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

Sally J. DeNardo, Paul H. Gumerlock, Michelle D. Winthrop, Philip Mack, Sung Gil Chi, Kathleen R. Lamborn, Sui Shen, Laird A. Miers, Ralph W deVere White, Gerald L Denardo

Research output: Contribution to journalArticle

18 Citations (Scopus)

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-β1; 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-β1 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 G1 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.

Original languageEnglish (US)
JournalCancer Research
Volume55
Issue number23 SUPPL.
StatePublished - 1995
Externally publishedYes

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Yttrium
Nude Mice
Apoptosis
Breast Neoplasms
Messenger RNA
Neoplasms
Radioimmunotherapy
Therapeutics
Transforming Growth Factors
Radiation
Heterografts
G1 Phase Cell Cycle Checkpoints
Injections
Tumor Burden
DNA Damage
Cell Death
Up-Regulation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Yttrium-90 chimeric L6 therapy of human breast cancer in nude mice and apoptosis-related messenger RNA expression. / DeNardo, Sally J.; Gumerlock, Paul H.; Winthrop, Michelle D.; Mack, Philip; Chi, Sung Gil; Lamborn, Kathleen R.; Shen, Sui; Miers, Laird A.; deVere White, Ralph W; Denardo, Gerald L.

In: Cancer Research, Vol. 55, No. 23 SUPPL., 1995.

Research output: Contribution to journalArticle

DeNardo, SJ, Gumerlock, PH, Winthrop, MD, Mack, P, Chi, SG, Lamborn, KR, Shen, S, Miers, LA, deVere White, RW & Denardo, GL 1995, 'Yttrium-90 chimeric L6 therapy of human breast cancer in nude mice and apoptosis-related messenger RNA expression', Cancer Research, vol. 55, no. 23 SUPPL..
DeNardo, Sally J. ; Gumerlock, Paul H. ; Winthrop, Michelle D. ; Mack, Philip ; Chi, Sung Gil ; Lamborn, Kathleen R. ; Shen, Sui ; Miers, Laird A. ; deVere White, Ralph W ; Denardo, Gerald L. / Yttrium-90 chimeric L6 therapy of human breast cancer in nude mice and apoptosis-related messenger RNA expression. In: Cancer Research. 1995 ; Vol. 55, No. 23 SUPPL.
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title = "Yttrium-90 chimeric L6 therapy of human breast cancer in nude mice and apoptosis-related messenger RNA expression",
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-β1; 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-β1 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 G1 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.",
author = "DeNardo, {Sally J.} and Gumerlock, {Paul H.} and Winthrop, {Michelle D.} and Philip Mack and Chi, {Sung Gil} and Lamborn, {Kathleen R.} and Sui Shen and Miers, {Laird A.} and {deVere White}, {Ralph W} and Denardo, {Gerald L}",
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AU - Gumerlock, Paul H.

AU - Winthrop, Michelle D.

AU - Mack, Philip

AU - Chi, Sung Gil

AU - Lamborn, Kathleen R.

AU - Shen, Sui

AU - Miers, Laird A.

AU - deVere White, Ralph W

AU - Denardo, Gerald L

PY - 1995

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N2 - 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-β1; 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-β1 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 G1 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.

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