Ro 03-8799: preferential relative uptake in human tumor xenografts compared to a murine tumor: comparison with...

The pharmacokinetics of Ro 03-8799 and SR-2508 were studied in 6 tumor cell lines (5 human, 1 murine) transplanted into athymic nude mice. The human tumors were rectocolic adenocarcinomas (HRT18, HT29) and melanomas (Be11, Na11+, Na11-), the rodent tumor was a mammary tumor (EMT6). The concentrations of drugs in tumor, blood, plasma, and red cells were measured by HPLC 15, 30, and 45 minutes after the simultaneous i.v. injection of 0.1 mg/g of each compound. Little or no difference was found between the concentrations in the plasma, blood, and red cells for either drug; SR-2508 concentration was higher than that of Ro 03-8799. Both compounds were concentrated in all the tumors, the concentration increases or decreases as a function of the time, depending on the cell line; there was more Ro 03-8799 in the pigmented melanomas than in the other tumors. The relative uptake of Ro 03-8799 and SR-2508 in the tumor was evaluated by the ratio of drug concentrations in the tumor and in the blood. The results suggest that Ro 03-8799 and SR-2508 accumulated in all the tumors, the relative uptake of Ro 03-8799 was higher than that of SR-2508. For human tumors, the ratios increased between 15 and 45 minutes. They ranged from 1.2 to 3.6 for SR-2508 and from 3.1 to 14.6 for Ro 03-8799. For Ro 03-8799, the highest ratios were found for the melanomas; the uptake was higher in the pigmented Na11+ tumors than in the non-pigmented Na11-. The ratios for EMT6 were about 2.3 for SR-2508 and 4.7 for Ro 03-8799; these ratios varied slightly between 15 and 45 minutes.