Investigational New Drugs

, Volume 28, Issue 1, pp 49–60

Differential gene expression triggered by highly cytotoxic α-Emitter-immunoconjugates in gastric cancer cells

  • Christof Seidl
  • Matthias Port
  • Christos Apostolidis
  • Frank Bruchertseifer
  • Markus Schwaiger
  • Reingard Senekowitsch-Schmidtke
  • Michael Abend
PRECLINICAL STUDIES

DOI: 10.1007/s10637-008-9214-4

Cite this article as:
Seidl, C., Port, M., Apostolidis, C. et al. Invest New Drugs (2010) 28: 49. doi:10.1007/s10637-008-9214-4

Summary

Immunoconjugates composed of the α-emitter 213Bi and the monoclonal antibody d9MAb specifically target HSC45-M2 gastric cancer cells expressing mutant d9-E-cadherin. These conjugates efficiently killed tumor cells in a nude mouse peritoneal carcinomatosis model. To elucidate the molecular responses of HSC45-M2 cells to α-emitter irradiation, whole genome gene expression profiling was performed. For that purpose HSC45-M2 cells were incubated with lethal doses of 213Bi-d9MAb. RNA was isolated at 6, 24 and 48 h after irradiation, transcribed into cDNA and hybridized to whole genome microarrays. Results of microarray analysis were validated using RTQ-PCR showing correspondence of approximately 90%. Following incubation with 213Bi-d9MAb, 682-1125 genes showed upregulation and 666-1278 genes showed downregulation at one time point, each. Eight genes appeared upregulated and 12 genes downregulated throughout. Molecular functions and biological processes of differentially expressed genes were categorized according to the PANTHER database. Following 213Bi-d9MAb irradiation also a time-dependent shift in terms of overrepresentation of biological processes was observed. Among the genes showing continuous upregulation, COL4A2, NEDD9 and C3 have not been associated with the cellular response to high LET radiation so far. The same holds true for WWP2, RFX3, HIST4H4 and JADE1 that showed continuous downregulation. According to PANTHER, three of the consistently upregulated (ITM2C, FLJ11000, MSMB) and downregulated (HCG9, GAS2L3, FLJ21439) genes, respectively, have not been associated with any biological process or molecular function so far. Thus, these findings revealed interesting new targets for selective elimination of tumor cells and new insights regarding response of tumor cells to α-emitter exposure.

Keywords

RadioimmunotherapyAlpha-emitter 213BiGastric cancerGene expression profilingWhole genome microarray

Abbreviations

DIG-POD

digoxigenin-phosphodiesterase

d9MAb

monoclonal antibody targeting mutant d9-E-cadherin

LET

linear energy transfer

MFC

micro fluidic card

PANTHER

Protein ANalysis THrough Evolutionary Relationships

RTQ-PCR

real time quantitative polymerase chain reaction

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Christof Seidl
    • 1
  • Matthias Port
    • 2
    • 3
  • Christos Apostolidis
    • 4
  • Frank Bruchertseifer
    • 4
  • Markus Schwaiger
    • 1
  • Reingard Senekowitsch-Schmidtke
    • 1
  • Michael Abend
    • 3
    • 5
  1. 1.Department of Nuclear MedicineTechnische Universität MünchenMunichGermany
  2. 2.Department of Hematology and OncologyHannover Medical SchoolHannoverGermany
  3. 3.Bundeswehr Institute of Radiobiology, German Armed ForcesMunichGermany
  4. 4.European Commission, Joint Research Centre, Institute for Transuranium ElementsKarlsruheGermany
  5. 5.Department of RadiooncologyTechnische Universität MünchenMunichGermany