CELL-PROLIFERATION KINETICS IN HUMAN TUMOR XENOGRAFTS MEASURED WITH IODODEOXYURIDINE LABELING AND FLOW-CYTOMETRY - A STUDY OF HETEROGENEITYAND A COMPARISON BETWEEN DIFFERENT METHODS OF CALCULATION AND OTHER PROLIFERATION MEASUREMENTS

The influence of overall treatment time in the results of fractionated radiation treatment was initially established in experimental tumors and, subsequently, in the clinic The availability of techniques (antib odies against halogenated thymidine analogues and flow cytometry) whic h permit determinations of the duration of the synthesis phase, the la beling index, and the tumor potential doubling time (T-pot) in a short period of time and requiring only a small biopsy of tumor tissue, has expanded interest in the relationship between tumor cell proliferatio n and response to irradiation. A valuable tool in the study of this re lationship are human tumor xenografts. Previous studies have shown a s ubstantial intratumoral heterogeneity in the determinations of T-pot. Different methods of calculation of the kinetic parameters have been p ublished. We have conducted a heterogeneity analysis and an evaluation of the different calculation methods in order to define the validity of T-pot as a proliferation rate measurement in human tumor xenografts . Results show the intertumoral variability in T-pot [between differen t types of human tumor xenografts systems (coefficient of variation = 88.2%)] to be greater than mean intratumoral variation (coefficient of variation = 30.8%); this suggests that this variation is potentially adequate to serve as a predictor of response. The diverse calculation methods provided significantly different absolute values but not diffe rent tumor ranking, probably because the time interval between labelin g and sampling was maintained, for all the samples, between 6 and 8 h. Our study has found significant differences between the labeling inde x and the S-phase fraction determined with the DNA profile in 9 out of 10 tumor types. No correlation was found between the DNA index of the tumors in this series and their proliferation rate.