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Investigational New Drugs

, Volume 25, Issue 5, pp 417–423 | Cite as

In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression

  • Axel-Rainer Hanauske
  • Ulrike Eismann
  • Olaf Oberschmidt
  • Heike Pospisil
  • Steve Hoffmann
  • Hartmut Hanauske-Abel
  • Doreen Ma
  • Victor Chen
  • Paolo Paoletti
  • Clet Niyikiza
PRECLINICAL STUDIES

Summary

Aim of the study

mRNA expression of genes involved in the mechanism of action of pemetrexed was correlated with in vitro chemosensitivity of freshly explanted human tumor specimens.

Experimental design

Chemosensitivity to pemetrexed was studied in soft-agar. Multiplex rtPCR experiments for reduced folate carrier (RFC), folate receptor-α (FR-α), folylpolyglutamate synthetase (FPGS), thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyl transferase (GARFT), mrp4, and mrp5 were performed in parallel. Correlations, threshold optimization, sensitivity, specificity, and efficiency were analyzed using the appropriate statistical methodologies.

Results

In 61 samples, low levels of TS, GARFT, DHFR, and mrp4 gene expression significantly correlated with chemosensitivity to pemetrexed. Optimization analyses demonstrated threshold values of 144 copies for TS and six copies for mrp4 relative to 104 copies of β-actin.

Conclusions

These results form a rational basis for the design of clinical trials to evaluate the expression of these enzymes as predictors for treatment outcome.

Keywords

Pemetrexed disodium Gene expression Freshly explanted human tumors Thymidilate synthase Dihydrofolate reductase Glycinamide ribonucleotide formyltransferase Mrp4 Mrp5 Predictive testing 

Notes

Acknowledgement

We are grateful for the financial support of Eli Lilly & Co. Indianapolis, Indiana, USA.

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Axel-Rainer Hanauske
    • 1
    • 5
  • Ulrike Eismann
    • 1
  • Olaf Oberschmidt
    • 1
  • Heike Pospisil
    • 2
  • Steve Hoffmann
    • 2
  • Hartmut Hanauske-Abel
    • 3
  • Doreen Ma
    • 4
  • Victor Chen
    • 4
  • Paolo Paoletti
    • 4
  • Clet Niyikiza
    • 4
  1. 1.Asklepios KlinikHamburgGermany
  2. 2.Zentrum für BioinformatikUniversität HamburgHamburgGermany
  3. 3.UMDNJ-New Jersey Medical SchoolNewarkUSA
  4. 4.Eli Lilly & CompanyIndianapolisUSA
  5. 5.HamburgGermany

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