Liposomes as drug carrier system for cis-diamminedichloroplatinum (II). II. Antitumor activity in vivo, induction of drug resistance, nephrotoxicity and Pt distribution.
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 (7 X 1 mg/kg). At a dose of 2 mg lip cis-DDP/kg (cumulative dose 14 mg cis-DDP/kg) the antitumor activity could not be increased by choosing another phospholipid composition of the liposomes [DPPC/DPPG/Chol (10:1:10)]. cis-DDP 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 2 mg 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, kidneys 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.
Steerenberg
P A
PA
Laboratory for Pathology, National Institute of Public Health and Environmental Protection (NIPHEP), Bilthoven, The Netherlands.
Storm
G
G
de Groot
G
G
Claessen
A
A
Bergers
J J
JJ
Franken
M A
MA
van Hoesel
Q G
QG
Wubs
K L
KL
de Jong
W H
WH
D000818:Animals; D002460:Cell Line; D002945:Cisplatin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004337:Drug Carriers; D004339:Drug Compounding; D004351:Drug Resistance; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D008081:Liposomes / Q000008:administration & dosage* / Q000138:chemical synthesis; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D010984:Platinum / Q000378:metabolism; D051381:Rats; D013154:Spleen / Q000032:analysis; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004337:Drug Carriers; D008081:Liposomes; D010984:Platinum; D002945:Cisplatin