| First Author | Newman MS | Year | 1999 |
| Journal | Cancer Chemother Pharmacol | Volume | 43 |
| Issue | 1 | Pages | 1-7 |
| PubMed ID | 9923534 | Mgi Jnum | J:51766 |
| Mgi Id | MGI:1326839 | Doi | 10.1007/s002800050855 |
| Citation | Newman MS, et al. (1999) Comparative pharmacokinetics, tissue distribution, and therapeutic effectiveness of cisplatin encapsulated in long-circulating, pegylated liposomes (SPI-077) in tumor-bearing mice [published erratum appears in Cancer Chemother Pharmacol 1999;43(6):524]. Cancer Chemother Pharmacol 43(1):1-7 |
| abstractText | PURPOSE: The pharmacokinetics (PK), biodistribution and therapeutic efficacy of cisplatin encapsulated in long-circulating pegylated (Stealth) liposomes (SPI-077) were compared with those of nonliposomal cisplatin in two murine (C26 colon carcinoma and Lewis lung) tumor models. METHODS: In therapeutic effectiveness studies, mice bearing murine C26 or Lewis lung tumors received multiple intravenous doses of SPI-077 or cisplatin in a variety of treatment schedules and cumulative doses. In the PK and biodistribution study, mice received a single intravenous bolus injection of 3 mg/kg of either SPI-077 or cisplatin 14 days after inoculation with 10(6) C26 tumor cells. Plasma and tissues were analyzed for total platinum (Pt) content by graphite furnace (flameless) atomic absorption spectrophotometery (GF-AAS). RESULTS: Efficacy studies showed that SPI-077 had superior antitumor activity compared to the same cumulative dose of cisplatin. When lower doses of SPI-077 were compared to cisplatin at its maximally tolerated dose in Lewis lung tumors, equivalent SPI-077 antitumor activity was seen at only half the cisplatin dose. Higher cumulative doses of SPI-077 were well tolerated and had increased antitumor effect. SPI-077 PK were characterized by a one-compartment model with nonlinear (saturable) elimination, whereas cisplatin PK were described by a two-compartment model with linear elimination. SPI-077 had a 55-fold lower [corrected] volume of distribution, 3-fold higher peak plasma levels, and a 60-fold larger plasma AUC compared with cisplatin. In addition, SPI-077-treated animals displayed a 4-fold reduction in Pt delivered to the kidneys (primary target organ of toxicity) relative to cisplatin, but a 28-fold higher tumor AUC than cisplatin. CONCLUSIONS: Based on the results of our studies, encapsulation of cisplatin in long-circulating pegylated liposomes has overcome limitations experienced with other liposomal cisplatin formulations. SPI-077 has a prolonged circulation time and increased tumor Pt disposition, and its antitumor effect is significantly improved compared to cisplatin in murine colon and lung cancer models. |
