The influence of proteasome inhibitor MG132, external radiation, and unlabeled antibody on the tumor uptake and biodistribution of 188Re-labeled anti-E6 C1P5 antibody in cervical cancer in mice

Rébécca Phaeton, Xing Guo Wang, Mark H. Einstein, Gary L. Goldberg, Arturo Casadevall, Ekaterina Dadachova

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Human papillomavirus (HPV) infection is considered a necessary step for the development of cervical cancer, and >95% of all cervical cancers have detectable HPV sequences. The authors of this report recently demonstrated the efficacy of radioimmunotherapy (RIT) targeting viral oncoprotein E6 in the treatment of experimental cervical cancer. They hypothesized that the pretreatment of tumor cells with various agents that cause cell death and/or elevation of E6 levels would increase the accumulation of radiolabeled antibodies to E6 in cervical tumors. METHODS: HPV type 16 (HPV-16)-positive CasKi cells were treated in vitro with up to 6 grays of external radiation, or with the proteasome inhibitor MG-132, or with unlabeled anti-E6 antibody C1P5; and cell death was assessed. The biodistribution of 188Re-labeled C1P5 antibody was determined in both control and radiation MG-132-treated CasKi tumor-bearing nude mice. RESULTS: 188Re-C1P5 antibody demonstrated tumor specificity, very low uptake, and fast clearance from the major organs. The amount of tumor uptake was enhanced by MG-132 but was unaffected by pretreatment with radiation. In addition, in vitro studies demonstrated an unanticipated effect of unlabeled antibody on the amount of cell death, a finding that was suggested by the authors' previous in vivo studies in a CasKi tumor model. CONCLUSIONS: The current results indicated that pretreatment of cervical tumors with the proteasome inhibitor MG-132 and with unlabeled antibody to E6 can serve as a means to generate nonviable cancer cells and to elevate the levels of target oncoproteins in the cells for increasing the accumulation of targeted radiolabeled antibodies in tumors. These results favor the further development of RIT for cervical cancers targeting viral antigens.

Original languageEnglish (US)
Pages (from-to)1067-1074
Number of pages8
JournalCancer
Volume116
Issue numberSUPPL. 4
DOIs
StatePublished - Feb 15 2010
Externally publishedYes

Fingerprint

Neoplasm Antibodies
Proteasome Inhibitors
Uterine Cervical Neoplasms
Radiation
Antibodies
Neoplasms
Radioimmunotherapy
Cell Death
Oncogene Proteins
Papillomavirus Infections
Human papillomavirus 16
Viral Antigens
benzyloxycarbonylleucyl-leucyl-leucine aldehyde
Nude Mice
Cause of Death
Anti-Idiotypic Antibodies

Keywords

  • Re
  • Cervical cancer
  • Chemotherapy
  • Radiolabeled antibodies
  • Viral antigens

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The influence of proteasome inhibitor MG132, external radiation, and unlabeled antibody on the tumor uptake and biodistribution of 188Re-labeled anti-E6 C1P5 antibody in cervical cancer in mice. / Phaeton, Rébécca; Wang, Xing Guo; Einstein, Mark H.; Goldberg, Gary L.; Casadevall, Arturo; Dadachova, Ekaterina.

In: Cancer, Vol. 116, No. SUPPL. 4, 15.02.2010, p. 1067-1074.

Research output: Contribution to journalArticle

Phaeton, Rébécca ; Wang, Xing Guo ; Einstein, Mark H. ; Goldberg, Gary L. ; Casadevall, Arturo ; Dadachova, Ekaterina. / The influence of proteasome inhibitor MG132, external radiation, and unlabeled antibody on the tumor uptake and biodistribution of 188Re-labeled anti-E6 C1P5 antibody in cervical cancer in mice. In: Cancer. 2010 ; Vol. 116, No. SUPPL. 4. pp. 1067-1074.
@article{9e5a4a32ebf646ec9a1016b3f7b38e5a,
title = "The influence of proteasome inhibitor MG132, external radiation, and unlabeled antibody on the tumor uptake and biodistribution of 188Re-labeled anti-E6 C1P5 antibody in cervical cancer in mice",
abstract = "BACKGROUND: Human papillomavirus (HPV) infection is considered a necessary step for the development of cervical cancer, and >95{\%} of all cervical cancers have detectable HPV sequences. The authors of this report recently demonstrated the efficacy of radioimmunotherapy (RIT) targeting viral oncoprotein E6 in the treatment of experimental cervical cancer. They hypothesized that the pretreatment of tumor cells with various agents that cause cell death and/or elevation of E6 levels would increase the accumulation of radiolabeled antibodies to E6 in cervical tumors. METHODS: HPV type 16 (HPV-16)-positive CasKi cells were treated in vitro with up to 6 grays of external radiation, or with the proteasome inhibitor MG-132, or with unlabeled anti-E6 antibody C1P5; and cell death was assessed. The biodistribution of 188Re-labeled C1P5 antibody was determined in both control and radiation MG-132-treated CasKi tumor-bearing nude mice. RESULTS: 188Re-C1P5 antibody demonstrated tumor specificity, very low uptake, and fast clearance from the major organs. The amount of tumor uptake was enhanced by MG-132 but was unaffected by pretreatment with radiation. In addition, in vitro studies demonstrated an unanticipated effect of unlabeled antibody on the amount of cell death, a finding that was suggested by the authors' previous in vivo studies in a CasKi tumor model. CONCLUSIONS: The current results indicated that pretreatment of cervical tumors with the proteasome inhibitor MG-132 and with unlabeled antibody to E6 can serve as a means to generate nonviable cancer cells and to elevate the levels of target oncoproteins in the cells for increasing the accumulation of targeted radiolabeled antibodies in tumors. These results favor the further development of RIT for cervical cancers targeting viral antigens.",
keywords = "Re, Cervical cancer, Chemotherapy, Radiolabeled antibodies, Viral antigens",
author = "R{\'e}b{\'e}cca Phaeton and Wang, {Xing Guo} and Einstein, {Mark H.} and Goldberg, {Gary L.} and Arturo Casadevall and Ekaterina Dadachova",
year = "2010",
month = "2",
day = "15",
doi = "10.1002/cncr.24794",
language = "English (US)",
volume = "116",
pages = "1067--1074",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "SUPPL. 4",

