Increased cytotoxicity and reversal of resistance to cis-diamminedichloro-platinum(II) with entrapment of cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in multilamellar lipid vesicles.
The role of liposome entrapment in modulating the cytotoxicity of a lipophilic cisplatin derivative was assessed. cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ +(II) (NDDP) was tested in suspension (free NDDP) or entrapped in multilamellar vesicles composed of dimyristoylphosphatidyl choline and dimyristoylphosphatidyl glycerol (L-NDDP). Against LoVo colon carcinoma cells sensitive to cisplatin, L-NDDP was two times more cytotoxic in vitro than free NDDP and cisplatin (Do 7 microM for L-NDDP, 15 microM for free NDDP, and 16 microM for cisplatin). Against LoVo cells resistant to a concentration of 3 micrograms/ml of cisplatin, L-NDDP was three times more cytotoxic than free NDDP and cisplatin (Do 14 microM for L-NDDP, 45 microM for free NDDP, and 48 microM for cisplatin). In in vivo studies, free NDDP was less potent and less active than L-NDDP against i.p. L-1210 leukemia (free NDDP, optimum %T/C 148 at a dose of 75 mg/kg; L-NDDP, optimum %T/C 185 at a dose of 25 mg/kg) and i.p. L1210/PDD leukemia (free NDDP, optimum %T/C 128 at a dose of 50 mg/kg on Days 1, 5, and 9; L-NDDP, optimum %T/C 200 at a dose of 12.5 mg/kg on Days 1, 5, and 9). Free NDDP administered i.v. was inactive against liver metastases of M5076 reticulosarcoma (%T/C 102) while L-NDDP showed significant activity (%T/C 140). The single dose i.v. LD50 in mice of free NDDP and L-NDDP were similar (79.4 mg/kg for free NDDP and 64.5 mg/kg for L-NDDP). These studies show that NDDP is a liposome-dependent drug since it can only be satisfactorily formulated in the liposomal form and since the liposomal carrier plays a crucial role in determining its antitumor activity.
Perez-Soler
R
R
Department of Clinical Immunology and Biological Therapy, University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Yang
L Y
LY
Drewinko
B
B
Lauterzstain
J
J
Khokhar
A R
AR
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D008081:Liposomes; D009944:Organoplatinum Compounds; C054367:bis-neodecanoato-1,2-diaminocyclohexaneplatinum(II)