Investigational New Drugs

, Volume 20, Issue 3, pp 281–295 | Cite as

5,6-Dimethylxanthenone-4-Acetic Acid (DMXAA): a New Biological Response Modifier for Cancer Therapy

  • Shufeng Zhou
  • Philip Kestell
  • Bruce C. Baguley
  • James W. Paxton


The investigational anti-cancer drug5,6-dimethylxanthenone-4-acetic acid(DMXAA) was developed by the AucklandCancer Society Research Centre (ACSRC). Ithas recently completed Phase I trials inNew Zealand and UK under the direction ofthe Cancer Research Campaign's Phase I/IIClinical Trials Committee. As a biologicalresponse modifier, pharmacological andtoxicological properties of DMXAA areremarkably different from most conventionalchemotherapeutic agents. Induction ofcytokines (particularly tumour necrosisfactor (TNF-α), serotonin and nitricoxide (NO)), anti-vascular andanti-angiogenic effects are considered tobe major mechanisms of action based on invitro and animal studies. In cancerpatients of Phase I study, DMXAA alsoexhibited various biological effects,including induction of TNF-α,serotonin and NO, which are consistent withthose effects observed in in vitroand animal studies. Preclinical studiesindicated that DMXAA had more potentanti-tumour activity compared toflavone-8-acetic acid (FAA). In contrast toFAA that did not show anti-tumour activityin cancer patients, DMXAA (22 mg/kg byintravenous infusion over 20 min) resultedin partial response in one patient withmetastatic cervical squamous carcinoma in aPhase I study where 65 cancer patients wereenrolled in New Zealand. The maximumtolerated dose (MTD) in mouse, rabbit, ratand human was 30, 99, 330, and 99 mg/kgrespectively. The dose-limiting toxicity ofDMXAA in cancer patients included acutereversible tremor, cognitive impairment,visual disturbance, dyspnoea and anxiety.The plasma protein binding and distributioninto blood cells of DMXAA are dependent onspecies and drug concentration. DMXAA isextensively metabolised, mainly byglucuronidation of its acetic acid sidechain and 6-methylhydroxylation, givingrise to DMXAA acyl glucuronide (DMXAA-G),and 6-hydroxymethyl-5-methylxanthenone-4-aceticacid (6-OH-MXAA), which are excreted intobile and urine. DMXAA-G has been shown tobe chemically reactive, undergoinghydrolysis, intramolecular migration andcovalent binding. Studies have indicatedthat DMXAA glucuronidation is catalysed byuridine diphosphateglucuronosyltransferases (UGT1A9 andUGT2B7), and 6-methylhydroxylation bycytochrome P450 (CYP1A2). Non-linear plasmapharmacokinetics of DMXAA has been observedin animals and patients, presumably due tosaturation of the elimination process andplasma protein binding. Species differencesin DMXAA plasma pharmacokinetics have beenobserved, with the rabbit having thegreatest plasma clearance, followed by thehuman, rat and mouse. In vivo disposition studies inthese species didnot provide an explanation for thedifferences in MTD. Co-administration ofDMXAA with other drugs has been shown toresult in enhanced anti-tumour activity andalterations in pharmacokinetics, asreported for the combination of DMXAA withmelphalan, thalidomide, cyproheptadine, andthe bioreductive agent tirapazamine, inmouse models. Species-dependentDMXAA-thalidomide pharmacokineticinteractions have been observed.Co-administration of thalidomidesignificantly increased the plasma area ofthe plasma concentration-time curve (AUC)of DMXAA in mice, but had no effect onDMXAA's pharmacokinetics in the rat. Itappears that the pharmacological andtoxicological properties of DMXAA as a newbiological response modifier are unlikelyto be predicted based on preclinicalstudies. Similar to many biologicalresponse modifiers, DMXAA alone did notshow striking anti-tumour activity inpatients. However, preclinical studies ofDMXAA-drug combinations indicate that DMXAAmay have a potential role in cancertreatment when co-administered with otherdrugs. Further studies are required toexplore the molecular targets of DMXAA andmechanisms for the interactions with otherdrugs co-administered during combinationtreatment, which may allow for theoptimisation of DMXAA-based chemotherapy.

