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Protracted dosing of the lipophilic camptothecin analogue AR-67 in non-small cell lung cancer xenografts and humans

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Abstract

Purpose

Although preclinical studies on camptothecin antitumor effect have demonstrated the superiority of low-dose protracted dosing, these findings were not replicated in the clinic. 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a camptothecin analogue currently under investigation in early phase clinical trials. To maximize the therapeutic potential of AR-67, we sought to identify factors that affect response to treatment.

Methods

After determining the maximum tolerated dose using neutropenia as a toxicity endpoint, xenografts received AR-67 under varying dosing schedules and were monitored for survival. On the last treatment day, tumor tissue was collected and topoisomerase 1 (Top1), γH2AX, caspase 3 and PARP protein content was evaluated. AR-67 plasma and tumor pharmacokinetics were also studied in mice and cancer patients who were administered AR-67 as a 1-h intravenous infusion on days 1, 4, 8, 12 and 15 every 21 days.

Results

Low-dose protracted dosing schedules increased animal survival compared to less frequent, but higher-dose courses and the expression of Top1 and γH2AX were schedule dependent. Fatigue and neutropenia were the dose-limiting toxicities identified in patients receiving AR-67. Finally, elimination of AR-67 from the tumor site was slower in both xenografts and tumor of a patient enrolled in the pilot clinical trial.

Conclusions

We demonstrated that low-dose protracted dosing schedules of AR-67 are therapeutically effective and Top1 reflects the biological activity of AR-67 in xenografts. Moreover, the tumor pharmacokinetics as well as the efficacy and safety of AR-67 given intermittently to cancer patients warrant further investigation.

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Acknowledgments

The authors would like to thank the patients for their participation in this pilot study and Dr. Jamie Horn for sample handling and processing. Moreover, we would like to acknowledge all the health care professionals at the Markey Cancer Center that cared for the study participants. This study was funded by the Markey Cancer Center Pilot Grant and by CA123867.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Room 323, Lexington, KY, 40536, USA

    Eleftheria Tsakalozou, Eyob D. Adane, Yali Liang & Markos Leggas

  2. Division of Medical Oncology, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, 800 Rose St., Lexington, KY, 40536, USA

    Susanne M. Arnold

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  1. Eleftheria Tsakalozou
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  2. Eyob D. Adane
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Correspondence to Markos Leggas.

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Tsakalozou, E., Adane, E.D., Liang, Y. et al. Protracted dosing of the lipophilic camptothecin analogue AR-67 in non-small cell lung cancer xenografts and humans. Cancer Chemother Pharmacol 74, 45–54 (2014). https://doi.org/10.1007/s00280-014-2472-2

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