The alkylator treosulfan shows activity towards human renal-cell carcinoma in vivo and in vitro

Abstract

Treosulfan (L-threitol-1,4-bismethanesulfonate, Ovastat) was tested on human renal tumor cells growing as xenografts in athymic nude mice and as monolayers in vitro, in comparison with clinically used cytostatic drugs (in vivo, cyclophosphamide, vinblastine, and 5-fluorouracil; in vitro, vinblastine and 5-fluoro-2'-deoxyuridine) which were administered at equitoxic or equivalent dose levels, respectively. Four human renal tumor xenografts (N-U 2, N-U 26, MRI-H 121, KTCTL-1M) were investigated in vivo, and seven renal tumor cell lines (KTCTL-1M, KTCTL-2, KTCTL-26A, KTCTL-30, KTCTL-84, MRI-H 121, N-U 2) under in vitro conditions. The investigations of the four human renal tumor xenografts revealed that treosulfan is capable of inducing pronounced growth inhibitions ranging from 60-100% in comparison with untreated control tumors. In the xenografted renal-cell carcinoma KTCTL-1M, treosulfan administered at the highest dose level (1 x 3,500 mg/kg) even effected a complete remission lasting for more than three weeks in all animals treated with this dose. It was more effective in the N-U 2 carcinoma growing in vivo than the comparative compounds cyclophosphamide and vinblastine. In the heterotransplanted renal-cell carcinoma N-U 26, treosulfan showed a similar activity as the two established cytostatic drugs tested whereas, in the renal sarcoma MRI-H 121, both cyclophosphamide and vinblastine were slightly more effective than treosulfan. In four renal-cell carcinomas growing as monolayers in vitro (KTCTL-1M, KTCTL-2, KTCTL-84, N-U 2), treosulfan induced cell growth inhibitions by about 50% at peak plasma concentration in comparison with untreated control cultures. The IC50 values ranged from 5 x 10(-6) to 10(-4) mol/l in all seven monolayer cultures investigated 5-Fluoro-2'-deoxyuridine (floxuridine) was similarly active in vitro as treosulfan with respect to the molar concentrations inducing growth inhibition and to the IC50 values, whereas vinblastine was more effective than treosulfan in most of the human renal tumor cell monolayers investigated. These results reveal the remarkable antitumor efficacy of treosulfan towards human renal-cell carcinomas, especially under in vivo conditions. This activity was similarly high or even better than in cyclophosphamide and vinblastine. The in vitro data obtained in monolayer cultures also confirmed the remarkable antiproliferative activity of treosulfan in renal tumor cells, but did not mirror very well the pattern of antitumor activity observed in vivo.