Cellular pharmacology of liposomal cis-bis-neodecanoate-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in mouse resident peritoneal macrophages, Kupffer cells, and hepatocytes

J. Lautersztain, Roman Perez-Soler, J. Turpin, A. R. Khokhar, Z. H. Siddik, K. Schmidt, G. Lopez-Berestein

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Abstract

The in vitro and in vivo interaction of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) (L-NDDP) with mouse resident peritoneal macrophages (RPM), Kupffer cells (KC), and hepatocytes was studied. The peak in vitro uptake of L-NDDP by RPM was 12.5 ng elemental platinum/100 μg cell protein and constituted 0.2% of the platinum available for phagocytosis. The subsequent release of platinum by RPM was rapid initially, with a 20-fold increase over the first 4 h, followed by a plateau; ultrafilterable (free) platinum constituted 50% of the total platinum released at 24 h. The retained intracellular platinum in RPM at 24 h was close to 50% of that initially present. The peak in vitro uptake of L-NDDP by KC was 11.3 ng platinum/100 μg cell protein and amounted to 0.2% of the platinum available for phagocytosis. The release of platinum by KC was detectable only after 4 h of incubation and increased 3-fold over the next 14 h. The ultrafilterable platinum released by KC at 18 h was 40% of the total platinum released. The retained intracellular platinum in KC at 18 h was 33% of that initially present. The peak in vitro uptake of L-NDDP by hepatocytes was almost 50 ng platinum/100 μg cell protein and constituted 0.8% of the platinum available for intake. Following the i.v. injection of L-NDDP, hepatocytes contained up to 6-fold higher platinum concentrations than KC. This observation was supported by transmission electron microscopy showing a higher concentration of multilamellar vesicles within hepatocytes than in KC, 5 min after i.v. injection of L-NDDP. These findings suggest that L-NDDP becomes available to the liver following i.v. injection, that both macrophages and hepatocytes play a role in the metabolism of L-NDDP, and that Kupffer cells could mediate a sustained release of platinum in the liver following the interaction with L-NDDP, indicating the potential of L-NDDP for the treatment of tumors in the liver.

Original languageEnglish (US)
Pages (from-to)1300-1306
Number of pages7
JournalCancer Research
Volume48
Issue number5
StatePublished - 1988
Externally publishedYes

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Kupffer Cells
Peritoneal Macrophages
Platinum
Hepatocytes
Pharmacology
Phagocytosis
Injections
Liver
bis-neodecanoato-1,2-diaminocyclohexaneplatinum(II)
Proteins
Transmission Electron Microscopy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Cellular pharmacology of liposomal cis-bis-neodecanoate-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in mouse resident peritoneal macrophages, Kupffer cells, and hepatocytes. / Lautersztain, J.; Perez-Soler, Roman; Turpin, J.; Khokhar, A. R.; Siddik, Z. H.; Schmidt, K.; Lopez-Berestein, G.

In: Cancer Research, Vol. 48, No. 5, 1988, p. 1300-1306.

Research output: Contribution to journalArticle

Lautersztain, J. ; Perez-Soler, Roman ; Turpin, J. ; Khokhar, A. R. ; Siddik, Z. H. ; Schmidt, K. ; Lopez-Berestein, G. / Cellular pharmacology of liposomal cis-bis-neodecanoate-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in mouse resident peritoneal macrophages, Kupffer cells, and hepatocytes. In: Cancer Research. 1988 ; Vol. 48, No. 5. pp. 1300-1306.
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abstract = "The in vitro and in vivo interaction of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) (L-NDDP) with mouse resident peritoneal macrophages (RPM), Kupffer cells (KC), and hepatocytes was studied. The peak in vitro uptake of L-NDDP by RPM was 12.5 ng elemental platinum/100 μg cell protein and constituted 0.2{\%} of the platinum available for phagocytosis. The subsequent release of platinum by RPM was rapid initially, with a 20-fold increase over the first 4 h, followed by a plateau; ultrafilterable (free) platinum constituted 50{\%} of the total platinum released at 24 h. The retained intracellular platinum in RPM at 24 h was close to 50{\%} of that initially present. The peak in vitro uptake of L-NDDP by KC was 11.3 ng platinum/100 μg cell protein and amounted to 0.2{\%} of the platinum available for phagocytosis. The release of platinum by KC was detectable only after 4 h of incubation and increased 3-fold over the next 14 h. The ultrafilterable platinum released by KC at 18 h was 40{\%} of the total platinum released. The retained intracellular platinum in KC at 18 h was 33{\%} of that initially present. The peak in vitro uptake of L-NDDP by hepatocytes was almost 50 ng platinum/100 μg cell protein and constituted 0.8{\%} of the platinum available for intake. Following the i.v. injection of L-NDDP, hepatocytes contained up to 6-fold higher platinum concentrations than KC. This observation was supported by transmission electron microscopy showing a higher concentration of multilamellar vesicles within hepatocytes than in KC, 5 min after i.v. injection of L-NDDP. These findings suggest that L-NDDP becomes available to the liver following i.v. injection, that both macrophages and hepatocytes play a role in the metabolism of L-NDDP, and that Kupffer cells could mediate a sustained release of platinum in the liver following the interaction with L-NDDP, indicating the potential of L-NDDP for the treatment of tumors in the liver.",
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T1 - Cellular pharmacology of liposomal cis-bis-neodecanoate-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in mouse resident peritoneal macrophages, Kupffer cells, and hepatocytes

AU - Lautersztain, J.

AU - Perez-Soler, Roman

AU - Turpin, J.

AU - Khokhar, A. R.

AU - Siddik, Z. H.

AU - Schmidt, K.

AU - Lopez-Berestein, G.

PY - 1988

Y1 - 1988

N2 - The in vitro and in vivo interaction of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) (L-NDDP) with mouse resident peritoneal macrophages (RPM), Kupffer cells (KC), and hepatocytes was studied. The peak in vitro uptake of L-NDDP by RPM was 12.5 ng elemental platinum/100 μg cell protein and constituted 0.2% of the platinum available for phagocytosis. The subsequent release of platinum by RPM was rapid initially, with a 20-fold increase over the first 4 h, followed by a plateau; ultrafilterable (free) platinum constituted 50% of the total platinum released at 24 h. The retained intracellular platinum in RPM at 24 h was close to 50% of that initially present. The peak in vitro uptake of L-NDDP by KC was 11.3 ng platinum/100 μg cell protein and amounted to 0.2% of the platinum available for phagocytosis. The release of platinum by KC was detectable only after 4 h of incubation and increased 3-fold over the next 14 h. The ultrafilterable platinum released by KC at 18 h was 40% of the total platinum released. The retained intracellular platinum in KC at 18 h was 33% of that initially present. The peak in vitro uptake of L-NDDP by hepatocytes was almost 50 ng platinum/100 μg cell protein and constituted 0.8% of the platinum available for intake. Following the i.v. injection of L-NDDP, hepatocytes contained up to 6-fold higher platinum concentrations than KC. This observation was supported by transmission electron microscopy showing a higher concentration of multilamellar vesicles within hepatocytes than in KC, 5 min after i.v. injection of L-NDDP. These findings suggest that L-NDDP becomes available to the liver following i.v. injection, that both macrophages and hepatocytes play a role in the metabolism of L-NDDP, and that Kupffer cells could mediate a sustained release of platinum in the liver following the interaction with L-NDDP, indicating the potential of L-NDDP for the treatment of tumors in the liver.

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