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Phase I and pharmacokinetic study of mitomycin C and celecoxib as potential modulators of tumor resistance to irinotecan in patients with solid malignancies

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Abstract

Purpose

Based on the preclinical evidence of topoisomerase I (Topo-1) upregulation by mitomycin C(MMC) and decreased NF-κB activation by celecoxib, we evaluated combinations of irinotecan/MMC and irinotecan/MMC/celecoxib in patients with advanced solid malignancies.

Patients–methods

Initially, patients received MMC on day 1 and irinotecan on days 2, 8, 15 and 22, every 6 weeks. MMC dose was fixed at 6 mg/m2 and cumulative doses of >36 mg/m2 were not permitted. Irinotecan was escalated in 25 mg/m2 increments. Due to late-onset diarrhea, the schedule was subsequently shortened to 4 weeks, omitting irinotecan on days 15 and 22. In the second part of the study, celecoxib 400 mg orally twice daily was added to irinotecan/MMC regimen. Potential pharmacokinetic interactions and Topo-1 and DT-diaphorase (NQ01) gene expressions in peripheral-mononuclear cells were evaluated.

Results

Forty-five patients were enrolled. Irinotecan 125 mg/m2 on days 2 and 8 in combination with MMC 6 mg/m2 on day 1 every 4 weeks is recommended for future studies; myelosuppression and diarrhea are dose-limiting. The addition of celecoxib resulted in unacceptable toxicities despite reductions on irinotecan’s dose. No relevant pharmacokinetic interactions occurred between irinotecan and MMC, and mean increases in Topo-1, were observed. Sixteen of 36 patients evaluable for response-assessment had discernable anti-tumor activity, including 1 complete, 4 partial, 10 minor and 1 tumor marker response. Four patients had prolonged (>4 months) disease-stability (stable disease, not included in CR or PR). Patients experiencing complete and partial responses had higher increments in Topo-1 expression.

Conclusions

Modulation of irinotecan by MMC is feasible, devoid of pharmacological interactions and active in solid malignancies. The lack of improvement in therapeutic index does not support the addition of celecoxib.

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Authors and Affiliations

  1. The Division of Hematology/Oncology, Departments of Internal Medicine, The Ohio State University College of Medicine and Public Health, Columbus, OH, USA

    Y. Xu, W. Duan, G. Otterson & C. Shapiro

  2. The University of Wisconsin, Madison, WI, USA

    J. M. Kolesar

  3. The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210-1240, USA

    L. J. Schaaf

  4. The Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX, USA

    R. Drengler & J. Kuhn

  5. The Division of Hematology/Oncology, Departments of Internal Medicine and Pharmacology, The Ohio State University College of Medicine and Public Health, Columbus, OH, USA

    M. A. Villalona-Calero

Authors
  1. Y. Xu
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  2. J. M. Kolesar
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  3. L. J. Schaaf
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  4. R. Drengler
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  5. W. Duan
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  6. G. Otterson
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  7. C. Shapiro
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  9. M. A. Villalona-Calero
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Corresponding author

Correspondence to M. A. Villalona-Calero.

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Xu, Y., Kolesar, J.M., Schaaf, L.J. et al. Phase I and pharmacokinetic study of mitomycin C and celecoxib as potential modulators of tumor resistance to irinotecan in patients with solid malignancies. Cancer Chemother Pharmacol 63, 1073–1082 (2009). https://doi.org/10.1007/s00280-008-0826-3

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  • DOI: https://doi.org/10.1007/s00280-008-0826-3

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