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Treatment and Prophylaxis of Experimental Liver Metastases of M5076 Reticulosarcoma with cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum(II) Encapsulated in Multilamellar Vesicles¹

Departments of Clinical Immunology and Biological Therapy [R. P-S., G. L-B.] and Chemotherapy Research [A. R. K.], The University of Texas, M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77030

cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum(II) (NDDP) was encapsulated in multilamellar vesicles composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol at a 7:3 molar ratio. Compared with cisplatin, i.v. administration of an equimolar dose of liposome-encapsulated NDDP (L-NDDP) resulted in 15-fold higher peak platinum levels in the spleen (204.7 versus 13.3 µg/g dry tissue), 5-fold higher in the lungs (116.4 versus 21.0 µg/g dry tissue), 3-fold higher in the liver (71.6 versus 23.9 µgg dry tissue), and 4-fold higher in the blood (14.8 versus 3.9 µg/ml). At the optimal dose and schedule, L-NDDP administered i.p. in mice bearing peritoneal L1210 leukemia resulted in the percentage of median survival time of treated mice divided by median survival time of control mice (%T/C) of 312 versus 225 for cisplatin and free NDDP. When administered i.v., L-NDDP was also more active than cisplatin against L1210 leukemia inoculated i.v. (%T/C 186 versus 142). L-NDDP was markedly active against L1210 leukemia resistant to cisplatin (%T/C, 200 versus 112 for cisplatin). In mice bearing liver metastases of M5076 reticulosarcoma, L-NDDP was significantly more effective than cisplatin at equimolar doses (mean survival time, 57 ± 9 (SD) days for L-NDDP versus 42 ± 3 days for cisplatin, P< 0.05). L-NDDP was also effective in preventing liver metastases of M5076 when administered up to 24 h prior to tumor inoculation (mean survival, 28 ± 2 days for L-NDDP versus 22 ± 2 days for cisplatin, P < 0.05). L-NDDP is significantly non-cross-resistant with cisplatin and more effective against phagocytic and nonphagocytic murine tumors.

¹ Supported in part by NIH Grant 5511-23 to R. P-S., National Cancer Institute Grant CA41581 to A. R. K., and a grant from The Liposome Company, Inc., Princeton, NJ.

² To whom requests for reprints should be addressed at Department of Clinical Immunology and Biological Therapy, Box 41, University of Texas, M. D. Anderson Hospital, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 3/12/87. Revised 6/18/87. Revised 8/31/87. Accepted 9/ 8/87.