Effects on the Monocyte-Macrophage System and Antitumor Activity Against L1210 Leukemia of cis-bis-Cyclopentenecarboxylato-trans-R,R-1,2-Diaminocyclohexane-Platinum (II) Encapsulated in Multilamellar Vesicles2

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Abstract
Multilamellar vesicles (MLVs) composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol at a molar ratio of 7:3 were used as carriers of cis-bis-cyclopentenecarboxylato-trans-R,R-1,2-diaminocyclohexane-platinum (II) (CPDP). The encapsulation efficiency of liposomal CPDP (L-CPDP) was 87.6%, and its stability in normal saline at 14 days was 94.4%. The in vitro and in vivo effects on the function of the monocyte-macrophage system and the antitumor activity against L1210 leukemia were investigated in CD-1 and (C57BL/6J × DBA/2J)F1mice. L-CPDP and cisplatin (CDDP) caused a comparable inhibition of murine-resident peritoneal macrophage (PM) protein and RNA synthesis and Superoxide anion release. PM-mediated tumor cell cytotoxicity was completely inhibited at a concentration of 10 μg CDDP and L-CPDP/ml but not at concentrations of 1 and 5 μg/ml. The differences in plasma clearance of 99mTc-labeled MLV and phagocytic capacity of the liver among animals pretreated with the maximum tolerated doses of L-CPDP (25 mg/kg), empty liposomes, or CDDP (10 mg/kg) were not statistically significant (plasma clearance % of control: 105,110, and 100, respectively: P>.05; liver uptake % of control: 87, 96, and 104, respectively: P>.05). At the maximum tolerated doses, the antitumor activity of L-CPDP against L1210 leukemia was similar to that of CDDP when a single dose was administered [median survival of treated mice/median survival of control mice×100 (%T/C): 181 vs. 175] and slightly higher with the use of a triple-dose schedule (%T/C: 275 vs. 225). L-CPDP is easy to prepare, has a high-encapsulation efficiency and stability, is not more toxic than CDDP to the monocytemacrophage system, and is at least as effective as CDDP against L1210 leukemia.