Antitumor activity of XR5944, a novel and potent topoisomerase poison

Stewart, Angela; Mistry, Prakash; Dangerfield, Wendy; Bootle, Douglas; Baker, Mark; Kofler, Barbara; Okiji, Sade; Baguley, Bruce C.; Denny, William A.; Charlton, Peter

doi:10.1097/00001813-200104000-00009

Cited by 56 publications

(64 citation statements)

References 18 publications

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“…XR5944 is a novel bis-phenazine that has shown potent cytotoxic activity in a range of human and murine tumour cell lines in vitro, as well as significant antitumour activity against human tumour xenografts in vivo and ex vivo (Cree et al, 2001;Gamage et al, 2001;Stewart et al, 2001). XR5944 has recently entered phase I clinical trials.…”

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confidence: 99%

Antitumour activity of XR5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell lines

Harris¹,

Mistry²,

Freathy³

et al. 2005

Br J Cancer

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XR5944 (MLN944), a novel bis-phenazine, has demonstrated potent cytotoxic activity against a variety of murine and human tumour models. In the present study, the antitumour activity of XR5944 was investigated in combination with 5-fluorouracil (5-FU) or irinotecan in human colon carcinoma cell lines and xenografts. In vitro cytotoxicity of the combinations following exposure to the drugs sequentially or simultaneously was evaluated by the sulphorhodamine-B assay and interactions were determined using medianeffect analysis. Antagonism was observed (CI41) following exposure of HT29 cells simultaneously to XR5944 and 5-FU or SN38 (active metabolite of irinotecan). In contrast, sequential exposure of either combination in either order demonstrated at least an additive response (CIp1). At least an additive response was also observed with these combinations in HCT116 cells regardless of schedule. Antitumour activity in HT29 xenografts in nude mice was enhanced by sequential administration of 5-FU (65 mg kg À1 ) or irinotecan (CPT-11) (35 mg kg À1 ) 48 h before XR5944 (5, 10, or 15 mg kg À1 ) compared to single agent treatment at the same or higher doses. Administration of irinotecan (35 mg kg À1 ) and XR5944 (15 mg kg À1 ) just 30 min apart yielded similar efficacy to sequential administration 48 h apart. All combinations were well tolerated. These data suggest that combinations of XR5944 with irinotecan or 5-FU are of significant interest in the treatment of colon cancer.

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mentioning

confidence: 99%

Antitumour activity of XR5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell lines

Harris¹,

Mistry²,

Freathy³

et al. 2005

Br J Cancer

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“…MLN944 was developed in a drug design program intended to create topoisomerase inhibitors (1). Potent cytotoxicity of MLN944 has been seen in Jurkat and Chinese hamster ovary cell lines and has translated to human colon carcinoma xenograft models in mice (2). Recently, MLN944 was shown to be significantly more potent than doxorubicin, topotecan and paclitaxel against a variety of human tumors ex vivo (3).…”

Section: Introductionmentioning

confidence: 99%

“…MLN944 was originally reported to function as a topoisomerase I and II inhibitor due to its ability to stimulate the isolation of cleavable complexes containing topoisomerase I or II (2). Subsequently, MLN944 was found not to inhibit topoisomerase I or II catalytic activity in DNA supercoiling assays (5).…”

Section: Introductionmentioning

confidence: 99%

The antiproliferative agent MLN944 preferentially inhibits transcription

Byers

Schafer²,

Sappal³

et al. 2005

Molecular Cancer Therapeutics

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MLN944 is a novel compound currently being codeveloped by Millennium Pharmaceuticals and Xenova Ltd. as a cancer therapeutic and is in a phase I clinical trial for solid tumors. Although MLN944 was originally proposed to function as a topoisomerase I and II inhibitor, more recent data has shown that it is a DNA-intercalating agent that does not inhibit the catalytic activity of topoisomerase I or II. We show here that MLN944 inhibits incorporation of radiolabeled precursors into RNA preferentially over incorporation into DNA and protein in HCT116 and H460 cells. To determine if MLN944 inhibits transcription, a human RNA polymerase II in vitro transcription system was used. MLN944 inhibited initiation when added before or after the formation of preinitiation complexes and inhibited elongation at higher concentrations. The preferential inhibition of initiation differentiates MLN944 from actinomycin D, which more strongly inhibits elongation. Transcription of all RNA polymerases was inhibited in nuclei isolated from HeLa cells treated with low concentrations of MLN944. Our data are consistent with transcription as the target of the potent cytotoxic effects of MLN944. [Mol Cancer Ther 2005;4(8):1260 -7]

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“…Initially, it was thought to interfere with the normal function of topoisomerase I and II (Stewart et al, 2001). Recent studies, however, have indicated that the agent intercalates into DNA and inhibits transcription, but has no effect on the catalytic activity of either topoisomerase I or II (Dai et al, 2004;Byers et al, 2005).…”

mentioning

confidence: 99%

“…Complete tumour regression was seen at well-tolerated doses of XR5944. XR5944 even delayed tumour growth in the HT29 human colon carcinoma, which is relatively refractory to cytotoxic chemotherapy (Stewart et al, 2001).…”

mentioning

confidence: 99%

First-into-man phase I and pharmacokinetic study of XR5944.14, a novel agent with a unique mechanism of action

et al. 2007

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The bis-phenazine XR5944.14 is a novel cytotoxic agent which intercalates into DNA and inhibits transcription. The objectives of this study were to determine the dose-limiting toxicity (DLT), the maximum tolerated dose (MTD) and to describe the pharmacokinetics (PKs) of XR5944.14 when given at doses ranging from 3.6 to 36 mg m À2 every 3 weeks to patients with advanced tumours. Twentyseven patients were treated with a total of 77 cycles. Dose-limiting toxicities occurred at doses X24 mg m À2 . Oral mucositis was the most common DLT. Two patients developed acute renal failure possibly related to the study drug. Other less-severe toxicities were diarrhoea, nausea, vomiting and fatigue. Haematological toxicity was mild. One patient showed an objective partial response. Pharmacokinetic analysis was performed during the first cycle of treatment and plasma was assayed for XR5944.14 using a validated liquid chromatography tandem mass spectrometry. The systemic exposure of XR5944.14 increased more than proportionally with increasing dose, with inter-patient variability increasing from dose level 24 mg m À2 onwards. The lack of correlation between toxicity and PK values makes it difficult to recommend a dose for further study in phase 2 trials. More work is needed to explain the inter-and intra-individual variation in PKs and pharmacodynamics.

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Antitumor activity of XR5944, a novel and potent topoisomerase poison

Cited by 56 publications

References 18 publications

Antitumour activity of XR5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell lines

Antitumour activity of XR5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell lines

The antiproliferative agent MLN944 preferentially inhibits transcription

First-into-man phase I and pharmacokinetic study of XR5944.14, a novel agent with a unique mechanism of action

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