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 vesicles

Roman Perez-Soler, L. Y. Yang, B. Drewinko, J. Lauterzstain, A. R. Khokhar

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)4509-4512
Number of pages4
JournalCancer Research
Volume48
Issue number16
StatePublished - 1988
Externally publishedYes

Fingerprint

Cisplatin
Lipids
Leukemia L1210
Liposomes
bis-neodecanoato-1,2-diaminocyclohexaneplatinum(II)
Lethal Dose 50
Choline
Non-Hodgkin's Lymphoma
Glycerol
Suspensions
Colon
Neoplasm Metastasis
Carcinoma
Liver

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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 vesicles. / Perez-Soler, Roman; Yang, L. Y.; Drewinko, B.; Lauterzstain, J.; Khokhar, A. R.

In: Cancer Research, Vol. 48, No. 16, 1988, p. 4509-4512.

Research output: Contribution to journalArticle

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title = "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 vesicles",
abstract = "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.",
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T1 - 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 vesicles

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AU - Yang, L. Y.

AU - Drewinko, B.

AU - Lauterzstain, J.

AU - Khokhar, A. R.

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