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Cytokinetic Effects of Interferon in Colorectal Cancer Tumors: Implications in the Design of the Interferon/5-Fluorouracil Combinations

Servizio di Oncologia [S. C., E. D. F., A. F., G. C.], Laboratorio Analisi [C. G., M. A., M. B.], and Divisione di Chirurgia [G. F., F. L.], Ospedali Riuniti, P. le Cinelli 4, 61100 Pesaro, and Cattedra di Semeiotica Chirurgica, Università di Ancona, Ancona [Q. O., V. S.], Italy

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-_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.

¹ To whom requests for reprints should be addressed, at Servizio di Oncologia, Ospedali Riuniti. P. le Cinelli 4, 61100 Pesaro, Italy.

² Recipient of a grant from Associazione Italiana Ricerca Cancro (AIRC).

Received 6/ 9/93. Accepted 9/14/93.