distribution DMXXA excretion metabolism 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Jameson MB, Thomson PI, Baguley BC, Evans BD, Harvey VJ, McCrystal MR Kestell P Phase I pharmacokinetic and pharmacodynamic study of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent. Proc Annu Meet Am Soc Clin Oncol 19:182a, 2000Google Scholar
  2. 2.
    Bibby MC, Phillips RM, Double JA, Pratesi G: Anti-tumor activity of flavone acetic acid (NSC-347512) in mice – Influence of immune status. Br J Cancer 63:57–62, 1991Google Scholar
  3. 3.
    Zwi LJ, Baguley BC, Gavin JB, Wilson WR: Blood flow failure as a major determinant in the antitumor action of flavone acetic acid (NSC 347512). J Natl Cancer Inst 81:1005–1013, 1989Google Scholar
  4. 4.
    Cao ZH, Baguley BC, Ching LM: (2001) Interferon-inducible protein 10 induction and inhibition of angiogenesis in vivo by the antitumor agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Cancer Res 61:1517–1521, 2001Google Scholar
  5. 5.
    Thomsen LL, Ching L-M, Baguley BC: Evidence for the production of nitric oxide by activated macrophages treated with the antitumor agents flavone-8-acetic acid and xanthenone-4-acetic acid. Cancer Res 50:6966–6970, 1990Google Scholar
  6. 6.
    Thomsen LL, Ching L-M, Zhuang L, Gavin JB, Baguley BC: Tumor-dependent increased plasma nitrate concentrations as an indication of the antitumor effect of flavone-8-acetic acid and analogues in mice. Cancer Res 51:77–81, 1991Google Scholar
  7. 7.
    Philpott M, Baguley BC, Ching L-M: Induction of tumour necrosis factor-alpha by single and repeated doses of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid. Cancer Chemother Pharmacol 36:143–148, 1995Google Scholar
  8. 8.
    Baguley BC, Zhuang L, Kestell P: Increased plasma serotonin following treatment with flavone-8-acetic acid, 5,6-dimethylxanthenone-4-acetic acid, vinblastine, and colchicine: relation to vascular effects. Oncol Res 9:55–60, 1997Google Scholar
  9. 9.
    Joseph WR, Cao Z, Mountjoy KG, Marshall ES, Baguley BC, Ching L-M: Stimulation of tumours to synthesize tumor necrosis factor-a in situ using 5,6-dimethylxanthenone-4-acetic acid: a novel approach to cancer therapy. Cancer Res 59:633–638, 1999Google Scholar
  10. 10.
    Hornung RL, Back TL, Zaharto DS, Urba WJ, Longo DL, Wiltrout RH: Augmentation of natural killer (NK) activity, induction of interferon and development of tumor immunity during the successful treatment of established murine renal cancer using flavone acetic acid (FAA) and interleukin 2. J Immunol 141:3671–3679, 1988Google Scholar
  11. 11.
    Pang JH, Cao Z, Joseph WR, Baguley BC, Ching L-M: Antitumour activity of the novel immune modulator 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice lacking the interferon-gamma receptor. Eur J Cancer 34:1282–1289, 1998Google Scholar
  12. 12.
    Ching L-M, Joseph WR, Crosier KE, Baguley BC: Induction of tumour necrosis factor-a messenger RNA in humans and murine cells by the flavone acetic acid analogue 5,6-dimethylxanthenone-4-acetic acid (NSC 640488). Cancer Res 54:870–872, 1994Google Scholar
  13. 13.
    Browne WL, Wilson WR, Baguley BC, Ching L-M: Suppression of serum tumour necrosis factor-a by thalidomide does not lead to reversal of tumour vascular collapse and anti-tumour activity of 5,6-dimethylxanthenone-4-acetic acid. Anticancer Res 18:4409–4414, 1998Google Scholar
  14. 14.
    Baguley BC, Calveley SB, Crowe KK, Fray LM, O'Rourke SA, Smith GP: Comparison of the effects of flavone acetic acid, fostriecin, homoharringtonine and tumour necrosis factor on Colon 38 tumours in mice. Eur J Cancer Clin Oncol 25:263–269, 1986Google Scholar
  15. 15.
