Cancer Chemotherapy and Pharmacology

, Volume 20, Issue 3, pp 188–192 | Cite as

Distribution of nitroimidazoles and L-phenylalanine mustard in mammary adenocarcinoma 16/C tumors

  • P. E. Noker
  • L. Simpson-Herren
  • S. D. Wagoner
Original Articles Nitroimidazoles, L-PAM, Tumor Distribution, Mammary Adenocarcinoma


Using the triphenylmethane dye, lissamine green, as an indicator of blood perfusion, we have demonstrated that L-phenylalanine mustard (L-PAM) is differentially distributed in mice bearing mammary adenocarcinoma 16/C tumors. Following i.p. administration, concentrations of L-PAM in various regions of the tumors vary by as much as 10-fold or more between regions of low and high perfusion. Since the nitroimidazoles, metronidazole and misonidazole, increase the cytotoxicity of certain antitumor agents, these compounds were investigated for their ability to increase the distribution of L-PAM into tumor regions of low perfusion. Administration of metronidazole (400 mg/kg) or misonidazole (800 mg/kg) 1 h prior to L-PAM and lissamine green resulted in elevated plasma levels of L-PAM and increased concentrations of L-PAM in tumor regions of high perfusion. A slight increase in the normally low levels of L-PAM in tumor regions of low perfusion was observed but the increase was not statistically significant. In contrast to the uneven distribution of L-PAM, metronidazole and misonidazole were evenly distributed throughout plasma and tumor regions of both high and low perfusion. Bioassay of tumors following in vivo exposure to metronidazole and L-PAM indicated decreased viability in fragments from tumor regions of high perfusion, but not from tumor regions of low perfusion. These studies demonstrate that the nitroimidazoles increased L-PAM levels in plasma and in tumor regions of both high and low perfusion but did not induce a uniform distribution of L-PAM throughout the tumors. The nitroimidazoles may enhance the effectiveness of L-PAM as an antitumor agent by increasing the concentration of drug that reaches a tumor.


