Evaluation of antitumor activity of navelbine (vinorelbine ditartrate) against human breast carcinoma xenografts based on its pharmacokinetics in nude mice

The In vitro antitumor activity of navelbine (NVB, KW- 2307), a newly synthesized vlnca alkaloid, was compared with that of adrlamycln (ADM) against human breast carcinomas Inoculated into nude mice at the maximum tolerated dose (MTO) and clinically equivalent dose (CED). The plasma levels of NVB after Intravenous Injection Into nude mice at doses of 1.2 and 4.8 mg/kg diminished rapidly during the early phase (0-1 h), followed by a very long shallow one. NVB was still detected 96 h after administration at a dose of 4.8 mg/kg. The pharmacokinetlc parameters of NVB In plasma Indicated that NVB extensively distributes to tissues. The CED of NVB was provisionally decided to be 4.8 mg/kg based on the comparison of AUC values at 24-oo h between human patients and nude mice. When compared by a single Injection of MTD (NVB, 16 mg/kg; ADM 12 mg/kg), NVB was effective against all four tumor lines, MC-2, MC-8, MMKY and H-31, while ADM was effective only against H- 31. On the other hand, the body weight loss by NVB was mild as compared with that by ADM, Indicating that the antitumor activity of NVB is superior to that of ADM at their MTDs. A single Injection of NVB at its CED (4.8 mg/ kg) produced a poor antitumor effect and no or little toxlclty In terms of body weight loss, as compared with those at MTD. However, when NVB was administered Intermittently at CED, It exhibited significant antitumor activity against three tumor lines. The body weight loss was still mild even on this Intermittent schedule. These results Indicate that NVB can offer antitumor activity against human breast carcinoma xenografts at its CED.