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 carcinomat osis of two etoposide formulations: an aqueous solution (Etp-sol) and particles suspended in oil (the addition products of iodine and the et hyl esters of the fatty acids obtained from poppy-seed oil (Lipiodol) or sesame oil; Etp-oil). We also investigated tissue distribution of e toposide in rats treated with Etp-oil and Etp-sol. Etoposide was injec ted intraperitoneally at concentrations ranging from 52 to 392 mg/kg ( increasing geometrically by a factor of 1.4). The 50% lethal dose (LD( 50)), determined over a 2-week period of observation, was 135 mg/kg fo r Etp-oil and 108 mg/kg for Etp-sol. Autopsy findings included macrosc opic intestinal bleeding, necrosis of the intestinal mucosa, and pulmo nary congestion in mice from both treatment groups. In the efficacy tr ials. 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 Et p-oil group survived to day 60 compared with 3 of 20 mice in the Etp-s ol group. Toxicity-related deaths occurred in 1 of 20 mice treated wit h 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 eit her treatment group. Our findings showed that the Etp-oil was associat ed with a lower toxicity and a higher efficacy than the Etp-sol. To ev aluate 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 chromat ography. Compared with Etp-sol, Etp-oil delivered significantly greate r amounts of etoposide and for a longer period to the omentum, taken a s representative of the intraperitoneal tissue, and the etoposide conc entration in blood plasma was increased more slowly and decreased more gradually.