Growth fraction of human tumors: Assays and complications

Abstract

T he fraction of cells actively proliferating in human tumors is expected to be useful in predicting tumor response to therapy. 1,2 There are several excellent reviews 3-5 and a comprehensive monograph 6 describing both static and flow cytometry assays developed to measure growth fraction. This article introduces a new method, and in describing our results using clinical samples, provides a basis for understanding why this information is useful or necessary and identifies factors that may limit our ability to define growth fraction accurately for different tumor types. The doubling time of a tumor has long been known to be a valuable prognostic indicator. As an obvious generalization, patient survival is shorter when the tumor grows more rapidly, although tumor size and doubling time can vary independently] The recent application of accelerated radiotherapy to overcome rapid tumor cell repopulation a is in large part responsible for the current interest in categorizing tumors into slowly and rapidly proliferating. 9 There are three major kinetic factors contributing to tumor doubling time: growth fraction (GF), cell cycle time, and cell loss rate. l~ Although no method is able to accurately determine cell loss rate in human tumors, the two remaining factors are used to describe potential tumor doubling time (Tpot), which is proportional to the S phase duration (T~) divided by the labeling index (LI), or alternatively, the cell cycle duration divided by the GF. II It has been argued that Tpo t is more informative than GF alone in predicting tumor response to accelerated radiotherapy because Tpo~ includes a measure of rate of cell proliferation (Ts) as well as state of proliferation (LI). However, when analyzing the components that determine Tpo, it is common for tumors of the same tissue of origin