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Pharmacokinetics of fotemustine and BCNU in plasma, liver and tumor tissue of rats bearing two lines of Walker 256 carcinoma

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Summary

The plasma and tissue pharmacokinetics of fotemustine (diethyl-1-[3-(2-chlorethyl)-3-nitrosoureido]-ethylphosphonate) and BCNU (1,3-bis-[2-chlorethyl]-1-nitrosourea) were investigated in healthy control rats and in animals bearing either the nitrosourea-sensitive line A (W256/A) or the nitrosourea-resistant line B (W256/B) of Walker 256 carcinoma. The antitumor activities of these nitrosoureas were similar following i.v. doses ranging from 10 to 40 mg/kg. For both drugs, the survival of tumor-bearing rats was lower in the W256/B than in the sensitive W256/A line. Some sex differences were observed, female rats being more responsive than males to both drugs. Nitrosourea concentrations were assayed in plasma and tissues by differential pulse polarography so as to assess whether the pharmacokinetics could explain the differences in antitumor activity. The antineoplastic effects of fotemustine seemed to be influenced by its pharmacokinetics. The plasma AUC of the intact nitrosourea was higher in females than in males. Fotemustine was cleared 2–5 times more slowly than BCNU from tumor tissue, and its clearance was higher in W256/B- than in W256/A-bearing rats. This suggests that the antitumor activity in the responsive line might partly be due to longer exposure of the growing tumor to the drug. The distribution volume of both nitrosoureas in plasma was higher in tumor-bearing animals than in healthy controls, indicating that the tumor tissue probably constitutes an additional distribution space.

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Abbreviations

BCNU:

1,3-bis-[2-chlorethyl]-1-nitrosourea

W256/A:

Walker carcinoma 256 line A

W256/B:

Walker carcinoma 256 line B

References

  1. 1.

    Bartosek I, Donelli MG, Guaitani A (1974) Modification of drug metabolism induced in the host by the presence of a tumor. Recent Results Cancer Res 49: 95

  2. 2.

    Bartosek I, Daniel S, Sykora S (1978) Differential pulse polarographic determination of submicrogram quantities of carmustine and related compounds in biological samples. J Pharm Sci 67: 1160

  3. 3.

    Bartosek I, Russo RG, Cattaneo MT (1984) Pharmacokinetics of nitrosoureas: Levels of 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) in organs of normal and Walker 256/B carcinoma-bearing rats after i.v. bolus. Tumori 70: 491

  4. 4.

    Bartosek I, Corada M, Dallarda S, Lucas C, Deloffre P, Guaitani A (1991) Pharmacokinetic profile of fotemustine in rat plasma by electrochemical detection. Xenobiotica 21: 235

  5. 5.

    Boutin JA, Norbeck K, Moldeus P, Genton A, Paraire M, Bizzari JP, Lavielle G, Cudennec CA (1989) Effects of the new nitrosourea derivative, fotemustine, on glutathione reductase activity in rat tissues in vivo and in isolated rat hepatocytes. Eur J Cancer Clin Oncol 25: 1311

  6. 6.

    Chatterjee S, Price B (1977) Regression analysis by sample. J Wiley, New York, p 120

  7. 7.

    Colvin M, Cowens JW, Brundrett RB, Kramer BS, Ludlum DB (1974) Decomposition of BCNU (1,3-bis-(2-chloroethyl)-1-nitrosourea) in aqueous solution. Biochem Biophys Res Commun 60: 515

  8. 8.

    Dallarda S (1986) Tossicità, attività antitumorale e farmacocinetica delcis-diclorodiamminoplatino(II)libero e legato alle proteine. Tesi di laurea, Università degli Studi, Milano

  9. 9.

    Deloffre P, Cudennec CA, Lavielle G, Bizzari JP (1987) Approach to the mechanism of action and mutagenicity of the new nitrosourea Sevier 10036 (abstract, poster). Proceedings, 15th International Congress of Chemotherapy, Istanbul, July 20–25

  10. 10.

    Deloffre P, Paraire M, Cudennec CA, Lavielle G, Bizzari JP (1989) Caractéristiques pharmacologiques d'une nouvelle nitrosourée: la fotémustine. Bull Cancer 76: 550

  11. 11.

    Donelli MG, D'Incalci M, Garattini S (1984) Pharmacokinetics studies of anticancer drugs in tumor bearing animals. Cancer Treat Rep 68: 381

  12. 12.

    Donelli MG, Guaitani A, Torti L, Damia G, Corti F, Bianchi M, Tortoreto M, Pantarotto C, Bartosek I (1986) Different sensitivity of two Walker carcinoma lines to cyclophosphamide: correlation with drug distribution, biotransformation and macromolecule binding. Oncology 43: 257

  13. 13.

    Fiebig HH, Eisenbrand G, Zeller WJ, Deutsch-Wenzel T (1977) Water soluble derivatives and bifunctional analogs of the anticancer agent 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU). Eur J Cancer Clin Oncol 13: 937

  14. 14.

