Thymidine arrest and synchrony of cellular growth in vivo

Thymidine (TdR) has been used to study the kinetics of in vitro cell proliferation and is currently being used clinically as a single agent at high doses. We have explored the in vivo cytokinetic effects of TdR on rapidly proliferating cell populations by continuous infusions in rats. The nucleoside was lethal at high doses when serum levels approached 10(-2) M.. At levels of 10(-3) M, TdR exposure for greater than 24 hours resulted in bone marrow hypocellularity and peripheral myelosuppression. Pathologic findings were also noted in the intestinal mucosa. Serum TdR levels of 10(-4) M were sufficient to induce arrest of cell growth in S phase by inhibition of DNA synthesis. Subsequent release after TdR exposure produced partial synchronization of the bone marrow and intestinal mucosa cell populations, as shown by microfluorometry and labeling studies to monitor DNA synthesis. A similar arrest of cell cycle traverse has been demonstrated in a tumor cell population by infusing rats bearing transplantable subcutaneous myeloblastomas. The inhibition of DNA synthesis, as determined by labeling studies, was comparable for bone marrow, intestinal mucosa, and myeloblastoma at serum TdR levels of 10(-3) M. This arrest of myeloblast cell growth was dependent on tumor burden and did not effect survival when maintained during 72-hour infusions. The continuous infusion of TdR provides an approach for studying cell kinetics in vivo, and findings similar to those described here have been observed in our clinical studies.