Cytokinetic effects of interferon in colorectal cancer tumors: implications in the design of the interferon/5-fluorouracil combinations.
Interferon (IFN) has been shown to enhance the cytotoxic effects of 5-fluorouracil (5FUra) in colorectal cancer, and clinical trials with this combination resulted in higher response rate with respect to 5FUra alone. IFN is generally administered s.c. three times a week. This prolonged exposure could determine a block of tumor cells in the G0-G1 phase of the cell cycle, thus rendering tumor cells insensitive to 5FUra, an S-phase specific agent. In order to verify the presence of this block, 21 operable colorectal cancer patients were treated with IFN-alpha 2b at the dose of 3 megaunits every other day in the week before operation, while another 22 represented the control group. Samples of tumor tissue were taken at endoscopy and operation. [3H]Thymidine labeling index and flow cytometry were used to assess the S-phase fraction. In IFN treated patients, we found a significant statistical difference between the mean percentage of S-phase fractions evaluated either by labeling index (P = 0.00001) or by flow cytometry (P < 0.001). On the contrary, this difference was not present in the control group: labeling index, P = 0.06; flow cytometry, P = 0.08. Furthermore a significant increase in the G0-G1 phase of the cell cycle was found after IFN administration (P < 0.001) but not in the control group. Our results suggest that IFN reduces the S-phase fraction in colorectal cancer tumors. This action should be considered in the design of the 5FUra/IFN combination because it could decrease 5FUra activity, leading to a loss or a decrease in the advantage of 5FUra modulation by IFN.
Cascinu
S
S
Servizo di Oncologia, Ospedali Riuniti, Pesaro, Italy.
Del Ferro
E
E
Fedeli
A
A
Grianti
C
C
Foglietti
G
G
Olivieri
Q
Q
Acetoso
M
M
Bartolucci
M
M
Saba
V
V
Lungarotti
F
F
D000328:Adult; D000368:Aged; D002453:Cell Cycle / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology / Q000628:therapy*; D004347:Drug Interactions; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008875:Middle Aged; D011994:Recombinant Proteins; D016196:S Phase / Q000187:drug effects
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D005472:Fluorouracil