This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Perez-Soler, R. Articles by Khokhar, A. R. Search for Related Content PubMed PubMed Citation Articles by Perez-Soler, R. Articles by Khokhar, A. R.

Increased Cytotoxicity and Reversal of Resistance to cis-Diamminedichloroplatinum(II) with Entrapment of cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum(II) in Multilamellar Lipid Vesicles¹

Immunobiology and Drug Carriers Section, Department of Clinical Immunology and Biological Therapy [R. P. S., J. L.], and the Departments of Laboratory Medicine [L. Y. Y., B. D.], and Medical Oncology [A. R. K.], The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030

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 µM for L-NDDP, 15 µM for free NDDP, and 16 µM for cisplatin). Against LoVo cells resistant to a concentration of 3 µg/ml of cisplatin, L-NDDP was three times more cytotoxic than free NDDP and cisplatin (Do 14 µM for L-NDDP, 45 µM for free NDDP, and 48 µM 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.

¹ This work was supported in part by NIH grants 1-RO1 CA41581 to ARK and 1-RO1 CA23272 to BD, and by a grant from The Liposome Co., Inc., Princeton, NJ.

² To whom requests for reprints should be addressed, at Department of Clinical Immunology and Biological Therapy, Immunobiology and Drug Carriers Section, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 2/ 3/88. Revised 5/10/88. Accepted 5/19/88.

This article has been cited by other articles:

				C. Lu, R. Perez-Soler, B. Piperdi, G. L. Walsh, S. G. Swisher, W. R. Smythe, H. J. Shin, J. Y. Ro, L. Feng, M. Truong, et al. Phase II Study of a Liposome-Entrapped Cisplatin Analog (L-NDDP) Administered Intrapleurally and Pathologic Response Rates in Patients With Malignant Pleural Mesothelioma J. Clin. Oncol., May 20, 2005; 23(15): 3495 - 3501. [Abstract] [Full Text] [PDF]