Preclinical Efficacy and Pharmacokinetics of AP5346, A Novel Diaminocyclohexane-Platinum Tumor-Targeting Drug Delivery System
- 1 April 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 12 (7), 2248-2254
- https://doi.org/10.1158/1078-0432.ccr-05-2169
Abstract
Purpose: AP5346 is designed to target a diaminocyclohexane platinum (Pt) moiety to tumors through pH-sensitive linkage to a 25 kDa hydroxypropylmethacrylamide polymer. The goal of these studies was to determine the rate of release of Pt as a function of pH, the antitumor activity, and plasma and tumor pharmacokinetics of AP5346 in preclinical models. Experimental Design: Antitumor activity was assessed in mice bearing B16F10 melanoma and M5076 and 2008 ovarian carcinomas. Pt levels in plasma, tumors, and tumor DNA were measured by atomic absorption and inductively coupled plasma mass spectrometry. Results: AP5346 did not release Pt when suspended in 5% dextrose and released only 3.5% of its Pt in 24 hours in buffer at pH 7.4; the rate of release was 7-fold higher at pH 5.4. When given at their respective maximum tolerated doses, the antitumor activity of AP5346 was superior to that of oxaliplatin against both the B16 melanoma and 2008 human ovarian carcinoma. It was more effective than cisplatin in both cisplatin-sensitive and cisplatin-resistant variants of the M5076 tumor. When given at equitoxic doses, the peak plasma concentration was 25-fold higher, and AUC(0-∞) was 93 times higher, for AP5346 than for oxaliplatin. AP5346 delivered 16.3-fold more Pt to the tumor and 14.2-fold more Pt to tumor DNA than oxaliplatin based on AUC(1-168). Conclusions: AP5346 has a substantially better therapeutic index than oxaliplatin. AP5346 produced a marked increase in the delivery of diaminocyclohexane Pt to the tumor and tumor DNA over and above that attainable with oxaliplatin.Keywords
This publication has 10 references indexed in Scilit:
- Advantages of liposomal delivery systems for anthracyclinesSeminars in Oncology, 2004
- A Phase I and Pharmacological Study of the Platinum Polymer AP5280 Given as an Intravenous Infusion Once Every 3 Weeks in Patients with Solid TumorsClinical Cancer Research, 2004
- Cellular pH regulators: potentially promising molecular targets for cancer chemotherapyCancer Treatment Reviews, 2003
- At the acidic edge: emerging functions for lysosomal membrane proteinsTrends in Cell Biology, 2003
- Pharmacokinetics of Oxaliplatin in HumansMedical Oncology, 2002
- A phase II study of STEALTH cisplatin (SPI-77) in patients with advanced non-small cell lung cancerLung Cancer, 2001
- HPMA copolymer platinates as novel antitumour agents: in vitro properties, pharmacokinetics and antitumour activity in vivoEuropean Journal of Cancer, 1999
- A targeted supradose cisplatin chemoradiation protocol for advanced head and neck cancerThe American Journal of Surgery, 1994
- New types of synthetic infusion solutions. III. Elimination and retention of poly‐[N‐(2‐hydroxypropyl)methacrylamide] in a test organismJournal of Biomedical Materials Research, 1976
- New types of synthetic infusion solutions. I. Investigation of the effect of solutions of some hydrophilic polymers on bloodJournal of Biomedical Materials Research, 1973