken before and two tumors each were taken 3, 6, and 24 h after injection of 150 μCi Y-90-CHL6. Tumor expression of mRNA was amplified by PCR for p53, PIC1, c-myc, and transforming growth factor-β ; quantitated; and standardized to N-ras. Tumors received radiation doses of 2000, 3000, and 5000 rads, respectively, for the groups of mice that received 100, 150, and 250 μCi Y-90-ChL6, and tumor regression occurred in each group, with mean tumor volumes decreased 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 treatment deaths occurred, although tumors subsequently recurred. Continuous up-regulation of transforming growth factor-β and c-myc mRNA expression was observed from 3 to 24 h after treatment Expression of p53 and PIC1 increased at 3 h and subsequently decreased to the untreated control levels. These observations are consistent with previous observations of early responses of p53 and PIC1 to cellular DNA damage and subsequent G cell cycle arrest or apoptosis. Apoptosis-associated gene expression patterns observed in this tumor model provide evidence that changes are initiated in the first 24 h of RIT associated with radiation doses of 100-700 rads. These preliminary data suggest that insight into the molecular basis of RIF-induced tumor regression may be gained by further studies using different radiation doses. 1 1 1
  • Authors

    Published In

  • Cancer Research  Journal
  • Author List

  • DeNardo SJ; Gumerlock PH; Winthrop MD; Mack PC; Chi SG; Lamborn KR; Shen S; Miers LA; Devere White RW; DeNardo GL
  • Volume

  • 55
  • Issue

  • 23 SUPPL.