التفاصيل البيبلوغرافية
| العنوان: |
Phase I and pharmacokinetic study of mitomycin C and celecoxib as potential modulators of tumor resistance to irinotecan in patients with solid malignancies. |
| المؤلفون: |
Xu, Y.1, Kolesar, J. M.2, Schaaf, L. J.3, Drengler, R.4, Duan, W.1, Otterson, G.1, Shapiro, C.1, Kuhn, J.4, Villalona-Calero, M. A.5 miguel.villalona@osumc.edu |
| المصدر: |
Cancer Chemotherapy & Pharmacology. May2009, Vol. 63 Issue 6, p1073-1082. 10p. 7 Charts, 2 Graphs. |
| مصطلحات موضوعية: |
*CLINICAL trials, *MITOMYCIN C, *CELECOXIB, *ANTINEOPLASTIC antibiotics, *TUMOR markers, *DRUG resistance in cancer cells, *PHARMACOKINETICS |
| مستخلص: |
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. 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. 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. 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. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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