Pharmacokinetics of neamine in rats and anti-cervical cancer activity in vitro and in vivo.

OBJECTIVE

To study the pharmacokinetics of neamine in rats and to evaluate its anti-cervical cancer activity.

METHODS

The plasma level of neamine was determined by HPLC-ELSD. Pharmacokinetic parameters were calculated using DAS 2.0 software. Tissue microarray analysis was conducted to examine angiogenin (ANG) expression in normal and cancerous cervical tissues and to determine its correlation with clinical and pathologic presentations of cervical cancers. The anti-cervical cancer activity of neamine was assessed both in vitro and in vivo.

RESULTS

After intravenous (i.v.) administration of 15, 30, and 60 mg kg(-1) neamine, the pharmacokinetic parameters were as follows: AUC(0-t), 9,398.0 ± 653.4, 19,235.2 ± 2,939.0, and 35,437.7 ± 3,772.2 mg L(-1) min; C max, 170.8 ± 13.1, 353.3 ± 15.8, and 464.0 ± 33.1 mg L(-1); T 1/2, 34.9 ± 4.1, 46.8 ± 5.1, and 58.0 ± 12.5 min, respectively. The bioavailability of neamine administered through intramuscular, subcutaneous, intraperitoneal and intragastric route was 14.0 ± 3.0, 8.4 ± 0.6, 6.5 ± 3.3, and 3.1 ± 0.2 %, respectively. Up-regulated ANG expression and increased nuclear translocation were observed in cervical cancers as compared to normal cervical tissues. Moreover, upregulation of ANG was positively correlated with primary tumor invasion. Neamine inhibited ANG-induced HUVEC and HeLa cell proliferation as well as nuclear translocation of ANG. Consistently, neamine inhibited both the establishment and progression of xenograft human cervical cancers in athymic mice.

CONCLUSIONS

The bioavailability of neamine administered through extravascular routes was low. The half-life of neamine through i.v. administration was short. This suggests that a higher dosing frequency in order to maintain a therapeutic effect. Neamine holds potential against cervical cancer. The mechanisms of neamine inhibition are through blocking nuclear translocation of ANG thereby inhibiting both angiogenesis and cancer cell proliferation.