Ex vivo characterization of XR11576 (MLN576) against ovarian cancer and other solid tumors

XR11576 (MLN576) is a novel monophenazine with a mechanism of action that includes interaction with both Topoisomerase (Topo) I and II. The aim of this study was to evaluate its cytotoxicity against fresh tumor cells taken from patients with a variety of solid tumors. Cells were obtained from 89 patients and exposed for 6 days to XR11576 alone, or in combination with doxorubicin, cisplatin, treosulfan, paclitaxel or vinorelbine. Cell survival was measured using the ATP-Tumor Chemosensitivity Assay (ATP-TCA). Immunohistochemical staining of Topo I, Topo IIalpha and MDR1 was performed on paraffin-embedded blocks in those tumors for which tissue was available (n = 49). Overall, the median IC90 and IC50 values of XR11576 in tumor-derived cells were 242 and 110 nM, respectively. In all samples XR11576 was more potent than the Other cytotoxics tested. Breast and gynecological malignancies were most sensitive to XR11576, while the potency of this compound was slightly attenuated in gastrointestinal tumors, in which the median IC90 and IC50 values were 308 and 212 nM, respectively. Cases of synergism were identified when combining XR11576 with vinorelbine (nine of 30 samples) and doxorubicin (12 of 38 samples), while the addition of paclitaxel resulted in an antagonistic effect (CI50>1.2) in 38 of 42 tumors. A very modest correlation by linear regression analysis was found between the intensity of MDR1 staining and the IC50 of XR11576 (r = 0.311, p = 0.0312), but not with the IC90 (r = 0.247, NS). These data support the rapid introduction of XR11576 to clinical trials and suggest that it may be effective against a broad spectrum of tumor types.