Toxicity and antitumor activity of cis-bis-cyclopentenecarboxylato-1,2-diaminocyclohexane platinum(II) encapsulated in multilamellar vesicles.

Abstract

The potential of multilamellar vesicles (MLVs) as carriers of cis-bis-cyclopentenecarboxylato-1,2-diaminocyclohexane platinum(II) (CPDP), a lipophilic cisplatin derivative, was assessed. MLVs composed of dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), and cholesterol at different molar ratios were tested. The MLV-CPDP preparation with the highest antitumor activity against L1210 leukemia in vivo was DMPC:DMPG 7:3-CPDP. The encapsulation efficiency of this preparation was 66 +/- 4% (SD); the stability in 0.9% NaCl solution at 4 degrees C was 89% at 14 days and 93% 18 h after incubation in human AB serum at 37 degrees C. The toxicities of DMPC:DMPG 7:3-CPDP and free CPDP (suspended in hydroxypropyl cellulose) administered i.p. were similar (50% lethal dose = 75 versus 91 mg/kg; blood urea nitrogen values 96 h after the administration of the 50% lethal dose = 32.0 versus 34.4 mg/dl). The mean %T/C [(median survival time of treated mice divided by median survival time of control mice) X 100] obtained after a single i.p. injection of the optimal dose of each preparation tested was 215 (range 200 to 232) for DMPC:DMPG 7:3-CPDP, 175 (range 158 to 209) for DMPG-CPDP, 162 (range 136 to 179) for free CPDP, and 178 (range 169 to 189) for cisplatin. Using a multiple i.p. injection schedule (injections on Days 1, 5, and 9), DMPC:DMPG 7:3-CPDP was more active than free CPDP and cisplatin (%T/C: 403, 284, and 253% respectively). DMPC:DMPG 7:3-CPDP is less toxic and more active against L1210 leukemia in vivo than is cisplatin. The encapsulation of CPDP in MLVs composed of DMPC:DMPG 7:3 provides an adequate vehicle for the administration of this lipophilic compound and enhances its antitumor activity against L1210 leukemia.

• Authors: R Perez-Soler, A R Khokhar, M P Hacker, G Lopez-Berestein
• Journal: Cancer research (Cancer Res) Vol. 46 Issue 12 Pt 1 Pg. 6269-73 (Dec 1986) ISSN: 0008-5472 [Print] United States
• PMID: 3779646 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Liposomes
• Organoplatinum Compounds
• Pharmaceutical Vehicles
• Phosphatidylglycerols
• bis(cyclopentenecarboxylato)-1,2-diaminocyclohexane-platinum(II)
• dimyristoylphosphatidylglycerol
• Dimyristoylphosphatidylcholine

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology, toxicity)
• Dimyristoylphosphatidylcholine (analysis)
• Drug Stability
• Kidney (drug effects)
• Leukemia L1210 (drug therapy, pathology)
• Liposomes (administration & dosage, analysis)
• Mice
• Mice, Inbred Strains
• Organoplatinum Compounds (administration & dosage, pharmacology)
• Pharmaceutical Vehicles
• Phosphatidylglycerols (analysis)