Cell Proliferation and the Action of Cytotoxic Agents on Haemopoietic Tissue

Abstract

Summary. The effect of several cytotoxic agents on maturing erythroid cells and repopulating stem cells has been investigated. The results demonstrate the extent to which the effect of these agents depend on the rate at which the cells are proliferating. They also show the need to consider damage to the maturing cells as a possible critical factor when proliferation‐dependent agents are administered repeatedly.

Changes in sensitivity to radiation and ICRF 159 during the life of monolayer cultures of EMT6 tumour line

“…Thus, cytotoxicity decreases as the non-proliferating component of the cell culture increases. This cycle specificity has been reported by other workers, both in vivo (Blackett and Adams 1972) and in vitro (Hallowes, West and Hellmann, 1974) using other cell systems.…”

“…This effect was only found when the cells were exposed to the drug during the premitotic (G2) phase, with little or no effect from exposures to the drug at other phases of the cell cyckb. Similarly, studies on erythroid maturation in C57BL mice indicate that the drug has a similar action in vivo (Blackett and Adams, 1972). In studies using the spontaneously metastasizing Lewis lung tumour, ICRF 159 has been shown to function as an antimetastatic agent at doses which have little effect on the primary growth (Burrage, Salsbury, Burrage and Hellmann, 1970).…”

Effect of cumulative etoposide doses on the outcome of autologous peripheral-blood progenitor-cell transplantation for lymphoma

“…26,27 Our results show that prior administration of high doses of etoposide (4750 mg/m 2 ) was the most important factor affecting CD34 þ cell yield and platelet recovery. This is an unexpected finding, since although several cytotoxic agents, such as busulfan, melphalan, carmustine, platinum derivates, nitrogen mustard, or chlorambucil have been associated with stem-cell damage; 6,7,[13][14][15][16][28][29][30] etoposide is not usually included among them. This is clinically important, because etoposide-containing regimens are often used as salvage therapy for lymphomas.…”

ICRF-159 enhancement of radiation response in combined modality therapies. I. Time/dose relationships for tumour response

“…and Sharpe et al (1970) have reported that the cytotoxic effect of ICRF-159 was limited to a very brief period (G2/M) of the cell cycle, and that for short incubations cell kill was independent of dose. In addition to the cytotoxic effect, ICRF-159 can act concomitantly as a cytostatic agent, preventing cells from entering mitosis (Hallowes et al, 1974;Blackett & Adams, 1972). Recently, Taylor & Bleehen (1977a) have shown that the manifestations of cytotoxicity are dependent on both drug exposure time and drug concentration.…”

“…Using PHA-stimulated human lymphocytes (Sharpe et al, 1970) and erythroid maturation in C57BL mice (Blackett & Adams, 1972), ICRF-159 was found to prevent the entrance of cells into mitosis if the cells were exposed during the premitotic and early mitotic (G2/M) phases of the cell cycle. Furthermore, drug cytotoxicity has been reported to be scheduledependent rather than dose-dependent (Hallowes et al, 1974;Stephens & Creighton, 1974).…”