Cell kinetics in human malignancies studied with in vivo administration of bromodeoxyuridine and flow cytometry.
Bromodeoxyuridine (BrdUrd) is a pyrimidine analogue which is incorporated into the DNA of proliferating cells. When in vivo BrdUrd infusion is coupled with bivariate flow cytometry to measure cell BrdUrd incorporation and DNA content, both the percentage of DNA-synthesizing cells [BrdUrd-labeling index (LI)] and the DNA synthesis time (TS) can be determined on the same tissue sample. From experimentally determined LI and TS, the potential doubling time of the population and its cell production rate are calculated. To ascertain whether the BrdUrd infusion method is clinically feasible and if data are reliable, we studied patients with leukemia, refractory anemia, multiple myeloma, and brain and gastric tumors. The BrdUrd incorporation data were compared with those determined on duplicate samples with the techniques conventionally used for LI and TS values, i.e., 3H- and 14C-labeled thymidine autoradiography, respectively. The complete BrdUrd procedure takes 6-9 h, and no immediate toxicity from BrdUrd administration has been observed. In an 8-month period, 154 patients were studied. Successful LI and TS determinations were obtained in 78.9 and 59.7% of cases, respectively, more often in hematological than in solid tumors. The values for LI and TS assessed with the BrdUrd technique were very close to those found with 3H- and 14C-labeled thymidine autoradiography (r = 0.88, P less than 0.005, and r = 0.89; P less than 0.005, respectively). The potential doubling time and production rate were accordingly similar. These data indicate that in vivo BrdUrd infusion coupled with flow cytometry measurements can be performed in clinical settings and that this method is reliable. It could be used for kinetic studies in clinical trials aimed at evaluating the prognostic relevance of proliferative parameters and for planning radio- and/or chemotherapy.