Cumulative Cytostatic Effect of ICRF 159

Summary. The response of EMT6 mouse tumour cells to ICRF 159, both with and without X-radiation, has been measured during the life of monolayer cultures. The cytotoxic effect of ICRF 159 was found to be proliferation-dependent. Flow cytofluorimetry studies of cell cycle distribution showed that ICRF 159 prevented cell division while allowing DNA synthesis to continue. This anti-mitotic action and the cytotoxic effect of the drug were found to be closely related. Increased sensitivity to X-radiation was observed in cultures pretreated for 24 h with 200 ,ug/ml ICRF 159. In exponential and early plateau cultures this was seen as a reduced shoulder of the survival curve. In late plateau cultures there was no apparent reduction of the shoulder, but an increase in slope.

Section: Discussionsupporting

confidence: 56%

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

Taylor¹,

Bleehen²

1977

“…This is in distinct contrast to an earlier suggestion that ICRF-159 blocked the transit of cells from G2 into mitosis (Sharpe et al, 1970). Hallowes et al (1974) have observed that the effect of exposure to the drug is reversible, provided a threshold-level concentration is not maintained in the medium. With repeated exposures, the drug effect was cumulative, resulting in an inhibition of cell division with continued DNA synthesis.…”

contrasting

confidence: 55%

ICRF-159 enhancement of radiation response in combined modality therapies. II. Differential responses of tumour and normal tissues

Kovacs¹,

Evans²,

Burholt³

et al. 1979

Summary.-The combined effect of the chemotherapeutic agent ICRF-159 and radiation on the proliferative status of tumour/normal systems has been evaluated using the Lewis lung tumour in BDF1 mice. We have previously shown that a 25 mg/kg dose of ICRF-159, given at 3h intervals x4 before irradiation, significantly enhanced tumour growth retardation relative to a single dose of 100 mg/kg before irradiation. Whilst both single and fractionated drug treatments produced a transient inhibition of cell proliferation, comparisons of the temporal recovery from the antiproliferative effect of radiation in both tumour and intestinal epithelium suggested that single acute doses of ICRF-159 fail to potentiate the radiation response of either tissue. Protracted drug administration before irradiation, however, markedly decreases the postradiation proliferative recovery of the tumour, without significantly altering intestinal recovery. The data suggest that both drug concentration and/or exposure time determine the interactions seen with combined modes.

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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). Taylor & Bleehen (1977a) have recently reported that prolonged exposure to low concentrations of ICRF-159 are more lethal to the EMT6 tumour-cell line than high concentrations.…”

mentioning

confidence: 99%

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

Kovacs¹,

Evans²,

Schenken³

et al. 1979

Summary-The combined effect of the chemotherapeutic agent ICRF-159 and irradiation were evaluated using the Lewis lung tumour (LL). At a daily dose of 25 mg/kg, ICOF given alone prevented the progressive growth of LL. Daily pretreatment also potentiated the effects of radiation (600 rad) on tumour growth, provided the pretreatment kinetics of the tumour permitted a response to radiation alone. Single acute doses of the drug failed to alter the growth of LL, and when combined with radiation failed to enhance the radiation effect. Fractionation of the drug (25 mg/kg; 4 doses at 3h intervals) before irradiation, however, results in immediate effects on tumour growth which are more than additive. The results suggest that a low dose of ICRF-159 for extended periods is more effective in enhancing radiotherapy than a high dose provided acutely.