    Sayers TJ, Wiltrout TA, McCormick K, Husted C, Wiltrout RH: Antitumor effects of-interferon and-interferon on a murine renal cancer (Renca) in vitro and in vivo. Cancer Res 50:5414–5420, 1990Google Scholar
  16. 16.
    Ching L-M, Young HA, Eberly K, Yu CR: Induction of STAT and NF kappa B activation by the antitumor agents 5,6-dimethylxanthenone-4-acetic acid and flavone acetic acid in a murine macrophage cell line. Biochem Pharmacol 58:1173–1181, 1999Google Scholar
  17. 17.
    Eader LA, Gusella L, Dorman L, Young HA: Induction of multiple cytokine gene expression and IRF-1 mRNA by flavone acetic acid in a murine macrophage cell line. Cell Immunol 157:211–222, 1994Google Scholar
  18. 18.
    Perera PY, Barber SA, Ching L-M, Vogel SN: Activation of LPS-inducible genes by the antitumor agent 5,6-dimethylxanthenone-4-acetic acid in primary murine macrophages. Dissection of signaling pathways leading to gene induction and tyrosine phosphorylation. J Immunol 153:4684–4693, 1994Google Scholar
  19. 19.
    Angiolillo AL, Sgadari C, Taub DD, Liao F, Farber JM, Maheshwari S, Kleinman HK, Reaman GH, Tosato G: Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med 182:155–162, 1995Google Scholar
  20. 20.
    Schrum S, Probst P, Fleischer B, Zipfel PF: Synthesis of the CC-chemokines MIP-1alpha, MIP-1beta, and RANTES is associated with a type 1 immune response. J Immunol 157:3598–3604, 1996Google Scholar
  21. 21.
    Ching L-M, Baguley BC: Effect of flavone acetic acid (NSC 347,512) on splenic cytotoxic effector cells and their role in tumour necrosis. Eur J Cancer Clin Oncol 25:821–828, 1989Google Scholar
  22. 22.
    Pratesi G, Rodolfo M, Rovetta G, Parmiani G: Role of T cells and tumor necrosis factor in antitumor activity and toxicity of flavone acetic acid. Eur J Cancer 26:1079–1083, 1990Google Scholar
  23. 23.
    Rewcastle GW, Atwell GI, Li ZA, Baguley BC, Denny WA: Potential antitumour agents. 61. Structure-activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9H-xanthenone-4-acetic acids. J Med Chem 34:217–222, 1991Google Scholar
  24. 24.
    Laws AL, Matthew AM, Double JA, Bibby MC: Preclinical in vitro and in vivo activity of 5,6-dimethylxanthenone-4-acetic acid. Br J Cancer 71:1204–1209, 1995Google Scholar
  25. 25.
    Baguley BC, Cole G, Thomsen LL, Li Z: Serotonin involvement in the antitumour and host effects of flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid. Cancer Chemother Pharmacol 33:77–81, 1993Google Scholar
  26. 26.
    Zwi LJ, Baguley BC, Gavin JB, Wilson WR: Correlation between immune and vascular activities of xanthenone acetic acid on tumour agents. Oncol Res 6:79–85, 1994Google Scholar
  27. 27.
    McKeage MJ, Kestell P, Denny WA, Baguley BC: Plasma pharmacokinetics of the antitumour agents 5,6-dimethylxanthenone-4-acetic acid, xanthenone-4-acetic acid and flavone-8-acetic acid in mice. Cancer Chemother Pharmacol 28:409–413, 1991Google Scholar
  28. 28.
    Webster LK, Ellis AG, Kestell P, Rewcastle GW: Metabolism and elimination of 5,6-dimethylxanthenone-4-acetic acid in the isolated perfused rat liver. Drug Metab Dispos 23:363–368, 1995Google Scholar
  29. 29.
    Kestell P, Paxton JW, Rewcastle GW, Dunlop I, Baguley BC: Plasma disposition, metabolism and excretion of the experimental antitumour agent 5,6-dimethylxanthenone-4-acetic acid in the mouse, rat and rabbit. Cancer Chemother Pharmacol 43:323–330, 1999aGoogle Scholar
  30. 30.
