Analysis of the cell population kinetics of transplanted tumours of widely-differing growth rate.

Abstract

THE principal object of studies of the cell population kinetics of tumours is to explain how a tumour attains its particular growth rate, and thus to make a more informed judgement on methods of growth control. The growth rates of tumours show wide variations, both between and within individual species. In man, volume doubling times for primary and secondary lung tumours range from about two weeks to many months (Steel and Lamerton, 1966); in experimental animals, spontaneous tumours with volume doubling times of a few days are common and under repeated transplantation doubling times of less than 24 hours can be attained. The problem is to identify the proliferative characteristics of the cell populations which have such widely different growth rates.Such a problem must necessarily be treated as one of comparative biology. Our ultimate aim is an understanding of the growth rate of tumours in man, but the limitations imposed by experiments on human beings rule out at present a thorough analysis of the cell population kinetics of human tumours. The scope for experiment on animal tumours, particularly transplanted tumours, is much greater. What must be done therefore, is to look first at the simplified cases provided by experimental tumours, and then to extend the investigations to tumours that are progressively closer to the human counterpart.The approach in the present work has been to analyse by a variety of techniques the cell population kinetics of tumours of known growth rate, in order to find the extent of agreement between them and to characterise, as far as possible, the state of proliferation of the tumour cell population. A similar approach has been used by Mendelsohn (1965). Great importance is attached to the simultaneous measurement of volume doubling time, for whether measurements of cell proliferation are consistent with the overall tumour growth rate is the conclusive test of their significance.The growth rate of a tumour is the resultant of cell production and cell loss (Fig. 1). Cell loss is an extremely difficult parameter to measure (Steel, 1966) and there are at present no direct methods by which it can be estimated; cell loss would, however, be indicated by a discrepancy between total cell production rate and overall growth rate. The state of cell proliferation in a tumour is best specified by a distribution of cell cycle times, this being taken to include both the distribution for proliferating cells as well as information on the fraction of cells which are essentially non-proliferating. The distribution of cell cycle times may or may not take a standard mathematical form. In the more heterogeneous tumours, the fact that the availability of nutrients to different regions may vary widely, some regions showing various degrees of starvation, suggests that a

The growth and cell population kinetics of spontaneous tumours in domestic animals.

“…The difference between the distributions of doubling time for tumours in domestic animals and man may be significant (P = 0'05, calculated from the distributions of the logarithm of doubling time). A comparison of labelling indices is also consistent with a slightly higher growth rate in the animal tumours: the median labelling index for the tumours in the present series is about 5 %, as compared with a median of 3 % for a group of 170 human tumours (Steel, 1967). While these differences are in the direction which one might expect from the differences in lifespan they are nevertheless sufficiently small to confirm the basic starting point of this work that spontaneous tumours in domestic animals serve as a good model for human cancer.…”

“…Among the dog tumours of this series there were other examples of what was apparently a wide distribution of grain counts; as was noted in the discussion of case 5 it was difficult to find an autoradiographic exposure which allowed recognition of the low-labelled cells without heavy labelling obscuring the appearance of other nuclei. When applied to tumour cell populations in which cell loss occurs, T has been called the potential doubling time (Steel, 1967). A theoretical discussion of the parameter A has been presented (Steel, 1968) where it is shown that although A has a possible range of values from 0 7 to 1-4, values higher than unity are unlikely, and when the population doubling time is longer than 2 days, A will be within the range 0 7 to 0 8.…”

“…1.-The distribution of volume doubling times for tumours in man and in domestic animals. The human data are collected from the literature (Steel, 1967). The animal data are from the present study: the numbers indicate the case number of individual lung metastases or primary tumours; for cases 6 and 9 the range of doubling times is shown.…”

Effects of 5-fluorouracil on the cell kinetic and growth parameters of hepatoma 3924A

“…The results presented here are from studies designed to relate quantitatively the effects of 5-FU at a cellular level with the observed retardation of tumour growth. Methods available for growth fraction (Mendelsohn, 1962;Steel, Adams and Barrett, 1966) and cell loss (Steel, 1968) determinations by 3H-thymidine incorporation do not account for wide fluctuations resulting from residual synchrony from the pulse label and from the transition of growing to non-growing cells. Perturbations in cellular proliferation and cell killing resulting from cycle-specific drugs such as 5-FU would only magnify the fluctuations in both these parameters.…”

Tumour volume response, initial cell kill and cellular repopulation in B16 melanoma treated with cyclophosphamide and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea

“…Measurements of the size of s.c. and i.m. tumours were made by the calibration curve technique (Steel, Adams and Barrett, 1966). For s.c. tumours the product of two superficial diameters was used as a measure of tumour size, and for i.m.…”