Safety and efficacy of intraperitoneal injection of etoposide in oil suspension in mice with peritoneal carcinomatosis.
We compared the safety and efficacy in mice with peritoneal carcinomatosis of two etoposide formulations: an aqueous solution (Etp-sol) and particles suspended in oil (the addition products of iodine and the ethyl esters of the fatty acids obtained from poppy-seed oil (Lipiodol) or sesame oil; Etp-oil). We also investigated tissue distribution of etoposide in rats treated with Etp-oil and Etp-sol. Etoposide was injected intraperitoneally at concentrations ranging from 52 to 392 mg/kg (increasing geometrically by a factor of 1.4). The 50% lethal dose (LD50), determined over a 2-week period of observation, was 135 mg/kg for Etp-oil and 108 mg/kg for Etp-sol. Autopsy findings included macroscopic intestinal bleeding, necrosis of the intestinal mucosa, and pulmonary congestion in mice from both treatment groups. In the efficacy trials. 10(6) P388 leukemia cells were transplanted into CDF1 male mice, and Etp-oil and Etp-sol were injected at doses of 20 mg/kg and 80 mg/kg. In the groups receiving the 20 mg/kg dose, 11 of 19 mice in the Etp-oil group survived to day 60 compared with 3 of 20 mice in the Etp-sol group. Toxicity-related deaths occurred in 1 of 20 mice treated with 80 mg/kg Etp-oil and in 8 of 20 mice treated with 80 mg/kg Etp-sol. No cancer-related deaths were associated with the 80 mg/kg dose in either treatment group. Our findings showed that the Etp-oil was associated with a lower toxicity and a higher efficacy than the Etp-sol. To evaluate tissue distribution, rats were injected intraperitoneally with 5 mg/kg body weight of Etp-sol or Etp-oil. The tissue distribution of etoposide was subsequently analyzed by high performance liquid chromatography. Compared with Etp-sol, Etp-oil delivered significantly greater amounts of etoposide and for a longer period to the omentum, taken as representative of the intraperitoneal tissue, and the etoposide concentration in blood plasma was increased more slowly and decreased more gradually.
Lee
J S
JS
First Department of Surgery, Kyoto Prefectural University of Medicine, Japan.
Takahashi
T
T
Hagiwara
A
A
Yoneyama
C
C
Itoh
M
M
Sasabe
T
T
Muranishi
S
S
Tashima
S
S
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005047:Etoposide / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007455:Iodine; D007459:Iodized Oil; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D012715:Sesame Oil; D014867:Water
D004337:Drug Carriers; D014867:Water; D005047:Etoposide; D007459:Iodized Oil; D012715:Sesame Oil; D007455:Iodine