The in vitro cytotoxicity, protein binding, partitioning of
platinum from whole blood into erythrocytes, its exchange back into plasma, and the in vitro biotransformation in plasma were studied for the new nonnephrotoxic
platinum analogue
oxaliplatin. The cytotoxicity studies were carried out against a panel of human tumor cell lines derived from
carcinomas of the ovary (A2780, A2780/cp), bladder (TCCSUP, RT4), colon (HT-29),
melanoma (SKMEL-2, HTB144), and
glioma (U373MG and U87MG). The relative potency of the five
platinum complexes was
oxaliplatin =
tetraplatin >
cisplatin >
iproplatin >
carboplatin.
Oxaliplatin was active against HT-29 and only minimally cross-resistant with
cisplatin against A2780/cp. Both bladder
carcinoma cell lines, both
melanoma cell lines, and one of the two
glioblastoma cell lines were resistant to both
oxaliplatin and
tetraplatin. The cytotoxicity profiles of the
drug pairs
oxaliplatin-
tetraplatin and
cisplatin-
carboplatin showed statistically significant correlation by the Spearman rank correlation test.
Oxaliplatin was similar to
cisplatin and
tetraplatin in protein binding; 85-88% of all
platinum from
oxaliplatin (5, 10, or 20 micrograms/ml) was bound to
plasma proteins within the first 5 h with an average half-life of 1.71 +/- 0.06 h. When
oxaliplatin was incubated in whole blood (5, 10, and 20 micrograms/ml), the erythrocytes took up 37.1 +/- 2.1% of the total
platinum in 2 h (maximum uptake) which was not exchangeable into plasma. Thus the erythrocyte-bound fraction does not serve as a reservoir of
drug. In plasma,
oxaliplatin was unchanged at 0.5 h, but at 1 h, 30% of the total
platinum in plasma was in a peak which had identical retention to that of (trans-1,2-diaminocyclohexane)dichloroplatinum(II), the major biotransformation product of
tetraplatin. At 2 h, (trans-1,2-diaminocyclohexane)dichloroplatinum(II) and three other
platinum-containing peaks were detected but no unchanged
oxaliplatin. All the
platinum eluted in a single peak near the
solvent front at 4 h. The marked similarity in cytotoxicity between
oxaliplatin and
tetraplatin may be due to the formation of (trans-1,2-diaminocyclohexane)dichloroplatinum(II) in tissue
culture media.