    Filippeschi S, Colombo T, Bassani D, De Francesco L, Arioli P, D'Incalci M, Bartosek I, Guaitani A (1988) Antitumor activity of the novel nitrosourea S10036 in rodent tumors. Anticancer Res 8: 1351

  15. 15.

    Fischel JL, Formento P, Etienne MC, Gioanni J, Frenay M, Deloffre P, Bizzarri JP, Milano G (1990) In vitro chemosensitivity testing of fotemustine (S 10036), a new antitumor nitrosourea. Cancer Chemother Pharmacol 25: 337

  16. 16.

    Garattini S, Bizzi A, Donelli MG, Guaitani A, Samanin R, Spreafico F (1980) Anbrexia and cancer in animals and man. Cancer Treat Rev 7: 115

  17. 17.

    Geran RI, Greenberg NH, MacDonald MM, Schumacher AM, Abbott BJ (1972) Protocol for screening chemical agents and natural products against animal tumors and other biological systems, third revision. Cancer Chemother Rep 3 (3): 1

  18. 18.

    Guaitani A, Della Torre P, Morasca L, Pintus C, Bartosek I (1983) Two lines of Walker carcinoma 256: their peculiarities and different interactions with the host. Tumori 69: 1

  19. 19.

    Guaitani A, Recchia M, Carli M, Rocchetti M, Bartosek I, Garattini S (1985) Walker carcinoma 256: a model for studies on tumor induced anorexia and cachexia. Oncology 39: 173

  20. 20.

    Hill DL, Kirk MC, Struck RF (1975) Microsomal metabolism of nitrosoureas. Cancer Res 35: 296

  21. 21.

    Institute of Laboratory Animal Resources (1985) Guide for the care and use of laboratory animals. Publication 85-23. NIH, Bethesda, Maryland

  22. 22.

    Jacquillat C, Kayat D, Banzet P, Weil M, Avril MF, Fumoleau P, Namer M, Bonneterre J, Kerbrat P, Bonerandi JJ, Bugat R, Montcuquet P, Audhuy B, Cupissol D, Lauvin R, Grosshans E, Vilmer C, Prache C, Bizzarri JP (1990) Chemotherapy by fotemustine in cerebral metastases of disseminated malignant melanoma. Cancer Chemother Pharmacol 25: 263

  23. 23.

    Khayat D, Lokiec F, Bizzarri JP, Weil M, Meeus L, Sellami M, Rouesse J, Banzet P, Jacquillant C (1987) Phase I clinical study of the new amino acid-linked nitrosourea, S 10036, administered on a weekly schedule. Cancer Res 47: 6782

  24. 24.

    Litterst CL, Magin R (1988) Alterations in plasma pharmacokinetics of cisplatin in tumor-bearing rats. Cancer Chemother Rep 22: 1

  25. 25.

    Meulemans A, Giroux B, Hannoun P, Henzel D, Bizzari JP, Mohler J (1989) Permeability of two nitrosoureas, carmustine and fotemustine, in rat cortex. Chemotherapy 35: 313

  26. 26.

    Montgomery JA, James R, McCaleb GS, Johnston TP (1967) The modes of decomposition of 1,3-bis-(2-chloroethyl)-1-nitrosourea and related compounds. J Med Chem 10: 668

  27. 27.

    Reed DJ (1980) Metabolism of nitrosoureas. In: Prestayko AW, Crooke ST, Baker LH, Carter SK, Schein PS (eds) Nitrosoureas. Current status and new developments. Academic Press, New York, pp 51–67

  28. 28.

    Reed DJ (1984) Synthesis and characterization of nitrosoureas. In: Offenbrite RM, Buhther GB (eds) Anticancer and interferon agents. Synthesis and properties. Marcel Dekker, New York, pp 177–202

  29. 29.

    Rosso R, Donelli MG, Franchi G, Garattini S (1971) Impairment of drug metabolism in tumor bearing animals. Eur J Cancer Clin Oncol 7: 565

  30. 30.

    Tapiero H, Ming-Biao Y, Catalin J, Paraire M, Deloffre P, Rustum Y, Bizzari JP, Tew KD (1989) Cytotoxicity and DNA damaging effects of a new nitrosourea, fotemustine-diethyl-1-(3-[2-chloroethyl]-3-nitrosoureido) ethylphosphonate-S 10036. Anticancer Res 9: 1617

  31. 31.

    UKCCCR (1988) Guidelines for the welfare of animals in experimental neoplasia. Br J Cancer 58: 109

  32. 32.

    Vecchi A, Deloffre P (1989) Comparison of the in vitro effects of fotemustine and carmustine on human immunocompetent cells (abstract P-0160). Proceedings, 5th European Conference on Clinical Oncology, London, September 3–7

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Correspondence to Amalia Guaitani.

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Guaitani, A., Corada, M., Lucas, C. et al. Pharmacokinetics of fotemustine and BCNU in plasma, liver and tumor tissue of rats bearing two lines of Walker 256 carcinoma. Cancer Chemother. Pharmacol. 28, 293–297 (1991). https://doi.org/10.1007/BF00685537

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Keywords

  • Tumor Tissue
  • Antitumor Activity
  • Differential Pulse
  • Distribution Space
  • BCNU