Platinum concentrations and DNA adduct levels in tumors and organs of cisplatin-treated LOU/M rats inoculated with cisplatin-sensitive or -resistant immunoglobulin M immunocytoma.
Female LOU/M rats, bearing either a cisplatin (cisDDP)-sensitive or -resistant IgM immunocytoma, were sacrificed at 1 or 24 h after cisDDP administration (i.v., 10 mg/kg of body weight). Platinum levels, determined with atomic absorption spectroscopy, were in the order kidney much greater than liver greater than tumor greater than spleen in the 1-h samples. In the 24-h samples, more platinum was found in spleens than in tumors; the levels in the kidneys were the same as those measured at 1 h, in the spleens they were higher, and in livers and tumors they were lower than at 1 h after the injection; the greatest decrease occurred in the resistant tumor. cisDDP-DNA adducts were detected after chromatography of digested DNA samples isolated from these tissues and from blood cells. The quantitation of the four cisDDP-DNA adducts (Pt-G, Pt-AG, Pt-GG, G-Pt-G, the same as found previously in cisDDP-reacted DNA) was performed with specific antibodies, in the competitive enzyme-linked immunosorbent assay. The cisDDP-DNA adduct levels in the various 1-h tissue samples showed the same ranking order as the platinum levels. The blood samples contained the lowest amount of adducts. Because of the high platinum level in the kidneys (26 mg/kg of wet tissue), the adducts in this organ also could be determined with atomic absorption spectroscopy (the four adducts comprised about 400 fmol/micrograms of DNA). Comparison of the atomic absorption spectroscopy and enzyme-linked immunosorbent assay data showed excellent agreement. Except for the kidney, all samples showed a decrease in adduct level between 1 and 24 h after cisDDP treatment. The data on the tumors indicated that the difference in susceptibility to cisDDP between the sensitive and resistant tumors is not due to a decreased platinum content or reduced DNA adduct formation in the resistant tumor.
Fichtinger-Schepman
A M
AM
Medical Biological Laboratory TNO, Rijswijk, The Netherlands.
Vendrik
C P
CP
van Dijk-Knijnenburg
W C
WC
de Jong
W H
WH
van der Minnen
A C
AC
Claessen
A M
AM
van der Velde-Visser
S D
SD
de Groot
G
G
Wubs
K L
KL
Steerenberg
P A
PA
D000818:Animals; D002945:Cisplatin / Q000493:pharmacokinetics*; D004273:DNA, Neoplasm / Q000378:metabolism*; D005260:Female; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D010984:Platinum / Q000493:pharmacokinetics*; D051381:Rats; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
D004273:DNA, Neoplasm; D010984:Platinum; D002945:Cisplatin