Adenocarcinoma Plasma Level Uniform Distribution Metronidazole Elevated Plasma 
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  1. 1.
    Ash DV, Smith MR, Bugden RD (1979) Distribution of misonidazole in human tumors and normal tissues. Br J Cancer 39: 503Google Scholar
  2. 2.
    Blasberg R, Horowitz M, Strong J, Molnar P, Patlak C, Owens E, Fenstermacher J (1985) Regional measurements of [14C] misonidazole distribution and blood flow in subcutaneous RT-9 experimental tumors. Cancer Res 45: 1692Google Scholar
  3. 3.
    Chirigos MA, Mead JAR (1964) Experiments on determination of melphalan by fluorescence. Interaction with protein and various solutions. Anal Biochem 7: 259Google Scholar
  4. 4.
    Evans TL, Chang SY, Alberts DS, Sipes IG, Brendel K (1982) In vitro degradation of L-phenylalanine mustard (L-PAM). Cancer Chemother Pharmacol 8: 175Google Scholar
  5. 5.
    Foster JL, Conroy PJ, Searle AJ, Willson RL (1976) Metronidazole (Flagyl): characterization as a cytotoxic drug specific for hypoxic tumour cells. Br J Cancer 33: 485Google Scholar
  6. 6.
    Furner RL, Brown RK (1980) L-Phenylalanine mustard (L-PAM): the first 25 years. Cancer Treat Rep 64: 559Google Scholar
  7. 7.
    Furner RL, Mellett LB, Brown RK, Ducan G (1976) A method for the measurement of L-phenylalanine mustard in the mouse and dog by high pressure liquid chromatography. Drug Metab Dispos 4: 577Google Scholar
  8. 8.
    Harrison SD Jr, Giles HD, Denine EP (1980) Antitumor drug toxicity in tumor-free and tumor-bearing mice. Cancer Chemother Pharmacol 4: 199Google Scholar
  9. 9.
    Hinchliffe M, McNally NJ, Stratford MRL (1983) The effect of radiosensitizers on the pharmacokinetics of melphalan and cyclophosphamide in the mouse. Br J Cancer 48: 375Google Scholar
  10. 10.
    Hirst DG, Brown JM, Hazlehurst JL (1982) Enhancement of CCNU cytotoxicity by misonidazole: possible therapeutic gain. Br J Cancer 46: 109Google Scholar
  11. 11.
    Horsman MR, Evans JW, Brown JW (1984) Enhancement of melphalan-induced tumor cell killing by misonidazole: an interaction of competing mechanisms. Br J Cancer 50: 305Google Scholar
  12. 12.
    Lee FYF, Workman P (1983) Modification of CCNU pharmacokinetics by misonidazole — a major mechanism of chemosensitization in mice. Br J Cancer 47: 659Google Scholar
  13. 13.
    McNally NJ (1982) Enhancement of chemotherapy agents. Int J Radiat Oncol Biol Phys 8: 593Google Scholar
  14. 14.
    McNally NJ, Hinchliffe M, deRonde J (1983) Enhancement of the action of alkylating agents by single high, or chronic low doses of misonidazole. Br J Cancer 48: 271Google Scholar
  15. 15.
    Noker PE, Simpson-Herren L, Wagoner SD (1985) Heterogeneity of response of mammary adenocarcinoma 16/C (mam ad 16/C) to melphalan (L-PAM). Proc Amer Assoc Cancer Res 26: 339Google Scholar
  16. 16.
    Noker PE, Wagoner SD, Simpson-Herren L (1986) Differential distribution of L-phenylalanine mustard (L-PAM) and radiation sensitizers (RS) in mammary adenocarcinoma 16/C (mam ad) tumors. Pharmacologist 28: 233Google Scholar
  17. 17.
    Randhawa VS, Stewart FA, Denekamp J, Stratford MRL (1985) Factors influencing the chemosensitization of melphalan by misonidazole. Br J Cancer 51: 219Google Scholar
  18. 18.
    Rich TA, Dische S, Saunders MI, Stratford MRL, Minchinton A (1981) A serial study of the concentration of misonidazole in human tumors correlated with histologic structure. Int J Radiat Oncol Biol Phys 7: 197Google Scholar
  19. 19.
    Rose CM, Millar JL, Peacock JH, Phelps TA, Stephens TC (1980) Differential enhancement of melphalan cytotoxicity in tumor and normal tissue by misonidazole. In: Radiation sensitizers. Masson, New York, p 250Google Scholar
  20. 20.
    Schwartz DE, Jeanet F (1976) Comparative pharmacokinetic studies of ornidazole and metronidazole in man. Chemotherapy 22: 19Google Scholar
  21. 21.
    Simpson-Herren L, Noker PE, Wagoner SD (1987) Variability of tumor response to chemotherapy. I. Contribution of host heterogeneity. Cancer Chemother Pharmacol (in press)Google Scholar
  22. 22.
    Simpson-Herren L, Noker PE, Wagnoer SD (1987) Variability of tumor response to chemotherapy. II. Contribution of tumor heterogeneity. Cancer Chemother Pharmacol (in press)Google Scholar
  23. 23.
    Smith E, Stratford IJ, Adams GE (1982) Enhancing effect of pre-treatment of cells with misonidazole in hypoxia on their response to melphalan in air. Br J Cancer 46: 117Google Scholar
  24. 24.
    Stambaugh JE, Feo LG, Manthei RW (1968) The isolation and identification of the urinary oxidative metabolites of metronidazole in man. J Pharmacol Exp Ther 161: 373Google Scholar
  25. 25.
    Tannock IF (1980) In vivo interaction of anti-cancer drugs with misonidazole or metronidazole: cyclophosphamide and BCNU. Br J Cancer 42: 871Google Scholar
  26. 26.
    Workman P (1980) Pharmacokinetics of hypoxic cell radiosensitizers. Cancer Clin Trials 3: 237Google Scholar
  27. 27.
    Workman P, Little CJ, Marten TR, Dale AD, Ruane RJ, Flockhart IR, Bleehen NM (1978) Estimation of the hypoxic cell-sensitizer misonidazole and itso-demethylated metabolite in biological materials by reversed-phase high-performance liquid chromatography. J Chromatog 145: 507Google Scholar
  28. 28.
    Workman P, Wiltshire CR, Plowman PN, Bleehen NM (1978) Monitoring salivary misonidazole in man: a possible alternative to plasma monitoring. Br J Cancer 38: 709Google Scholar

Copyright information

© Springer-Verlag 1987

Authors and Affiliations

  • P. E. Noker
    • 1
  • L. Simpson-Herren
    • 1
  • S. D. Wagoner
    • 1
  1. 1.Biochemistry DepartmentSouthern Research InstituteBirminghamUSA

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