    Zhou SF, Paxton JW, Kestell P, Tingle MD: Reversible binding of the novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid to plasma proteins and blood cells in various species. J Pharm Pharmacol 53:463–471, 2001aGoogle Scholar
  31. 31.
    Boxenbaum H: Interspecies variation in liver weight, hepatic weight, hepatic flow and antipyrine intrinsic clearance in extrapolation of data to benzodiazepines and phenytoin. J Pharmacokinet Biopham 8:165–176, 1980Google Scholar
  32. 32.
    Zhou SF, Paxton JW, Tingle MD, Kestell P, Jameson MB, Thomson PI, Baguley BC, dentification and reactivity of the major metabolite (β-1-glucuronide) of the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in humans. Xenobiotica 31:277–293, 2001bGoogle Scholar
  33. 33.
    Zhou SF, Kestell P, Tingle MD, Paxton JW: Determination of the covalent adducts of the novel anti-cancer agent 5,6-dimethylxanthenone-4-acetic acid in biological samples by high-performance liquid chromatography. J Chromatogr (B) 757:343–348, 2001cGoogle Scholar
  34. 34.
    Benet LZ, Spahn-Lugguth H, Iwakaw S, C. V, Mizuma T, Mayer S, Mutschler E, Lin ET: Predictability of the covalent binding of acidic drugs in man. Life Sci 53:141–146, 1993Google Scholar
  35. 35.
    Zhou SF, Paxton W, Tingle MD, McCall J, Kestell P: Determinaton of two major metabolites of the novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid in hepatic microsomal incubations by high-performance liquid chromatography with fluorescence detection. J Chromatogr (B) 734:129–136, 1999Google Scholar
  36. 36.
    Zhou SF, Paxton JW, Tingle MD, Kestell P: Species differences in the metabolism and inhibition of the novel antitumour agent 5,6-dimethylxanthenone-4-acetic acid in vitro: implications for prediction of metabolic interactions and toxicity in vivo. Xenobiotica (in press), 2001dGoogle Scholar
  37. 37.
    Davidson IWF, Parker JC, Beliles RP: Biological basis for extrapolation across mammalian species. Regul Toxicol Pharmacol 6:211–237, 1986Google Scholar
  38. 38.
    Zhou SF, Paxton JW, Tingle MD, Kestell P: Identification of the human liver cytochrome P450 isozyme responsible for the 6-methylhydroxylation of the novel anticancer drug 5,6-dimethylxanthenone-4-acetic acid. Drug Metab Dispos 28:1449–1456, 2000Google Scholar
  39. 39.
    Rodrigues AD: Use of in vitro human metabolism studies in drug development. Biochem Pharmacol 48:2147–2156, 1994Google Scholar
  40. 40.
    Eddershaw PJ, Dickins M: Advances in in vitro drug metabolism screening. Pharm Sci Tech Today 2:13–19, 1999Google Scholar
  41. 41.
    Streetman DS, Bertino JS, Nafziger AN, Phenotyping of drug-metabolizing enzymes in adults: a review of in vivo cytochrome P450 phenotyping probes. Pharmacogenetics 10:187–216, 2000Google Scholar
  42. 42.
    Miners JO, Valente L, Lillywhite KJ, Mackenzie PI, Burchell B, Baguley BC, Kestell P: Preclinical prediction of factors influencing the elimination of 5,6-dimethylxanthenone-4-acetic acid, a new anticancer drug. Cancer Res 57:284–289, 1997Google Scholar
  43. 43.
    de Montellano PRO: The cytochrome P450 oxidative system, in Handbook of drug metabolism (TF W ed) pp 203–227, Marcel Dekker Pub, New York, 1999Google Scholar
  44. 44.
    Landi MT, Sinha R, Lang NP, Kadlubar FF: Human cytochrome P4501A2, in Metabolic Polymorphisms and Susceptibility to Cancer (Ryder W ed) pp 173–195, IARC Scientific Publications, Lyon, 1999Google Scholar
  45. 45.
    Sesardic D, Boobis AR, Murray BP, Murray S, Segura J, Dela Torre R, Davies DS: Furafylline is a potent and selective inhibitor of cytochrome P450IA2 in man. Br J Clin Pharmacol 29:651–663, 1990Google Scholar
  46. 46.
