Abstract
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. 106 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.
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References
Cavalli F (1982) VP16-213 (Etoposide). A clinical review of its activity. Cancer Chemother Pharmacol 7: 81
Issell BF, Crooke ST (1979) Etoposide (VP16-213). Cancer Treat Rev 6: 107
Bender RA, Anderson T, Fisher RT, Young RC (1978) The activity of the epipodophyllotoxin VP16 in the treatment of combination chemotherapy resistant non-Hodgkin's lymphoma. Am J Hematol 5: 203
Cohen MH, Broder LE, Fossieck BE, Ihde DC, Minna JD (1977) Phase II clinical trial of weekly administration of VP16-213 in small cell bronchogenic carcinoma. Cancer Treat Rep 61: 489
European Organization for Research on the Treatment of Cancer, Clinical Screening Group (1973) Epipodophyllotoxin VP16-213 in treatment of acute leukemias, haematosarcomas and solid tumors. BMJ 3: 199
Fitzharris BM, Kaye SB, Saverymuttu S, Newlands ES, Barrett A, Peckham MJ, McElwain TJ (1980) VP16-213 as a single agent in advanced testicular tumors. Eur J Cancer 16: 1193
Issell BF (1982) The podophyllotoxin derivatives VP16-213 and VM26. Cancer Chemother Pharmacol 7: 73
Stahelin H (1973) Activity of a new glycosidic lignan derivative (VP16-213) related to podophyllotoxin in experimental tumors. Eur J Cancer 9: 215
Okamoto K, Nishikawa K, Seki T, Shibasaki C, Uchida T, Takahashi K (1985) The antitumor activity of intraperitoneally or orally administered etoposide in animals and its administration schedule dependency (in Japanese). Jpn J Cancer Chemother 12: 2331
Dombernowsky P, Nissen NI (1973) Schedule dependency of the antileukemic activity of the podophyllotoxin-derivative VP16-213 (NSC-141540) in L1210 leukemia. APMIS [A] 81 (5): 715
Hagiwara A, Takahashi T, Sawai K, Iwamoto A, Shimotuma M, Seiki K, Yoneyama C, Itoh M, Sasabe T (1990) A newly prepared carbon particles suspension as a lymphatic stainer and a drug carrier into the lymphatics. In: Nishi M, Uchino S, Yabuki S (eds) Progress in lymphology-XII. Excerpta Medica, Amsterdam New York Oxford, p 383
Hagiwara A, Takahashi T, Sasabe T, Itoh M, Lee M, Sakakura C, Shoubayashi S, Tashima S, Muranishi S (1992) Etoposide microcrystals suspended in oil: a new dosage form to peritoneal carcinomatosis in mice. Oncology 49: 233
Lee M, Takahashi T, Hagiwara A, Iwamoto A, Shimotuma M, Yoneyama C, Itoh M, Sasabe T, Muranishi S, Tajima S (1991) Toxic reduction of etoposide in diluted solution form injected intraperitoneally to mice (in Japanese). J Clin Exp Med 158 (13): 887
Zimm S, Cleary SM, Lucas WE, Weiss RJ, Markman M, Andrews PA, Schiefer MA, Kim S, Horton C, Howell SB (1987) Phase I pharmacokinetic study of intraperitoneal cisplatin and etoposide. Cancer Res 47: 1712
Dedrick RL, Myers CE, Bungay PM, DeVita VT (1978) Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat Rep 62: 1
Creger RJ, Pharm D, Fox RM, Lazarus HM (1990) Infusion of high doses of undiluted etoposide through central venous catheters during preparation for bone marrow transplantation. Cancer Invest 8: 13
Cavalli F, Sonntag RW, Jungi F, Senn HJ, Brunner KW (1978) VP16-213 monotherapy for remission induction of small cell lung cancer: a randomized trial using three dosage schedules. Cancer Treat Rep 62: 473
Schmoll HJ, Niederle N, Achterrath W (1981) Etopside (VP16-213): Eine antineoplastische Substanz aus der Reihe der Podophyllotoxine. Klin Wochenshr 59: 1177
Levi F, Mechkouri M, Roulon A, Bailleul F, Horvath C, Reinberg A, Mathe G (1985) Circadian rhythm in tolerance of mice for etoposide. Cancer Treat Rep 69: 1443
Jensen PB, Roed H, Skovsgaard T, Friche E, Vindelov L, Hansen HH, Thomsen MS (1990) Antitumor activity of the two epipodophyllotoxin derivatives VP-16 and VM-26 in preclinical systems: a comparison of in vitro and in vivo drug evaluation. Cancer Chemother Pharmacol 27: 194
Bennett CL, Sinkule JA, Schilsky RL, Senekjian E, Choi KE (1987) Phase I clinical and pharmacological study of 72-hour continuous infusion of etoposide in patients with advanced cancer. Cancer Res 47: 1952
Los G, Mutsaers PWA, Vijigh WJF, Baldew GS, Graaf PW, McVie JG (1989) Direct diffusion of cis-diamminedichloroplatinum(II) in intraperitoneal rat tumors after intraperitoneal chemotherapy: a comparison with systemic chemotherapy. Cancer Res 49: 3380
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Lee, J.S., Takahashi, T., Hagiwara, A. et al. Safety and efficacy of intraperitoneal injection of etoposide in oil suspension in mice with peritoneal carcinomatosis. Cancer Chemother. Pharmacol. 36, 211–216 (1995). https://doi.org/10.1007/BF00685848
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DOI: https://doi.org/10.1007/BF00685848