Dose and time effects of cis-diamminedichloroplatinum(II) and radiation on mouse duodenal crypts

Abstract

The effect of cis-platinum and radiation on mouse duodenal crypts was assessed using the microcolony assay. The diameters of regenerating crypts were measured at various times after X-rays and cis-platinum given either alone or in combination. It appeared that the appropriate time of assay after any of these treatments was 88 h. When 10 mg/kg of cis-platinum was administered 24 h before, 0.5 h before or 10 min after radiation, the X-ray survival curve for crypt stem cells was shifted towards lower doses, with a Dose Effect Factor (DEF) of 1.2-1.3. When the drug was given one week before X-rays, no effect on the survival curve was observed. The slope of the X-ray survival curve was not modified by cis-platinum. When the drug was given within 6 h time of X-rays, the increased killing of crypt cells by cis-platinum was the same irrespective of the sequence of administration. These data suggest that cis-platinum and radiation kill crypt cells by independent cellular mechanisms. A survival curve for crypt cells was also obtained after graded doses of cis-platinum alone. It was characterised by a D0 of 3.18 +/- 0.40 mg/kg (1 S.E.) and an extrapolation number N of 2.9 X 10(4). When the drug treatment was combined with a single dose of X-rays, this survival curve was shifted towards lower drug doses without a significant change in the slope (D0 = 2.87 +/- 0.37 mg/kg). This suggests that independent killing of crypt cells by the two agents occurred over a wide range of drug doses.