    Rendic S, Di Carlo FJ: Human cytochrome P450 enzyme: A status report summarizing their reactions, substrates, induction, and inhibitors. Drug Metab Rev 29:413–580, 1997Google Scholar
  47. 47.
    Burchell B, Brieley CH, Monaghan G, Clarke DJ: The structure and function of the UDP-glucuronosyltransferase gene family. Adv Pharmacol 42:335–338, 1998Google Scholar
  48. 48.
    Kestell P, Dunlop IC, McCrystal MR, Evans BD, Paxton JW, Gamage RS, Baguley BC: Plasma pharmacokinetics of N-[2-(dimethylamino)ethyl]acridine-4-c arboxamide in a phase I trial. Cancer Chemother Pharmacol 44:45–50, 1999bGoogle Scholar
  49. 49.
    Atassi G, Briet P, Berthelon J-J, Collonges: Synthesis and antitumour activity of some 8-substituted 4-oxo-4H-1-benzopyrans. Eur J Med Chem 20:393–402, 1985Google Scholar
  50. 50.
    Plowman J, Narayanan VL, Dykes D, Szarvasi E, Briet P, Yoder OC, Paull KD: Flavone acetic acid: A novel agent with preclinical antitumor activity against colon adenocarcinoma 38 in mice. Cancer Treat Rep 70:631–638, 1986Google Scholar
  51. 51.
    Kerr DJ, Kaye SB: Flavone acetic acid preclinical and clinical activity. Eur J Cancer Clin Oncol 25:1271–1272, 1989Google Scholar
  52. 52.
    Futami H, Eader LA, Back TT, Gruys E, Young HA, Wiltrout RH, Baguley BC: Cytokine induction and therapeutic synergy with interleukin-2 against murine renal and colon cancers by xanthenone-4-acetic acid derivatives. J Immunother 12:247–255, 1992Google Scholar
  53. 53.
    Patel S, Parkin SM, Bibby MC: The effect of 5,6-dimethylxanthenone-4-acetic acid on tumour necrosis factor production by human immune cells. Anticancer Res 17:141–150, 1997Google Scholar
  54. 54.
    Cummings J, Double JA, Bibby MC, Farmer P, Evens S, Kerr DJ, Kaye SB, Smyth JF: Characterization of the major metabolites of flavone acetic acid and comparison of their disposition in humans and mice. Cancer Res 49:3587–3593, 1989Google Scholar
  55. 55.
    Zhou SF, Chin R, Tingle MD, Kestell P, Paxton JW: Effects of anti-cancer drugs on the metabolism of the novel anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in human liver microsomes. Br J Clin Pharmacol 52:129–136, 2001eGoogle Scholar
  56. 56.
    Kestell P, Zhao L, Ching L-M, Baguley BC, Paxton JW: Modulation of the plasma pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid by thalidomide in mice. Cancer Chemother Pharmacol 46:135–141, 2000Google Scholar
  57. 57.
    Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G: Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 177:1675–1680, 1993Google Scholar
  58. 58.
    Ching L-M, Browne WL, Tchernegovski R, Gregory T, Baguley BC, Palmer BD: Interaction of thalidomide, phthalimide analogues of thalidomide and pentoxifylline with the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid: concomitant reduction of serum tumour necrosis factor-alpha and enhancement of anti-tumour activity. Br J Cancer 78:336–343, 1998Google Scholar
  59. 59.
    Cao Z, Joseph WR, Browne WL, Mountjoy KG, Palmer BD, Baguley BC, Ching L-M: Thalidomide increases both intratumoural tumour necrosis factor-a production and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic acid. Br J Cancer 80:716–723, 1999Google Scholar
  60. 60.
    Anthony M: Serotonin antagonists. Austral NZ J Med 14:888–895, 1984Google Scholar
  61. 61.
    Zhao L, Ketsell P, Zhuang L, Baguley BC: Effects of the serotonin receptor antagonist cyproheptadine on the activity and pharmacokinetic of 5,6-dimethylxanthenone-4-acetic (DMXAA). Cancer Chemother Pharmacol 47:491–497, 2001Google Scholar
  62. 62.
