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01.05.2009 | Original Article

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

verfasst von: Y. Xu, J. M. Kolesar, L. J. Schaaf, R. Drengler, W. Duan, G. Otterson, C. Shapiro, J. Kuhn, M. A. Villalona-Calero

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 6/2009

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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.

Hsiang YH, Liu LF (1988) Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 48:1722–1726PubMed

Shao RG, Cao CX, Zhang H et al (1999) Replication-medated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA: DNA-PK complexes. EMBO J 18:1397–1406PubMedCrossRef

Rothenberg ML (2001) Irinotecan (CPT–11): recent developments and future directions—colorectal cancer and beyond. Oncologist 6:66–80PubMedCrossRef

Xu Y, Villalona-Calero MA (2002) Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol 13:1841–1851PubMedCrossRef

Reid RJ, Benedetti P, Bjornsti MA (1998) Yeast as a model organism for studying the actions of DNA topoisomerase-targeted drugs. Biochim Biophys Acta 1400:289–300

Kanzawa F, Sugimoto Y, Minato K et al (1990) Establishment of a camptothecin analogue (CPT-11)-resistant cell line of human non-small cell lung cancer: characterization and mechanism of resistance. Cancer Res 50:5919–5924PubMed

Kano Y, Suzuki K, Akutsu M et al (1992) Effects of CPT-11 in combination with other anti-cancer agents in culture. Int J Cancer 50:604–610PubMedCrossRef

Gobert C, Bracco L, Rossi F et al (1996) Modulation of DNA topoisomerase I activity by p53. Biochemistry 35:5778–5786PubMedCrossRef

Cusack JC, Liu R, Baldwin AS (2000) Inducible chemoresistance to 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) in colorectal cancer cells and a xenograft model is overcome by inhibition of nuclear factor-κB activation. Cancer Res 60:2323–2330PubMed

10.

Baldwin AS (2001) Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB. J Clin Invest 107:241–246PubMedCrossRef

11.

Wang C, Cusack JC, Liu R, Baldwin AS (1999) Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-κB. Nat Med 5:412–417PubMedCrossRef

12.

Yamamoto Y, Yin MJ, Lin KM et al (1999) Sulindac inhibits activation of the NF-κB pathway. J Biol Chem 274:27307–27314PubMedCrossRef

13.

Yin M, Yamamoto T, Gaynor RB (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-beta. Nature 396:77–80PubMedCrossRef

14.

Knuth DW (1999) Bioanalytical method validation: determination of irinotecan (CPT-11) and its SN-38 and APC metabolites in human plasma by isocratic HPLC-FL with protein precipitation and emission wavelength switching (AvTech Laboratories, Inc). Pharmacia & Upjohn Study Report a0032518, 12 Feb 1999

15.

Knuth DW (1999) Bioanalytical method validation: Determination of the SN-38 glucuronide metabolite of irinotecan (CPT-11) in human plasma by isocratic HPLC-FL following hydrolysis (AvTech Laboratories, Inc). Pharmacia & Upjohn Study Report a0032541, 25 Feb 1999

16.

Method Validation Report Addendum No 7: Evaluation of the Specificity of the HPLC-FL Method for the Determination of CPT-11, SN-38 and APC in Human Plasma for the Coadministered Medication Celecoxib (SC-58635, Celebrex®) and SC-62807 and SC-60613 (2 metabolites of celecoxib). Smart Number CPTAIV-0020-VR1-AD7, 5 March 2003

17.

Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd edn. Marcel Dekker, New York

18.

Dorr RT, Von Hoff DD (eds) (1994) Cancer chemotherapy handbook. Norwalk, Appleton & Lange, p2

19.

Beidler DR, Cheng YC (1995) Camptothecin induction of a time and concentration dependent decrease of topoisomerase I and its implication into camptothecin activity. Mol Pharmacol 47:907–914PubMed

20.

Rothenberg ML, Meropol NJ, Poplin EA et al (2001) Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 19(18):3801–3807PubMed

21.

Fuchs CS, Moore MR, Harker G et al (2003) Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 21:807–814PubMedCrossRef

22.

Cadenas E (1995) Antioxidant and prooxidant functions of DT-diaphorase in quinine metabolism. Biochem Pharm 49:127–130PubMedCrossRef

23.

Kolesar J, Villalona-Calero M, Eckhardt G et al (1995) Detection of a point mutation in NQO1 (DT-diaphorase) in a patient with colon cancer. J Natl Caner Inst 87(13):1022–1024CrossRef

24.

Nabholtz JM, Senn HJ, Bezwoda WR et al (1999) Prospective randomized trial of docetaxel versus MMC plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 study group. J Clin Oncol 17(5):1413–1424PubMed

25.

Walters RS, Frye D, Au Buzdar et al (1992) A randomized trial of two dosage schedules of MMC C in advanced breast carcinoma. Cancer 69(2):476–481PubMedCrossRef

26.

Shimizu Y, Umezawa S, Hasumi K (1998) A phase II study of combined CPT-11 and mitomycin C in platinum refractory clear cell and mucinous ovarian carcinoma. Ann Acad Med Singapore 27(5):650–656PubMed

27.

Braun MS, Richman SD, Adlard JW et al (2006) Association of topoisomerase-1 (Topo1) with the efficacy of chemotherapy in a randomized trial for advanced colorectal cancer patients (FOCUS). J Clin Oncol 24(18S):10009

28.

Kohne F, de Greve J, Bokemeyer I et al (2005) Capecitabine plus irinotecan versus 5-FU/FA/irinotecan +/1 celecoxib in first line treatment of metastatic colorectal cancer. Safety results of the prospective multicenter EORTC phase III study 40015, ASCO 2005 GI Cancers Symposium, Abstract 3525

29.

El-Rayes BF, Zalupski MM, Shields AF et al (2005) A phase II trial of celecoxib, irinotecan and capecitabine in metastatic colorectal cancer. ASCO GI Cancers Symposium 2005, Abstract 3677

30.

Lee F, Roach G, Parasher G et al (2005) Irinotecan, capecitabine and celecoxib (ICC) is an effective palliative regimen for unreectable/metastatic cholangiocarcinoma. ASCO GI Cancers Symposium, Abstract 14830

31.

Trifan OC, Durham WF, Salazar VS et al (2002) Cyclooxygenase-2 inhibition with celecoxib enhances antitumor efficacy and reduces diarrhea side effect of CPT-11. Cancer Res 62(20):5778–5784PubMed

32.

Fuchs CS, Marshall J, Mitchell EP et al (2007) Updated results of BICC-C study comparing first-line irinotecan/fluoropymidine combinations ± celecoxib in mCRC: clinical data cut-off September 1, 2006. J Clin Oncol 25(18S):4027

Titel: Phase I and pharmacokinetic study of mitomycin C and celecoxib as potential modulators of tumor resistance to irinotecan in patients with solid malignancies
verfasst von: Y. Xu
J. M. Kolesar
L. J. Schaaf
R. Drengler
W. Duan
G. Otterson
C. Shapiro
J. Kuhn
M. A. Villalona-Calero
Publikationsdatum: 01.05.2009
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 6/2009
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-008-0826-3

Springer Medizin

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