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¹ Translational Oncology Research Centre, Department of Histopathology, Queen Alexandra Hospital, Portsmouth, United Kingdom and ² Xenova Ltd., Slough, United Kingdom

Requests for reprints: Ian A. Cree, Translational Oncology Research Centre, Department of Histopathology, Queen Alexandra Hospital, Michael Darmady Laboratory, E Level, Portsmouth PO6 3LY, United Kingdom. Phone: 44-239-9228-6378; Fax: 44-239-9228-6379. E-mail: ian.cree{at}port.ac.uk

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 II 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, II, and IIß 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 II 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.

Key Words: ATP • chemosensitivity • MDR1 • MLN944 • resistance • XR5944

Grant support: Xenova Ltd. UK.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Notes:Possible conflicts of interest (including financial and other relationships) for each author include the following: Dr. D. Norris (Xenova employee); Dr. P.A. Charlton (Xenova employee until September 2003); and I.A. Cree (director of Cantech Ltd.; received funding from Xenova).

Received 6/22/04; revised 8/18/04; accepted 10/15/04.