SEQUENCE-DEPENDENT ANTITUMOR EFFICACY OF COMBINATION CHEMOTHERAPY OF NEDAPLATIN, A NOVEL PLATINUM COMPLEX, WITH 5-FLUOROURACIL IN AN IN-VIVO MURINE TUMOR-MODEL

The antitumour efficacy of a sequential combination of nedaplatin (NDP ) and 5-fluorouracil (5-FU) was evaluated using Lewis lung carcinoma i n vivo. NDP was developed as a second generation platinum complex. Bec ause it has greater antitumour activity and lower nephrotoxicity than cisplatin (CDDP), we also compared the antitumour activity of NDP plus 5-FU with that of CDDP plus 5-FU, A fixed 5-FU dose was injected dail y for 5 days and increasing doses of either NDP or CDDP were injected once via the tail vein into the Lewis lung carcinoma-implanted mice. T he sequential administration of either NDP or CDDP prior to 5-FU (NF o r CF therapy) resulted in severe body weight loss followed by the deat h of the tumour-bearing mice when the high-dose of NDP or CDDP was adm inistered. In contrast, the sequential administration of 5-FU prior to NDP or CDDP (FN or FC therapy) resulted in synergistically enhanced i nhibition of tumour growth and prolonged survival in comparison with N DP, CDDP or 5-FU monotherapy. At the high-dose of NDP in FN therapy, a reduction of tumour size and long-term tumour-free survival were freq uently observed. The survival effect of the combinations of NDP with 5 -FU was superior to those of the combination of CDDP with 5-FU. In. co nclusion, the sequence-dependent antitumour efficacy and toxicity of t he combination of NDP or CDDP with 5-FU was demonstrated in this study , and FN therapy appeared to be the most efficient regimen as a clinic al therapy. (C) 1998 Elsevier Science Ltd. All rights reserved.