The influence of platinum drugs on the radiation response of rat kidneys

Abstract

The influence of a single bolus injection of platinum drugs on the radiation sensitivity of the kidneys was investigated in WAG/Rij rats. Drugs employed were cis-diammine-dichloroplatinum(li) (cisplatin, CDDP), cis-diammine-l,l-cyclobutanedicarboxylate platinum(II) (carboplatin, CBDCA) and cis-dichloro, trans-dihydroxybis-isopropylamine platinum(iv) (iproplatin, CHIP). Both kidneys were irradiated with a range of single X-ray doses while drugs were administered at 1 day or 1 week before irradiation. Maximum tolerated drug doses (defined as the LD 1, the dose resulting in a mortality of 1%) were given. Damage inflicted upon the kidneys was monitored by determination of several parameters indicative of kidney function. Isoeflective radiation doses were calculated from these data for each treatment group at 4–8-week intervals up to 80 weeks following treatment. At each assay time, dose modifying factors (DMF) were calculated for each drug/radiation combination. The mean DMFs were highest for CDDP: approximately 1.6. Those for CBDCA and CHIP were lower: approximately 1.1 and 1.2, respectively. The CHIP DMFs were significantly different from unity. When the radiation was given in 4 or 8 daily fractions (4 fractions/week) the DMFs for CDDP were identical to those obtained with single doses. For CBDCA and CHIP, however, the DMFs after fractionated treatments were not significantly different from unity. Analysis in terms of the linear-quadratic (LQ) model indicated that not one of the three drugs had an effect on the α β ratio, and hence on the fractionation sensitivity of the rat kidney. Consequently, if these data are extrapolated to the clinical setting, the administration of these drugs at the maximum tolerated dose preceding a fractionated radiation treatment should not be expected to result in extra, unexpected, radiation toxicity of the kidney.