    Kanwar JR, Kanwar RK, Pandey S, Ching LM, Krissansen GW (2001) Vascular attack by 5,6-dimethylxanthenone-4-acetic acid combined with B7.1 (CD80)-mediated immunotherapy overcomes immune resistance and leads to the eradication of large tumors and multiple tumor foci. Cancer Res 61:1948–1956, 2001Google Scholar
  63. 63.
    Pruijn FB, Vandaalen M, Holford NHG, Wilson WR: Mechanisms of enhancement of the antitumour activity of melphalan by the tumour-blood-flow inhibitor 5,6-dimethylxanthenone-4-acetic acid. Cancer Chemother Pharmacol 39:541–546, 1997Google Scholar
  64. 64.
    Cliffe S, Taylor ML, Rutland M, Baguley BC, Hill RP, Wilson WR: Combining bioreductive drugs (SR 4233 or SN 23862) with the vasoactive agents flavone acetic acid or 5,6-dimethylxanthenone acetic acid. Int J Radiat Oncol Biol Phys 29:373–377, 1994Google Scholar
  65. 65.
    Lash CJ, Li AE, Rutland M, Baguley BC, Zwi LJ, Wilson WR: Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs. Br J Cancer 78:439–445, 1998Google Scholar
  66. 66.
    Zhou SF, Paxton JW, Tingle MD, Kestell P, Ching L-M: In-vitro and in vivo kinetic interactions of the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid with thalidomide and diclofenac. Cancer Chemother Pharmacol 47:319–326, 2001fGoogle Scholar
  67. 67.
    Lin JH, Lu AYH: Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacol Rev 49:403–449, 1997Google Scholar
  68. 68.
    Faed EM: Properties of acyl glucuronide: implications for studies of the pharmacokinetics and metabolism of acidic drugs. Drug Metab Rev 15:1213–1249, 1984Google Scholar
  69. 69.
    Meech R, Mackenzie PI: Structure and function of uridine diphosphate glucuronosyltransferases. Clin Exp Pharmacol Physiol 24:907–915 1997Google Scholar
  70. 70.
    Obach RS: Nonspecific binding to microsomes: impact on scale-up of in vitro intrinsic clearance to hepatic clearance as assessed through examination of warfarin, imipramine, and propranolol. Drug Metab Dispos 25:1359–1369, 1997Google Scholar
  71. 71.
    Lewis DF: Quantitative structure-activity relationships in substrates, inducers, and inhibitors of cytochrome P4501 (CYP1). Drug Metab Rev 29:589–650, 1997Google Scholar
  72. 72.
    Dai R, Zhai S, Wei X, Pincus MR, Vestal RE, Friedman FK: Inhibition of human cytochrome P450 1A2 by flavone: A molecular modeling study. J Protein Chem 17:643–650, 1998Google Scholar
  73. 73.
    Wei XX, Dai RK, Zhai SP, Thummel KE, Friedman FK, Vestal RE: Inhibition of human liver cytochrome P-450 1A2 by the class IB antiarrhythmics mexiletine, lidocaine, and tocainide. J Pharmacol Exp Ther 289:853–858, 1999Google Scholar
  74. 74.
    Lozano JJ, Pastor M, Cruciani G, Gaedt K, Centeno NB, Gago F, Sanz F: 3D-QSAR methods on the basis of ligand-receptor complexes. Application of COMBINE and GRID/GOLPE methodologies to a series of CYP1A2 ligands. J Computer-Aided Mol Design 14:341–353, 2000Google Scholar
  75. 75.
    Bibby MC, Double JA, Loadman PM, Duke CV: Reduction of tumor blood flow by flavone acetic acid: A possible component of therapy. J Natl Cancer Inst 81:216–220, 1989Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Shufeng Zhou
    • 1
  • Philip Kestell
    • 2
  • Bruce C. Baguley
    • 2
  • James W. Paxton
    • 1
  1. 1.Division of Pharmacology and Clinical PharmacologyFaculty of Medical and Health SciencesNew Zealand
  2. 2.Auckland Cancer Society Research Centrethe University of AucklandAucklandNew Zealand

Personalised recommendations