Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 36, Issue 3, pp 211–216 | Cite as

Safety and efficacy of intraperitoneal injection of etoposide in oil suspension in mice with peritoneal carcinomatosis

  • Jung Soo Lee
  • Toshio Takahashi
  • Akeo Hagiwara
  • Chihiro Yoneyama
  • Michitoshi Itoh
  • Tsunetoshi Sasabe
  • Shozo Muranishi
  • Shigeru Tashima
Original Article Etoposide, Toxicity, Intraperitoneal Administration

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.

Key words

Etoposide Toxicity Intraperitoneal administration 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Cavalli F (1982) VP16-213 (Etoposide). A clinical review of its activity. Cancer Chemother Pharmacol 7: 81Google Scholar
  2. 2.
    Issell BF, Crooke ST (1979) Etoposide (VP16-213). Cancer Treat Rev 6: 107Google Scholar
  3. 3.
    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: 203Google Scholar
  4. 4.
    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: 489Google Scholar
  5. 5.
    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: 199Google Scholar
  6. 6.
    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: 1193Google Scholar
  7. 7.
    Issell BF (1982) The podophyllotoxin derivatives VP16-213 and VM26. Cancer Chemother Pharmacol 7: 73Google Scholar
  8. 8.
    Stahelin H (1973) Activity of a new glycosidic lignan derivative (VP16-213) related to podophyllotoxin in experimental tumors. Eur J Cancer 9: 215Google Scholar
  9. 9.
    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: 2331Google Scholar
  10. 10.
    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): 715Google Scholar
  11. 11.
    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 383Google Scholar
  12. 12.
    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: 233Google Scholar
  13. 13.
    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): 887Google Scholar
  14. 14.
    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: 1712Google Scholar
  15. 15.
    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: 1Google Scholar
  16. 16.
    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: 13Google Scholar
  17. 17.
    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: 473Google Scholar
  18. 18.
    Schmoll HJ, Niederle N, Achterrath W (1981) Etopside (VP16-213): Eine antineoplastische Substanz aus der Reihe der Podophyllotoxine. Klin Wochenshr 59: 1177Google Scholar
  19. 19.
    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: 1443Google Scholar
  20. 20.
    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: 194Google Scholar
  21. 21.
    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: 1952Google Scholar
  22. 22.
    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: 3380Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Jung Soo Lee
    • 1
  • Toshio Takahashi
    • 1
  • Akeo Hagiwara
    • 1
  • Chihiro Yoneyama
    • 1
  • Michitoshi Itoh
    • 1
  • Tsunetoshi Sasabe
    • 1
  • Shozo Muranishi
    • 2
  • Shigeru Tashima
    • 2
  1. 1.The First Department of SurgeryKyoto Prefectural University of MedicineKyotoJapan
  2. 2.Department of BiopharmacenticsKyoto College of PharmacyKyotoJapan

Personalised recommendations