[Critical reflections to the problem of timing in the synchronization therapy of human malignant tumors. Mitotic-index determination, cytophotometric and radioautographic studies (author's transl)].

Formerly (1969) we have been able to demonstrate that during a lengthy inhibition of the DNA synthesis with 5-fluoro-uracil (FU), cells assemble just before, at the outset of, and within the S-phase. By taking off the inhibition, these cells start off together for the rest of the life cycle and pass the S, G2 and M phase like a wave. By the experimental condition given, the time required for passing the S phase was rather constant for all tissues. It generally took about 8 h. The sensitivity of cells to radiation depends on the current phase of their life cycle. Normally they are highly radiosensitive during the transition from G1 to S phase and within the G2 phase. Therefore we tried to improve the effectiveness of radiotherapy by radiating the synchronized cell population in the G2 phase. In clinical treatment we give an infusion with 1 g FU in 1000 ml 5.4% Glucose for 12 h. 8--9 h after the end of the infusion radiation will be applied (Betatron, individual doses: 500 rad). This treatment will be repeated until a total dose of 5000--6000 rad. Until now nearly 300 cases of patients treated in this way have been published. The 5 year-results show only in about 60% of the patients a fast reduction of the tumor. The long term results are unsatisfactory. Beside many other points the most important reason for these clinical results might be the individual length of the S phase of the tumors which prevents that radiation can be given exactly in G2 phase in each case. With mitotic-index determination, with cytophotometric investigations and the double labelling technique (3H- and 14C-Thymidine) we therefore tried to find an answer to the following questions: 1. How long is the DNA synthesis time in the individual case of human ENT tumors? 2. Does the application of FU influence the length of the S phase? 3. Will the synchronization-degree become higher by using other methods of cell cycle inhibition? With the above mentioned experimental methods we found that the length of the S phase in human tumor spreads from about 8--16 h in the individual case. The application of FU has no influence on DNA synthesis time. By using FU the degree of synchronization is about 2.5 in according to former experimental work and that of other authors. These results will be discussed in detail as well as the conclusion we draw from our experiments: to give radiation not in G2 but in G1/S of the cell cycle. Long-term observation of the patients and further animal experiments shall demonstrate whether this technique of synchronization therapy will improve the clinical results.