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 th is combination resulted in higher response rate with respect to 5FUra alone. IFN is generally administered s.c. three times a week. This pro longed exposure could determine a block of tumor cells in the G0-G1 ph ase of the cell cycle, thus rendering tumor cells insensitive to 5FUra , an S-phase specific agent. In order to verify the presence of this b lock, 21 operable colorectal cancer patients were treated with IFN-alp ha2b at the dose of 3 megaunits every other day in the week before ope ration, while another 22 represented the control group. Samples of tum or tissue were taken at endoscopy and operation. [H-3]Thymidine labeli ng 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: labeli ng index, P = 0.06; flow cytometry, P = 0.08. Furthermore a significan t increase in the G0-G1 phase of the cell cycle was found after IFN ad ministration (P < 0.001) but not in the control group. Our results sug gest that IFN reduces the S-phase fraction in colorectal cancer tumors . This action should be considered in the design of the 5FUra/IFN comb ination because it could decrease 5FUra activity, leading to a loss or a decrease in the advantage of 5FUra modulation by IFN.