Sequence-dependent antitumour efficacy of combination chemotherapy of nedaplatin, a novel platinum complex, with 5-fluorouracil in an in vivo murine tumour model

The antitumour efficacy of a sequential combination of nedaplatin (NDP) and 5-fluorouracil (5-FU) was evaluated using Lewis lung carcinoma in vivo. NDP was developed as a second generation platinum complex. Because 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 daily 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. The sequential administration of either NDP or CDDP prior to 5-FU (NF or CF therapy) resulted in severe body weight loss followed by the death of the tumour-bearing mice when the high-dose of NDP or CDDP was administered. In contrast, the sequential administration of 5-FU prior to NDP or CDDP (FN or FC therapy) resulted in synergistically enhanced inhibition of tumour growth and prolonged survival in comparison with NDP, 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 frequently 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 conclusion, the sequence-dependent antitumour efficacy and toxicity of the 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 clinical therapy.