Cell Kinetics of Irradiated Experimental Tumors: Relationship Between the Proliferating and the Nonproliferating Pool

Abstract

The role of nonproliferating cells in tumor regeneration has been studied after subcurative doses of low L.E.T. irradiation. Radiation was applied in a single dose at three different levels, 0–47, 0–94 and 1–88 krad. Studies included estimation of the absolute number of cells per tumor, differential cell counts, and autoradiographic determination of kinetic variables, employing transplantable mouse mammary adenocarcinoma DBAH. Quantitative changes of morphologically denned proliferating and non‐proliferating cell pools were followed at different time intervals after irradiation. Irradiation resulted in reduction of the number of cells in both pools, with apparent sparing of nonproliferating cells. The regenerative period started with a gradual increase in the number of cells in the proliferating pool, whereas the number of cells in the nonproliferating pool continued to fall in tumors irradiated with 0–94 and 1 ‐88 krad. In the late phase of tumor regrowth, the increasing number of cells in the non proliferating pool corresponded to its replenishment by cell transition from the proliferating pool. In an effort to clarify whether cell transition from the nonproliferating to the proliferating pool may take place during the regrowth of radiation perturbed tumors, cell loss rates from both pools were estimated using experimental data. In addition to cell losses from the tumor as a whole, the ‘net loss rate’ of the non‐proliferating pool reflects the rate of cell transition from the nonproliferating to the proliferating pool, minus the rate of transition in the opposite direction. A similar definition applies to cell loss rates from the proliferating pool. The results showed: (1) high losses in both pools, with excess losses in the proliferating during the early phase after irradiation; (2) in the early stage of regrowth after irradiation, the cell net loss rate for the nonproliferating pool increased, in contrast to the behavior of cell loss rate for the proliferating pool and the average cell loss rate for the tumor as a whole; (3) in the late stage of regrowth a decrease in net loss rate for the nonproliferating pool reflects the excess production of nonproliferating cells over control tumors. These results suggest that cell transition from the nonproliferating to the proliferating pool takes place at the beginning of tumor regrowth after subcurative single‐dose irradiation.

Intrinsic radiation resistance of primary clonogenic blasts from children with newly diagnosed B-cell precursor acute lymphoblastic leukemia.

“…Weichselbaum explained that the repair of radiation-induced molecular damage may be facilitated if DNA replication is delayed by holding cells in G1 (71 ). Potmesil and Goldfeder reported that nonproliferating G. confined cells from mouse mammary adenocarcinoma cell lines DBAH and MT2 persist in irradiated tumors of mice and a transition of these nonproliferating cells to the proliferating pool takes place at the start of tumor recurrence (67). In contrast, Wallen et al reported that quiescent cells from the murine mammary carcinoma cell lines 66 and 67 are significantly more sensitive than proliferating cells from the same cell lines (72).…”

“…CD34 cDNA predicts a 373-amino acid polypeptide that is a type I integral membrane protein and has no sequence homology to any known protein (58). Notably, > 30% of the predicted amino acids in the NH2-terminal domain of this antigen are serine or threonine residues and CD34 antigen is a substrate for protein kinase C (PKC) (58,61 (65)(66)(67)(68)(69). Kimler and Anderson reported that 9L rat brain tumor cells are most resistant to radiation while in G1 phase (70).…”

Properties of Tumor Spheroid Growth Exhibited by Simple Mathematical Models

“…Proliferating cells are the target of most cancer therapies. The quiescent cell population has been implicated as a population resistant to some of these therapies, playing an important role in tumor regrowth (Potmesil and Goldfeder, 1980; Kallman et al, 1982). …”

Radiation response of proliferating and quiescent subpopulations isolated from multicellular spheroids

“…The majority of the tumours in experimental animals has a growth fraction of <80%, and similar studies of labelled mitoses suggested even smaller growth fractions in a series of well-studied human tumours (Steel, 1977). Quiescent cells may be important in tumour eradication because they are probably more resistant to proliferation-dependent treatment regimens, and since they retain the capacity to proliferate, there are suggestions that they may be the source for renewed growth after cancer therapy (Hermans & Barendsen, 1978;Kallman et al, 1979;Luke et al, 1985;Potmesil & Goldfeder, 1980;Sutherland & Durand, 1976;Sutherland, 1974;Valeriote & van Putten, 1975). In previous studies, we have isolated and characterized a quiescent subpopulation from EMT6/Ro fed plateau monolayers, and found that those quiescent cells were smaller, mostly in the G1 phase of the cell cycle, had a lower cellular RNA content, were not labelled by [3H]-thymidine after 2 cell cycle times, retained the capacity to divide after replating into fresh medium, and were more sensitive to y-ray radiation (Luk et al, 1985).…”