Phase I and pharmacokinetic study of mitomycin C and celecoxib as potential modulators of tumor resistance to irinotecan in patients with solid malignancies.
OBJECTIVE
Based on the preclinical evidence of topoisomerase I (Topo-1) upregulation by mitomycin C(MMC) and decreased NF-kappaB activation by celecoxib, we evaluated combinations of irinotecan/MMC and irinotecan/MMC/celecoxib in patients with advanced solid malignancies.


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/m(2) and cumulative doses of >36 mg/m(2) were not permitted. Irinotecan was escalated in 25 mg/m(2) 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/m(2) on days 2 and 8 in combination with MMC 6 mg/m(2) 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.
Xu
Y
Y
The Division of Hematology/Oncology, Departments of Internal Medicine, The Ohio State University College of Medicine and Public Health, Columbus, OH, USA.
Kolesar
J M
JM
Schaaf
L J
LJ
Drengler
R
R
Duan
W
W
Otterson
G
G
Shapiro
C
C
Kuhn
J
J
Villalona-Calero
M A
MA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000068579:Celecoxib; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
D011720:Pyrazoles; D013449:Sulfonamides; D016685:Mitomycin; D000077146:Irinotecan; D000068579:Celecoxib; D002166:Camptothecin
Cancer Res. 2000 May 1;60(9):2323-30
10811101
J Clin Oncol. 1999 May;17(5):1413-24
10334526
Oncologist. 2001;6(1):66-80
11161230
Nature. 1998 Nov 5;396(6706):77-80
9817203
Ann Oncol. 2002 Dec;13(12):1841-51
12453851
Int J Cancer. 1992 Feb 20;50(4):604-10
1537625
EMBO J. 1999 Mar 1;18(5):1397-406
10064605
J Biol Chem. 1999 Sep 17;274(38):27307-14
10480951
Biochem Pharmacol. 1995 Jan 18;49(2):127-40
7530954
Cancer. 1992 Jan 15;69(2):476-81
1728377
J Clin Oncol. 2003 Mar 1;21(5):807-14
12610178
Cancer Res. 2002 Oct 15;62(20):5778-84
12384538
Biochemistry. 1996 May 7;35(18):5778-86
8639538
Mol Pharmacol. 1995 May;47(5):907-14
7538195
Nat Med. 1999 Apr;5(4):412-7
10202930
J Clin Invest. 2001 Feb;107(3):241-6
11160144
J Natl Cancer Inst. 1995 Jul 5;87(13):1022-4
7629875
Cancer Res. 1990 Sep 15;50(18):5919-24
2168285
Ann Acad Med Singap. 1998 Sep;27(5):650-6
9919334
J Clin Oncol. 2001 Sep 15;19(18):3801-7
11559717
Biochim Biophys Acta. 1998 Oct 1;1400(1-3):289-300
9748633
Cancer Res. 1988 Apr 1;48(7):1722-6
2832051