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Liposomes as drug carrier system for cis-diamminedichloroplatinum (II)

II. Antitumor activity in vivo, induction of drug resistance, nephrotoxicity and Pt distribution

Summary

In this study we have investigated the use of liposomes as a drug carrier system for cis-diamminedichloroplatinum (II) (cis-DDP) in order to reduce the nephrotoxicity with preservation of antitumor activity. Liposomes (PC/PS/Chol 10:1:4) were prepared using hydration media containing no or a relatively low concentration of NaCl. It was found that cis-DDP containing liposomes (lip cis-DDP) injected i.v. to IgM immunocytoma-bearing LOU/M rats at a dose of 1 mg cis-DDP/kg (cumulative dose 7 mg cis-DDP/kg) showed less antitumor activity than the free drug. The optimal cumulative dose of free cis-DDP for induction of antitumor activity in this tumor system is 7 mg/kg (7x1 mg/kg). At a dose of 2 mg lip cis-DDP/kg (cumulative dose 14 mg cis-DDP/kg) the antitumor activity was almost equal to that of free cis-DDP. The antitumor activity could not be increased by choosing another phospholipid composition of the liposomes [DPPC/DPPG/Chol (10:1:10)] cis-DPP incorporated in DPPC/ DPPG/Chol liposomes showed a similar antitumor activity to cis-DDP incorporated in PC/PS/Chol liposomes. After an i.v. dose of 2mg lip cis-DDP/kg (PC/PS/Chol) kidney damage was less compared to the treatment with free cis-DDP (1 mg/kg). However, after a single dose of 2 mg cis-DDP/kg or a cumulative dose of 8 or 16 mg cis-DDP/kg, kedneys of rats treated with lip cis-DDP contained twice as much Pt as after treatment with free cis-DDP. Moreover, after treatment with lip cis-DDP, a twofold increase of the amount of Pt in tumor tissue was measured. In vitro studies with Pt recovered from spleens obtained from rats treated with lip cis-DDP i.v. showed that based on the equal amounts of Pt recovered the antitumor activity of the recovered Pt was reduced, indicating inactivation of cis-DDP in vivo. As during treatment with free cis-DDP, recurrence of the tumor was observed during the continued treatment with lip cis-DDP. It was found that these recurrent tumors were resistant to further therapy with cis-DDP. In conclusion, cis-DDP encapsulation into liposomes decreased the nephrotoxicity. The antitumor activity of cis-DDP is preserved by liposome encapsulation when it was used at a dose of 2 mg/kg, but it was reduced in terms of earlier onset of regrowth.

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Abbreviations

cis-DDP:

cis-Diamminedichloroplatinum(II)

Pt:

platinum

PC:

egg L-α-phosphatidylcholine

PS:

bovine L-α-phosphatidylserine

DPPC:

L-α-dipalmitoylphosphatidylcholine

DPPG:

L-α-dipalmitoylphosphatidylglycerol

Chol:

cholesterol

lip:

cis-DDP encapsulated in liposomes

PL:

phospholipid

AAS:

atomic absorption spectroscopy

RES:

reticuloendothelial system

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Correspondence to P. A. Steerenberg.

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Steerenberg, P.A., Storm, G., de Groot, G. et al. Liposomes as drug carrier system for cis-diamminedichloroplatinum (II). Cancer Chemother. Pharmacol. 21, 299–307 (1988). https://doi.org/10.1007/BF00264195

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Keywords

  • Tumor Tissue
  • Single Dose
  • Recurrent Tumor
  • Antitumor Activity
  • Early Onset