Pre-clinical evaluation of the activity of irinotecan as a basis for regional chemotherapy.
BACKGROUND
Irinotecan alone and in combination with 5-fluorouracil (5-FU) displays potent activity in advanced colorectal cancer. The aim of this study was to estimate the potential efficacy of irinotecan for hepatic arterial infusion (HAI) chemotherapy.


METHODS
We investigated the anti-proliferative effects of irinotecan alone and in combination with 5-FU in HT29 and NMG64/84 colon and COLO-357, MIA PaCa-2 and PANC-1 pancreatic cancer cell lines and in fresh tumors from patients with primary colon cancer (n=2) and colorectal liver metastases (n=11) in vitro, using the MTT growth assay and the human tumor colony-forming assay (HTCA), mimicking conditions which are achievable during HAI.


RESULTS
Irinotecan displayed concentration- and time-dependent cytotoxic effects in all tested cell lines. Treatment of cell lines with irinotecan followed by 5-FU did not result in synergistic anti-proliferative effects. In the HTCA, the sensitivity of each cell line varied depending on the incubation times (30, 90, 180 and 1440 min). Independent of the individual sensitivity, the IC50 concentration and time products were lowest when incubating with irinotecan for 30 min for all cell lines. The IC50 of irinotecan in HT29, NMG64/84, COLO-357, MIA PaCa-2 and PANC-1 cells at 30 min were 200, 160, 100, 400 and 150 microg/ml, respectively, in the HTCA. All isolated tumor samples displayed concentration-dependent inhibition of colony formation after exposure to irinotecan for 30 min. The IC50 of irinotecan of 5 of the 11 liver metastases was <100 microg/ml.


CONCLUSIONS
Irinotecan seems to be suitable for HAI therapy phase II studies. Due to the observation that several liver metastases had IC50 values that may be clinically achievable by HAI, patients with such tumors may benefit in the future from HAI using irinotecan.
Hofmann
Carmen
C
Department of Visceral and Transplantation Surgery, University of Ulm, Steinhoevelstrasse 9, 89075 Ulm, Germany.
Buttenschoen
Klaus
K
Straeter
Joern
J
Henne-Bruns
Doris
D
Kornmann
Marko
M
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000008:administration & dosage; D019073:HT29 Cells; D006499:Hepatic Artery; D006801:Humans; D007261:Infusions, Intra-Arterial; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology
D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin