Antitumor activity of titanocene dichloride in xenografted human renal-cell carcinoma.
Titanocene dichloride [(C5H5)2TiCl2] is a new-developed organometallic antitumor agent which is currently being investigated in clinical trials of phases I and II. In the present study, it was tested for antitumor activity in human renal tumors either growing as monolayers in vitro or as xenografts in athymic mice. For comparison, approved cytostatic drugs (in vitro, vinblastine and 5-fluoro-2'-deoxyuridine; in vivo, cyclophosphamide, vinblastine, and 5-fluorouracil) were administered in vitro and in vivo at equivalent or equitoxic dose levels, respectively. Under in vitro conditions, titanocene dichloride was active only moderately. When it was applied at peak plasma level of 10(4) mol/l, it induced cell growth inhibitions by 25-50% in all KTCTL cell lines investigated (KTCTL-1M, KTCTL-2, KTCTL-26A, KTCTL-30, KTCTL-84). In the N-U 2 carcinoma cell strain it was more effective and caused cell growth inhibitions of 70-80% at the 10(-4) mol/l level, the IC50 value amounting to 5 x 10(-6) mol/l. When titanocene dichloride was applied intraperitoneally (i.p.) according to the Q3Dx5 and Q2Dx5 regimens and investigated in the human renal-cell carcinoma N-U 2 growing as xenograft in athymic mice, it brought about significant and dose-dependent growth reductions by 50-75% in relation to untreated controls, whereas cyclophosphamide given as single bolus injection and vinblastine administered both as single and triple doses were slightly less effective in this xenograft. MKT 4 and MKT 5, two formulations of titanocene dichloride which are currently used in clinical trials, showed similar efficacy as titanocene dichloride towards the N-U 2 renal-cell carcinoma xenograft. In the heterotransplanted N-U 26 carcinoma, titanocene dichloride induced relative growth reductions by 50-56% and was similarly active as cyclophosphamide, but less effective than vinblastine applied as a single dose. Titanocene dichloride was again significantly active in the KTCTL-1M carcinoma xenograft and caused relative growth reductions by 50-65%. In the case of the MRI-H 121 renal sarcoma xenograft, however, the organometallic compound showed an only marginal activity which was surpassed by cyclophosphamide, vinblastine and 5-fluorouracil, all three drugs inducing significant relative growth inhibitions by 50-88%. These results confirm a significant and remarkable antitumor activity of titanocene dichloride in three out of four human renal tumors xenografted to athymic mice and suggest that clinical studies of phase II with titanocene dichloride towards renal-cell carcinoma in human patients should be done in the near future.
Köpf-Maier
P
P
Institut für Anatomie, Freie Universität Berlin, Germany.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; C020528:titanocene dichloride