Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1992 Sep;66(3):579–582. doi: 10.1038/bjc.1992.317

Tumour concentrations of flavone acetic acid (FAA) in human melanoma: comparison with mouse data.

T S Maughan 1, R Ward 1, I Dennis 1, D J Honess 1, P Workman 1, N M Bleehen 1
PMCID: PMC1977940  PMID: 1520597

Abstract

Flavone acetic acid (FAA) showed impressive effects against murine solid tumours but no activity in clinical studies. The mechanism of action in mice may involve damage to tumour vasculature or immunomodulation, and these effects may be species-specific. Alternatively, concentrations of FAA achieved in mouse tumours may be higher than in human tumours. It is important to resolve this issue since it raises important questions about the relevance of in vitro versus in vivo tumour screens and the development of FAA analogues. As part of a Cancer Research Campaign Phase II study of metastatic melanoma in which 8.4 g m-2 FAA was given as a 6 h infusion, six tumour biopsies were obtained from four patients. FAA tumour concentrations were determined by HPLC and compared with subcutaneous murine solid tumours within the same analytical laboratory. Tumour/plasma percentages (range 26-61%; mean +/- SD, 43.9 +/- 11.4%) were similar to those in mice, as was the area under the curve (AUC) extrapolated to infinity and the AUC above the putative activity threshold of 100 micrograms ml-1. We conclude that the exposure of drug-refractory human melanoma tissue to FAA was comparable to that of sensitive mouse tumours. This suggests that reduced penetration of FAA into human tumours is unlikely to explain the lack of antitumour activity observed in clinical studies and that differences in mechanism of action are predominant.

