Tne ex vivo characterization of XR5944 (MLN944) against a panel of human clinical tumor samples

Federica Di Nicolantonio, Louise A. Knight, Pauline A. Whitehouse, Stuart J. Mercer, Sanjay Sharma, Peter A. Charlton, David Norris, Ian A. Cree

Research output: Contribution to journalArticle

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Abstract

XR5944 (MLN944) is a novel DNA targeting agent with potent antitumor activity, both in vitro and in vivo, against several murine and human tumor models. We have used an ATP-tumor chemosensitivity assay to assess the ex vivo sensitivity of a variety of solid tumors (n = 90) and a CCRF-CEM leukemia cell line selected with XR5944. Differences in gene expression between the parental CCRF-CEM and the resistant subline were investigated by quantitative reverse transcription-PCR. Immunohistochemistry for topoisomerases I and Ilα and multidrug resistance (MDR1) protein was done on those tumors for which tissue was available (n = 32). The CCRF-CEM XR5944 line showed increased mRNA levels of MDR1, major vault protein, and MDR-associated protein 1 compared with the parental line, whereas the expression of topoisomerases I, IIα, and IIβ was essentially unchanged, suggesting that XR5944 is susceptible to MDR mechanisms. The median IC90 and IC50 values for XR5944 in tumor-derived cells were 68 and 26 nmol/L, respectively, 6-fold greater than in resistant cell lines. XR5944 was 40- to 300-fold more potent than the other cytotoxics tested, such as doxorubicin, topotecan, and paclitaxel. Breast and gynecologic malignancies were most sensitive to XR5944, whereas gastrointestinal tumors showed greater resistance. A positive correlation (r = 0.68; P <0.0001) was found between the IC50 values of XR5944 and P-glycoprotein/MDR1 staining but not with either topoisomerase I or IIα immunohistochemistry index. These data support the rapid introduction of XR5944 to clinical trials and suggest that it may be effective against a broad spectrum of tumor types, especially ovarian and breast cancer.

Original languageEnglish
Pages (from-to)1631-1637
Number of pages7
JournalMolecular Cancer Therapeutics
Volume3
Issue number12
Publication statusPublished - Dec 2004

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Neoplasms
Type I DNA Topoisomerase
Type II DNA Topoisomerase
P-Glycoprotein
Inhibitory Concentration 50
Immunohistochemistry
P-Glycoproteins
Topotecan
MLN 944
XR5944
Cell Line
Paclitaxel
Ovarian Neoplasms
Doxorubicin
Reverse Transcription
Leukemia
Breast
Adenosine Triphosphate
Clinical Trials
Staining and Labeling

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Di Nicolantonio, F., Knight, L. A., Whitehouse, P. A., Mercer, S. J., Sharma, S., Charlton, P. A., ... Cree, I. A. (2004). Tne ex vivo characterization of XR5944 (MLN944) against a panel of human clinical tumor samples. Molecular Cancer Therapeutics, 3(12), 1631-1637.

Tne ex vivo characterization of XR5944 (MLN944) against a panel of human clinical tumor samples. / Di Nicolantonio, Federica; Knight, Louise A.; Whitehouse, Pauline A.; Mercer, Stuart J.; Sharma, Sanjay; Charlton, Peter A.; Norris, David; Cree, Ian A.

In: Molecular Cancer Therapeutics, Vol. 3, No. 12, 12.2004, p. 1631-1637.

Research output: Contribution to journalArticle

Di Nicolantonio, F, Knight, LA, Whitehouse, PA, Mercer, SJ, Sharma, S, Charlton, PA, Norris, D & Cree, IA 2004, 'Tne ex vivo characterization of XR5944 (MLN944) against a panel of human clinical tumor samples', Molecular Cancer Therapeutics, vol. 3, no. 12, pp. 1631-1637.
Di Nicolantonio F, Knight LA, Whitehouse PA, Mercer SJ, Sharma S, Charlton PA et al. Tne ex vivo characterization of XR5944 (MLN944) against a panel of human clinical tumor samples. Molecular Cancer Therapeutics. 2004 Dec;3(12):1631-1637.
Di Nicolantonio, Federica ; Knight, Louise A. ; Whitehouse, Pauline A. ; Mercer, Stuart J. ; Sharma, Sanjay ; Charlton, Peter A. ; Norris, David ; Cree, Ian A. / Tne ex vivo characterization of XR5944 (MLN944) against a panel of human clinical tumor samples. In: Molecular Cancer Therapeutics. 2004 ; Vol. 3, No. 12. pp. 1631-1637.
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