}

TY - JOUR

T1 - The influence of proteasome inhibitor MG132, external radiation, and unlabeled antibody on the tumor uptake and biodistribution of 188Re-labeled anti-E6 C1P5 antibody in cervical cancer in mice

AU - Phaeton, Rébécca

AU - Wang, Xing Guo

AU - Einstein, Mark H.

AU - Goldberg, Gary L.

AU - Casadevall, Arturo

AU - Dadachova, Ekaterina

PY - 2010/2/15

Y1 - 2010/2/15

N2 - BACKGROUND: Human papillomavirus (HPV) infection is considered a necessary step for the development of cervical cancer, and >95% of all cervical cancers have detectable HPV sequences. The authors of this report recently demonstrated the efficacy of radioimmunotherapy (RIT) targeting viral oncoprotein E6 in the treatment of experimental cervical cancer. They hypothesized that the pretreatment of tumor cells with various agents that cause cell death and/or elevation of E6 levels would increase the accumulation of radiolabeled antibodies to E6 in cervical tumors. METHODS: HPV type 16 (HPV-16)-positive CasKi cells were treated in vitro with up to 6 grays of external radiation, or with the proteasome inhibitor MG-132, or with unlabeled anti-E6 antibody C1P5; and cell death was assessed. The biodistribution of 188Re-labeled C1P5 antibody was determined in both control and radiation MG-132-treated CasKi tumor-bearing nude mice. RESULTS: 188Re-C1P5 antibody demonstrated tumor specificity, very low uptake, and fast clearance from the major organs. The amount of tumor uptake was enhanced by MG-132 but was unaffected by pretreatment with radiation. In addition, in vitro studies demonstrated an unanticipated effect of unlabeled antibody on the amount of cell death, a finding that was suggested by the authors' previous in vivo studies in a CasKi tumor model. CONCLUSIONS: The current results indicated that pretreatment of cervical tumors with the proteasome inhibitor MG-132 and with unlabeled antibody to E6 can serve as a means to generate nonviable cancer cells and to elevate the levels of target oncoproteins in the cells for increasing the accumulation of targeted radiolabeled antibodies in tumors. These results favor the further development of RIT for cervical cancers targeting viral antigens.

AB - BACKGROUND: Human papillomavirus (HPV) infection is considered a necessary step for the development of cervical cancer, and >95% of all cervical cancers have detectable HPV sequences. The authors of this report recently demonstrated the efficacy of radioimmunotherapy (RIT) targeting viral oncoprotein E6 in the treatment of experimental cervical cancer. They hypothesized that the pretreatment of tumor cells with various agents that cause cell death and/or elevation of E6 levels would increase the accumulation of radiolabeled antibodies to E6 in cervical tumors. METHODS: HPV type 16 (HPV-16)-positive CasKi cells were treated in vitro with up to 6 grays of external radiation, or with the proteasome inhibitor MG-132, or with unlabeled anti-E6 antibody C1P5; and cell death was assessed. The biodistribution of 188Re-labeled C1P5 antibody was determined in both control and radiation MG-132-treated CasKi tumor-bearing nude mice. RESULTS: 188Re-C1P5 antibody demonstrated tumor specificity, very low uptake, and fast clearance from the major organs. The amount of tumor uptake was enhanced by MG-132 but was unaffected by pretreatment with radiation. In addition, in vitro studies demonstrated an unanticipated effect of unlabeled antibody on the amount of cell death, a finding that was suggested by the authors' previous in vivo studies in a CasKi tumor model. CONCLUSIONS: The current results indicated that pretreatment of cervical tumors with the proteasome inhibitor MG-132 and with unlabeled antibody to E6 can serve as a means to generate nonviable cancer cells and to elevate the levels of target oncoproteins in the cells for increasing the accumulation of targeted radiolabeled antibodies in tumors. These results favor the further development of RIT for cervical cancers targeting viral antigens.

KW - Re

KW - Cervical cancer

KW - Chemotherapy

KW - Radiolabeled antibodies

KW - Viral antigens

UR - http://www.scopus.com/inward/record.url?scp=76249132085&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=76249132085&partnerID=8YFLogxK

U2 - 10.1002/cncr.24794

DO - 10.1002/cncr.24794

M3 - Article

C2 - 20127955

AN - SCOPUS:76249132085

VL - 116

SP - 1067

EP - 1074

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - SUPPL. 4

ER -