Full text

PDF
579

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bibby M. C., Double J. A., Loadman P. M., Duke C. V. Reduction of tumor blood flow by flavone acetic acid: a possible component of therapy. J Natl Cancer Inst. 1989 Feb 1;81(3):216–220. doi: 10.1093/jnci/81.3.216. [DOI] [PubMed] [Google Scholar]
  2. Bibby M. C., Double J. A., Loadman P. M. Unique chemosensitivity of MAC 16 tumours to flavone acetic acid (LM975, NSC 347512). Br J Cancer. 1988 Sep;58(3):341–344. doi: 10.1038/bjc.1988.215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bibby M. C. Flavone acetic acid--an interesting novel therapeutic agent or just another disappointment? Br J Cancer. 1991 Jan;63(1):3–5. doi: 10.1038/bjc.1991.2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chabot G. G., Bissery M. C., Corbett T. H., Rutkowski K., Baker L. H. Pharmacodynamics and causes of dose-dependent pharmacokinetics of flavone-8-acetic acid (LM-975; NSC-347512) in mice. Cancer Chemother Pharmacol. 1989;24(1):15–22. doi: 10.1007/BF00254099. [DOI] [PubMed] [Google Scholar]
  5. Corbett T. H., Bissery M. C., Wozniak A., Plowman J., Polin L., Tapazoglou E., Dieckman J., Valeriote F. Activity of flavone acetic acid (NSC-347512) against solid tumors of mice. Invest New Drugs. 1986;4(3):207–220. doi: 10.1007/BF00179586. [DOI] [PubMed] [Google Scholar]
  6. Cummings J., Kerr D. J., Kaye S. B., Smyth J. F. Optimisation of a reversed-phase high-performance liquid chromatographic method for the determination of flavone acetic acid and its major human metabolites in plasma and urine. J Chromatogr. 1988 Sep 23;431(1):77–85. doi: 10.1016/s0378-4347(00)83071-6. [DOI] [PubMed] [Google Scholar]
  7. Cummings J., Smyth J. F. Flavone 8-acetic acid: our current understanding of its mechanism of action in solid tumours. Cancer Chemother Pharmacol. 1989;24(5):269–272. doi: 10.1007/BF00304756. [DOI] [PubMed] [Google Scholar]
  8. Damia G., Zanette M. L., Rossi C., Mandelli R., Ferrari A., D'Incalci M. Dose-dependent pharmacokinetics of flavone acetic acid in mice. Cancer Chemother Pharmacol. 1988;22(1):47–50. doi: 10.1007/BF00254180. [DOI] [PubMed] [Google Scholar]
  9. Evelhoch J. L., Bissery M. C., Chabot G. G., Simpson N. E., McCoy C. L., Heilbrun L. K., Corbett T. H. Flavone acetic acid (NSC 347512)-induced modulation of murine tumor physiology monitored by in vivo nuclear magnetic resonance spectroscopy. Cancer Res. 1988 Sep 1;48(17):4749–4755. [PubMed] [Google Scholar]
  10. Finlay G. J., Smith G. P., Fray L. M., Baguley B. C. Effect of flavone acetic acid on Lewis lung carcinoma: evidence for an indirect effect. J Natl Cancer Inst. 1988 Apr 20;80(4):241–245. doi: 10.1093/jnci/80.4.241. [DOI] [PubMed] [Google Scholar]
  11. Gouyette A., Kerr D. J., Kaye S. B., Setanoians A., Cassidy J., Bradley C., Forrest G., Soukop M. Flavone acetic acid: a nonlinear pharmacokinetic model. Cancer Chemother Pharmacol. 1988;22(2):114–119. doi: 10.1007/BF00257307. [DOI] [PubMed] [Google Scholar]
  12. Kerr D. J., Kaye S. B., Cassidy J., Bradley C., Rankin E. M., Adams L., Setanoians A., Young T., Forrest G., Soukop M. Phase I and pharmacokinetic study of flavone acetic acid. Cancer Res. 1987 Dec 15;47(24 Pt 1):6776–6781. [PubMed] [Google Scholar]
  13. Kerr D. J., Maughan T., Newlands E., Rustin G., Bleehen N. M., Lewis C., Kaye S. B. Phase II trials of flavone acetic acid in advanced malignant melanoma and colorectal carcinoma. Br J Cancer. 1989 Jul;60(1):104–106. doi: 10.1038/bjc.1989.230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Murray J. C., Smith K. A., Thurston G. Flavone acetic acid induces a coagulopathy in mice. Br J Cancer. 1989 Nov;60(5):729–733. doi: 10.1038/bjc.1989.348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Plowman J., Narayanan V. L., Dykes D., Szarvasi E., Briet P., Yoder O. C., Paull K. D. Flavone acetic acid: a novel agent with preclinical antitumor activity against colon adenocarcinoma 38 in mice. Cancer Treat Rep. 1986 May;70(5):631–635. [PubMed] [Google Scholar]
  16. SAPIRSTEIN L. A. Regional blood flow by fractional distribution of indicators. Am J Physiol. 1958 Apr;193(1):161–168. doi: 10.1152/ajplegacy.1958.193.1.161. [DOI] [PubMed] [Google Scholar]
  17. Urba W. J., Longo D. L., Lombardo F. A., Weiss R. B. Enhancement of natural killer activity in human peripheral blood by flavone acetic acid. J Natl Cancer Inst. 1988 Jun 1;80(7):521–525. doi: 10.1093/jnci/80.7.521. [DOI] [PubMed] [Google Scholar]
  18. Wiltrout R. H., Boyd M. R., Back T. C., Salup R. R., Arthur J. A., Hornung R. L. Flavone-8-acetic acid augments systemic natural killer cell activity and synergizes with IL-2 for treatment of murine renal cancer. J Immunol. 1988 May 1;140(9):3261–3265. [PubMed] [Google Scholar]
  19. Wiltrout R. H., Hornung R. L. Natural products as antitumor agents: direct versus indirect mechanisms of activity of flavonoids. J Natl Cancer Inst. 1988 Apr 20;80(4):220–222. doi: 10.1093/jnci/80.4.220. [DOI] [PubMed] [Google Scholar]
  20. Workman P. New drugs and novel agents. Curr Opin Oncol. 1989 Dec;1(2):213–221. [PubMed] [Google Scholar]
  21. Zaharko D. S., Grieshaber C. K., Plowman J., Cradock J. C. Therapeutic and pharmacokinetic relationships of flavone acetic acid: an agent with activity against solid tumors. Cancer Treat Rep. 1986 Dec;70(12):1415–1421. [PubMed] [Google Scholar]
  22. Zwi L. J., Baguley B. C., Gavin J. B., Wilson W. R. Blood flow failure as a major determinant in the antitumor action of flavone acetic acid. J Natl Cancer Inst. 1989 Jul 5;81(13):1005–1013. doi: 10.1093/jnci/81.13.1005. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES